ALBERT

Notes: Between 1979 and 1997, successive Conservative governments sought to reduce the scale of public sector activity and to introduce competition in the provision of public sector services. A central feature of this policy was the introduction of compulsory competitive tendering (CCT). CCT was initially confined to blue collar services but, by means of the Local Government Act 1992, it was extended to white collar, professional services, including financial services. However, though potentially extremely significant, the support for and implications of such a policy are issues which have been inadequately researched. Because of this, research has been under-taken into financial services CCT and has included a questionnaire survey of 300 professionally qualified accountants employed in 17 local authorities in the North West of England, drawn from county councils, district councils and metropolitan authorities. The article presents the findings of the survey, with a particular focus on the views of accountants on CCT in general and financial services CCT in particular. In addition, it provides evidence that the CCT process, irrespective of views on CCT and its appropriateness for specific activities, has changed culture and attitudes in the case of local government finance professionals.

Notes: The publication of a new report from the Audit Commission, coupled with the Labour government’s declared intention to modernize local authority decision making, marks the return to the policy agenda of long-familiar questions. This paper tests some of the assumptions underlying the reform programme against recent research evidence. Moves to improve effectiveness through establishing a ‘cabinet’ system, or delegation to officers or ‘lead’ councillors are considered in the light of councillors’ own preferences and practices. The ways in which councillors spend their time and their perceptions of the appropriateness of its distribution between activities is explored. The paper then examines the extent to which authorities have chosen to experiment with and adapt their own structures, and considers whether central imposition of radical change is either necessary or advisable.

Notes: Political mechanisms of accountability were marginalized by Conservative government reforms during the 1980s and 1990s which sought a more market-oriented approach within the public sector in order to enhance ‘consumerism’. In education, parents were given more choice between schools and were provided with more information on school performance. The promotion of market accountability has involved a reduction in the powers of local education authorities (LEAs) which had been central to the operation of political accountability. However, whilst market-based forms of accountability were firmly enhanced in principle by the legislation, to what extent have the forms of accountability operating within LEAs changed in practice? Interviews with Chief Officers and the Chair of the Education Committee are used to identify changing perceptions and practices of accountability in LEAs in Wales. The findings indicate that although local politicians and officials have been forced to operate within the legislative framework of market accountability, they have sought to impede its successful implementation. The policy community in Wales facilitated the LEAs’ capacity to respond in this way. The market-based reforms conflicted with fundamental values held in Wales, which remain those of professional accountability.

Notes: The characteristics and functioning of international policy processes are examined through the analysis of a case which explores the development of policy towards doping by athletes. Changes are traced in the dominant perception of the issue of doping in sport from a series of relatively self-contained problems which could be addressed by individual sports federations or competition organizers to one that requires extensive co-operation between federations and governments, and which has brought the issue of harmonization of policy to the forefront. The interests of the policy actors are identified and the role of two key organizations, the Council of Europe and the International Olympic Committee, in facilitating closer co-ordination, is examined. It is argued that the process is best understood by using the concept of a policy network as both a metaphor and as an analytical tool. The value of the concept of an epistemic community is also considered and it is suggested that not only are doctors and scientists marginal in shaping anti-doping policy, but that there are also limited conditions under which epistemic communities can fulfil an effective role in the policy process.

Notes: At the same time that comparative and international political scientists have been confronting the problems of analysing state behaviour under conditions of uncertainty, state-centred political scientists are attempting, somewhat belatedly, to deal with the increasing complexity and uncertainty which underpins modern governance. Yet despite similar research agendas these disciplines have continued to speak past each other. This article contends that policy transfer analysis can provide a context for integrating some key concerns of these disciplines. Further, we argue that the process of policy transfer should be examined through a structure and agency approach with three dimensions: global, international and transnational levels, the macro-level and the interorganizational level. This three-dimensional model employs the notion of a policy transfer network as a middle-range level of analysis which links a particular form of policy development (policy transfer), microdecision making in organizations, macrosystems and global, transnational and international systems. It is hoped that this approach will stimulate an empirical research agenda which will illuminate important policy developments in domestic and world politics.

Notes: How does network analysis fit into the development of public administration as an academic discipline? This article tries to bridge theoretical developments in public administration between the middle of the 1970s and the first half of the 1990s. The benchmarks being used are (1) the now classical account by Vincent Ostrom of The Intellectual Crisis in (American) Public Administration - published 25 years ago this year - and (2) Christopher Hood’s reconstruction of core values in (British) new public management. Rather than representing analytical developments as an endless succession of different or even mutually exclusive approaches, this contribution tries to reconcile different foci for analysing public administration. Administrative theory provides us with a rather stable meta-theoretical framework for studying the meaning of quality in government, governance and public administration at various levels of analysis. By relating the emergence of network analysis in PA to parallel developments such as the resurgence of (neo-)managerial and (neo-)institutional analysis, it also becomes clear that network analysis is useful as an analytical device, but that it needs to be linked to theoretical perspectives that provide us with operational assumptions about ‘networks’. Network analysis in itself only provides split ground for reinventing government and refounding public administration.

Notes: The policy network literature has provided important insight into the way in which public policy is made in Western societies. Most network studies have focused on processes within networks and have paid little attention to the conceptualization of policy outcomes and the theoretical link between network type and policy type. This article defines and categorizes environmental policy and suggests a proposition on the link between network types and environmental policy types. It is argued that the existence of tight and closed policy communities in sectors subject to environmental regulation is associated with the introduction of low cost environmental policies. In contrast, open and loose issue networks are associated with high cost environmental policies.

Notes: Multi-organizational partnerships are now an important means of governing and managing public programmes. They typically involve business, community and not-for-profit agencies alongside government bodies. Partnerships are frequently contrasted with competitive markets and bureaucratic hierarchies. A more complex reality is revealed once partnerships as an organizational form are distinguished from networks as a mode of social co-ordination or governance. Data from studies of UK urban regeneration partnerships are used to develop a four-stage partnership life cycle: pre-partnership collaboration; partnership creation; partnership programme delivery; and partnership termination. A different mode of governance - network, market or hierarchy - predominates at each stage. Separating organizational form from mode of governance enables a richer understanding of multi-organizational activity and provides the basis from which theory and practice can be developed. The key challenge for partnerships lies in managing the interaction of different modes of governance, which at some points will generate competition and at other points collaboration.

Notes: Networks have been a research issue in public administration for many years. Because of the difficulty of measuring networks, they have often been treated as a metaphor, a conceptual scheme, or a management technique (networking). The work on networks in public administration is almost all of the case study and rarely of the comparative case variety. This article presents the results of two studies of networks using social network analysis as a technique for studying structural relationships between organizations. This technique is utilized to show both the research and practical potential of network analysis as an evaluation methodology for organizations that jointly produce a service. In the first study, the network provides mental health services to seriously mentally ill adults. In the second study, the network attempts to prevent young people from abusing drugs and alcohol. The two studies were undertaken for different reasons. The first was an elaborate comparative study of four mental health networks and the relationship between network design and performance. The second was a much simpler consulting effort to help a local prevention partnership create linkages to other community organizations. However, in both of the studies the goal was to measure the structural ties in the network based on various types of relationships that exist in a given field of practice. These linkages are ties that bind the network together and become data that can be used to compare networks on their degree and type of integration. The article makes the argument that links in a network are one way that scholars can compare networks in similar or different policy domains. At the same time, the article argues that analysing linkages in an organization’s network is an effective and practical means of determining how well integrated any given organization is in a network.

Notes: This paper examines whether privatization and exposure to product market competition leads to changes in labour management and industrial relations. Three sets of propositions are examined: privatization will lead to lower changes in industrial relations institutions and processes; privatization will lead to lower average levels of remuneration relative to public sector firms; and privatization will lead to relatively higher levels of efficiency. In each instance it is hypothesized that competition will add to ownership effects. These propositions are examined drawing on data derived from the UK bus industry.

Notes: Since their introduction in 1984 Challenge funds have been widely adopted by central government. They are now used by twelve government departments to distribute competitively more than £3,250 million of Exchequer funds. The introduction of Challenge funds appears to have been politically driven, usually focusing on the objectives of cost and efficiency rather than quality and equity. They represent a further manifestation of the introduction of competition and ‘market style’ structures. This paper examines the key features of 41 Challenge funds and their operational characteristics. Numerous benefits, such as cost savings and innovation, arising from the introduction of Challenge funds have been put forward. By reviewing other studies, which have investigated the impact of the introduction of competition in producer and consumer markets, and through comparison with previous schemes it is possible to examine the potential impact of Challenge funds. Administrative and monitoring mechanisms are found to be centralizing control, despite assertions to the contrary. There is a growing concern that the level of information collection required is too arduous and it is used to control and regulate schemes rather than as a method of investigating where operations could be improved. Leverage from Challenge funds has been no more successful than earlier non-competitive initiatives. Competitive bidding could stifle innovation and participatory democracy is not encouraged or facilitated by Challenge funds.

Notes: Representatives of Dutch organizations were traditionally given a chance to defend the interests of their members in the many boards, councils and commissions that together form the corporatist channel in The Netherlands. The harmony and welfare the Dutch population has enjoyed since the Second World War are ascribed in part to the work of these institutions. They helped to bridge political gaps of class and religion by building compromise and consensus. But advisory committees and councils have also been described as somewhat shady and essentially closed institutions, forming an iron ring around the departments that hampered necessary policy changes. In this article, based on case studies on the selection of members of committees and a survey of all members of committees advising the central government, we will explore to what extent committees can still be described as bastions of conservatism. We will briefly describe selection processes, sketch a portrait of committee members and compare some characteristics of committee members and civil servants of individual ministries.

Notes: In this article attention is drawn to a striking difference between recent attempts to reform local government in the Netherlands and in Germany. What has been the prime focus of attention in the Netherlands in the 1980s is being emphasized in Germany in the 1990s, and what is being emphasized in the Netherlands in the 1990s has been the prime focus of attention in Germany in the 1980s. Trends in local goverment reform in the Netherlands have been going from a focus on more efficiency to a focus on more democracy, while trends in local government reform in Germany have been going the other way around. Likely explanations for these intersecting reform trends are built on four pillars: financial crises, legitimacy crises, formal institutions and informal institutions

Notes: Since the mid-1980s, successive French governments have attempted to ‘modernize’ the structures and methods of public administration. Although this vocabulary of ‘modernization’ is distinctly French, many of the actual reforms appear, at first sight, to be based on imported ‘new public management’ doctrines. In this article, we analyse the recent French reforms and the ideas underpinning them and we attempt to locate these reforms in their comparative context, employing data from a wide range of official reports and secondary sources and from a series of semi-structured interviews with senior officials. We build on the analyses of Hood (1991 and 1995) and Wright (1994) that if many governments are dealing with similar problems by adopting similar approaches to reforms based on private sector man-agement methods, the actual nature of the reforms in any individual state depends on the national context, or ‘initial endowment’. In France, the importance of administrative law, the successful experience of nationalized, monopoly, public-service providers in the post-war period, the political weight and established rights of civil servants, and the idea of the ‘general interest’, represented at the local level by the prefect, explain many of the distinctive features of the hybrid modernization reforms. In short, an analysis of the policy of modernization and its origin leads to conclusions which are highly consistent with new institutional explanations of policy making (Hall 1987)

Notes: In the introductory article to the special issue on Comparing Networks, the editors discuss the meaning of the concept of networks in relation to other recent conceptual developments in public administration such as (neo)institutional and (neo)managerial analysis. They trace the broadly understood historical development of network analysis back to the late 1960s and early 1970s and highlight some important factors in its development up to the present-day demands placed on public administration by both globalization and decentralization. The result is organizational fragmentation. Network analysis makes it clear that people working in government and administration will have to learn to think of organization as an external, not internal activity. The prospect is that hierarchical control will be replaced by continuing processes of bargaining among interested parties within most fields of public administration.

Notes: Quasi-market transformation (QMT) refers to the process by which the dominant organizational form in a field is replaced, following the introduction of a quasi-market. In this article, analysis of comparative case-study data reveals that, until the early 1990s, a common interpretive scheme, or set of values and norms, underpinned a set of structures and systems in many UK hospitals. These similarities of form are represented as the directly managed (DM) hospital archetype. When change initiatives challenged this archetype, the outcomes were negotiated and the interpretive scheme remained largely unscathed. Following the introduction of a quasi-market in 1991, a new trust hospital interpretive scheme has emerged. For the first time, UK hospitals have experienced transformation and now display an alternative set of structures and systems. This article explains how the trust hospital archetype has become legitimized through different tracks of change within individual hospitals.

Notes: This article offers an introduction to Niklas Luhmann’s theory of social systems as it pertains to public administration and policy, as a first step towards both a critique and its empirical application to empirical reality. It reconstructs Luhmann’s early writings on bureaucracy and policy-making and shows how this early, more empirical work grounded his abstract theory of social systems in general and the political system in particular. The article also introduces some central concepts of Luhmann’s more recent work on the autopoietic nature of social systems and considers the latter’s consequences for bureaucratic adaptiveness and governmental steering in the welfare state. One of the main benefits of applying Luhmann’s theory to public administration, the article concludes, is that it conceptualizes the central concerns of public administration within a complex picture of society as a whole, in which both the agency that issues decisions and the realm affected by these decisions are included.

Notes: This article presents a study of the local government review process in West Sussex. As in any local government reorganization the career and status concerns of individuals and broader positions of coalitions dominant in different organizations provide the dynamic to a ‘play of power’ which is in turn conditioned by external events and contextual factors. Underlying the analysis is a concern to assess whether in particular the presence of an independent commission facilitated the application of an element of policy analysis and learning into the process. It is concluded that little in the way of a reflective and deliberative process occurred. Equally it is noted that to achieve such qualities in public decision-making is a challenging and daunting task when major organizational interests are at stake.

Notes: Four sets of reforms of the National Health Service are employed to illustrate the changing character of policy making in this sector over a thirty year period, from the production of a carefully developed technocratic blueprint for its organization to the promulgation of a series of bright ideas accompanied by incentives for local actors to develop them into concrete organizational arrangements consonant with these ideas. We term this latter approach ‘manipulated emergence’ and relate it to the literatures of organizational culture and of post-Fordism. The approach adopted by the 1997 Labour government is largely, though not wholly consistent with this, and it remains to be seen whether the high-water mark of manipulated emergence has passed.

Notes: This article examines the implementation of privatization policies in two ‘Next Steps’ agencies. This is discussed with reference to the broader theoretical and empirical questions of how do institutions change and when are political actors constrained in implementing their policy choices. Cortell and Peterson’s framework for explaining institutional change, and the concept of intra-state policy networks are used to analyse the cases. The differential outcomes identified illustrate how constraints operate and how these may be overcome by strategic actors to produce change. Constraints in these cases arose from fragmentation and dependence in central government, from differing institutionalized beliefs and from the development of intra-state networks between the departments and agencies. The paper concludes by suggesting that the type of intra-state networks created through agencification can be seen to have an effect on policy outcomes and are worthy of more detailed research.

Notes: This article examines the claim that, by the late 1980s, the Welsh Office possessed sufficient autonomy to implement policies that diverged from those of the functional Whitehall ministries. Two case studies, housing and education, are examined as these are areas where institutional autonomy and distinctive needs might be expected to be most apparent in Wales. The conclusion of this article is that the claims of Welsh exceptionalism (certainly in terms of policies) have been much exaggerated and that the ‘centre’, Westminster and Whitehall, was able to impose its preferred policies in Wales, whatever appearances to the contrary.

Notes: Teaching Public Administration in Belgium, Jan Beyers and Yves Plees The Teaching of Public Administration in the UK, Chris Bellamy Teaching Public Administration in Ireland, Bernadette Connaughton Regionalism: a Review Article, Martin Rhodes Shrinking the State. The Political Underpinnings of Privatization , Harvey Feigenbaum, Jeffrey Henig and Chris Hamnett Public Policy Instruments. Evaluating the Tools of Public Administration, B. Guy Peters and Frans K.M. van Nispen Carrots, Sticks and Sermons. Policy Instruments and their Evaluation, Marie-Louise Bemelmans-Videc, Ray C. Rist and Evert Vedung Community Organizing. Building Social Capital as a Development Strategy , Ross Gittell and Avis Vidall Deregulation in the European Union: Environmental Perspectives , Ute Collier New Instruments for Environmental Policy, Jonathan Golub Re-imagining Political Community, Daniele Archibugi, David Held and Martin Köhler

Notes: This article is a revised version of an inaugural lecture, delivered at the University of Leeds on 30 April 1998. The focus of the lecture and, thus, of this article is concerned with administrative history and the civil service. The first part of the article is about the pioneers of the academic study of public administration, and the subject’s relationship with political philosophy. The second part examines the role of the Webbs and the British approach to public administration. The third part evaluates the contribution of the academics of the ‘Golden Age‘ of public administration. The fourth part deals with changing perceptions of public administration, with a particular emphasis on developments in the civil service; it is deliberately self-referential. The final part briefly considers the future of the academic study of public administration, concluding that it has one.

Notes: Like other liberal-democratic governments, Australia has been going through a process of dramatic change in political and administrative structures and processes. There has been the well-documented shift from controlling inputs to managing for results which has resulted in the desired enhancement of executive government’s responsibility and accountability for outcomes. A clear understanding of the evolving process of cabinet decision making points the way ahead to the next phase of reform. What lies ahead could, indeed, be more revolutionary than what has been achieved to date. Weber’s dynamic concept of authority and domination, when understood as Weber himself used it, can tell one much about change and future possible evolution. It helps, heuristically, to indicate that government decision-making processes have already evolved to a sophisticated level. However, there is still much development that should be undertaken to maintain the quality of decision making. For instance, the move to small policy-advising departments and separated administrative programme-delivery agencies could be seen as a natural evolution and quite predictable. Good governance relies much on attaining a balance, in Weber’s terms, between the ethics of intention (means) and the ethics of responsibility (ends). Together, they make the ‘true man’ who can have a ‘vocation of politics’ says Weber – but the ‘true man’ is hard to find. What is needed, therefore, are decision-making processes that are good at drawing out this balance. Well-established patterns of social action, encapsulated in Weber’s sociology and typographically oriented hermeneutics, can help identify how this could be achieved. For instance, when one understands Weber’s ideal types of authority structure as the core of a comprehensive conceptual model with constant interplay and movement over time, one can get a hint of how government decision making could be further enhanced.

Notes: A number of new governance structures has been introduced in the Danish public sector. These include contract agencies, user boards, boards of directors, marketization, corporatization, involving voluntary organizations in public services, EU-funded state border crossing co-operation, and Europeanization in many forms. Despite their obvious dissimilarities, these governance structures have one thing in common: they challenge the foundations of the public sector and territorial representative democracy by blurring the distinctions between politics and administration; between public and private; and between national and international. If politicians and voters are deprived of the capacity to make these distinctions, political responsibility is bound to fade away. Also, each new governance structure down-loads degrees of indeterminateness in the public sector since they may interact in unforeseen ways and introduce new actors, roles and practices in the public sector. This may cause the development of a more flexible public sector marked by ‘local’ appropriateness and adaptability but also by a multitude of inconsistent models and principles. To avoid the latter, a general discourse on values and their institutional requirements and the invention of public ‘domains’ is needed.

Notes: Policy network analysis has been criticized for failing to adopt a sufficiently dynamic approach to the study of policy-making processes. There have been, however, a number of studies illustrating how policy networks change, recognizing that they are not static entities but respond to changes in the policy environment. This article applies policy network analysis to the negotiation of plans to implement the 1994 EC Packaging and Packaging Waste Directive in the UK and provides a further contribution to the literature on the formation and transformation of policy networks. The analysis reveals significant changes in the structure and operation of the policy network during the period studied. The reasons for such changes confirm those put forward by other policy network analysts, such as the power of the actors involved and conflicts between them. Other reasons include the role of the government and the tight schedule laid out by the directive.

Notes: Books reviewed:Nicolai Dose And Matthias Finger, Public Administration In Germany And Switzerland: A Review SymposiumAndrew Jordan, The Multi-Level Politics Of European Environmental Governance: A Review ArticleTineke A. Abma, Evaluation For The 21st Century. A HandbookLennart Lundquist, Unmasking Administrative EviAnne Bergmans, Understanding Policy FiascoesMartha Blomqvist, Understanding Gender And OrganizationsLotte Jensen, Rationality And Power. Democracy In PracticeBill Jenkins, Strategic Planning And Management In Local GovernmentSusana Borrás, Policy-Making In The Eu. Conceptual Lenses And The Integration ProcessPekka Kettunen, Interaktive Politik In Europa. Regionen Im Netzwerk Der IntegrationTanja A. Börzel, Eu Committees As Influential PolicymakersTorill Nyseth, Government Is Us. Public Administration In An Anti-Government EraPeter Bogason, Teaching Political Science: Http://Www.Apsanet.Org/Teaching/Teaching On And By The Www

Notes: Local Public Spending Bodies (LPSBs) occupy an important position in the contemporary structures of governance in the UK. As exemplars of many of the diverse characteristics of the New Public Management, LPSBs inhabit the fuzzy space between the public and private spheres, both in terms of organizational structure and service delivery. One finding from recent research into the internal governance of three kinds of LPSBs – Further Education Colleges, Housing Associations and Training and Enterprise Councils – was that the language of strategy predominated over that of policy on the boards of such organizations. In this article we assess the significance of this finding. We contend that the two terms are not interchangeable and that a vital distinction needs to be maintained between them. Specifically we argue that policy refers to collections of decisions grounded in public values whereas the concept of strategy, particularly as currently understood in the context of the New Public Management, refers to the positioning of an organization in its struggle to survive and grow. We conclude that LPSBs have been invited to behave strategically within a framework of increasingly centralized policy objectives and resource allocations.

Notes: Following publication of the government’s proposals for a statutory framework of Best Value, and the introduction of regulations increasing the flexibility of CCT pending its abolition, this paper examines the relationship between the compulsory regime and its likely successor. First, the paper suggests that the Best Value frame-work is likely to impose a range of regulatory, monitoring and enforcement constraints similar in effect to the formal requirements that operate under CCT. Continuity with Conservative policy will be reinforced practically through transitional arrangements for the gradual abolition of CCT and the phased introduction of its replacement. Second, the paper argues that contracting is likely to continue to have a significant role under the new regime as the natural adjunct to the voluntary competitive processes that will be the preferred management tools for securing improvements in service performance. Open tendering and public-private sector partnership arrangements, both of which imply contractual governance, are given explicit priority in the consultation document over benchmarking, performance indicators and other comparative public management mechanisms. Third, the paper argues that local authorities are likely to want to retain and develop contracting arrangements that potentially permit a degree of control over service provision that might not be available were more radical service-providing alternatives to be adopted, involving the complete transfer of functions outside the public sector and/or their vesting in independent companies. Finally, the paper assesses the transition from CCT to Best Value from the theoretical perspective of responsive and reflexive regulation. Following a brief account of the reflexive failures of CCT, the paper argues that, although the Best Value framework is characterized by inherently reflexive processes involving self-review, consultation and standard-setting, its relative success is likely to depend ultimately both on the tightness with which legislation is drafted and on the manner of its practical interpretation, implementation and enforcement.

Notes: The period between 1957 and 1964 was one of immense yet underestimated political and administrative change. It culminated in what many have seen as a golden age in Whitehall. This is reflected by the wealth of records now available for the study of government and policy networks. The period is thus an ideal one for collaboration between historians and political scientists.The decisional case study examined in this article focuses on the early years of the Public Expenditure Survey Committee, as viewed from the perspective of welfare policy. The drive to ‘modernize’ government started with attempts to ‘roll back the state’ and to hive off the implementation of policy to executive agencies, very similar to those pursued in the 1980s by Mrs Thatcher and Next Steps. The reasoned rejection of such a policy was symbolized by the creation of PESC, a centralized attempt to allocate resources rationally. PESC itself, however, was initially a failure. External circumstances, such as the breakdown of political and administrative networks within the core executive, and internal tensions, including the Treasury’s covert attempt to impose its own departmental interest, led the Cabinet Secretary to conclude that the prioritization and strict control of forward expenditure commitments was ‘not possible’. This case study demonstrates how future studies of the core executive might be broadened and deepened.

Notes: The article discusses (1) the uses, advantages and drawbacks of the biographical approach in the study of public administration and (2) the application of theories of leadership to senior British civil servants. The argument is advanced that biographical case studies - looking at the personal qualities, careers and achievements of top mandarins - can illuminate the exercise of leadership in Whitehall and the changing role and culture of the civil service.

Notes: The period since 1979 has witnessed more radical change in the civil service than in any other peacetime era in its history. Such has been the order of change that Lord Bancroft, the former Head of the Home Civil Service, has suggested that the civil service was in danger of being ‘demolished’ and of there being a return to the ills of the ‘unreformed’ service before the 1850s. This would be to take the ‘two steps back’ of the article’s title before the Northcote-Trevelyan report and the Warren Fisher era. Against the background of this possible outcome, this article evaluates the Next Steps programme and the other initiatives promoted by recent Conservative governments, before concluding that the requirements of the work and a markedly unified career civil service need not be compatible, and that there is at least the possibility that the various changes when fully implemented could represent ‘one step forward’.

Notes: The term ‘multi-level governance’ synthesizes the overlapping nature of the European Union and implicit theories of EU-state-subnational interdependence. Although stimulating as an overriding framework, the concept’s explanatory powers are not self-evident. Using illustrations from implementation of the structural funds within three French regions, this article endeavours to operationalize multi-level governance by concentrating upon what it could help to study and what it might contribute in terms of analysing change. A case is made for focusing research upon variations in patterns of governance through developing a rapprochment between the study of public action and that of political representation.

Notes: Using a transaction cost perspective, this article explores the administrative costs involved in quasi-market systems of public service delivery. Employing the historical example of the interwar National Health Insurance scheme, it revives Beveridge’s early criticisms of the duplication and expense incurred by the utilization of approved societies for benefit administration purposes. To this we should add the costs incurred by central audit and actuarial evaluation, the main mechanisms through which the societies were centrally regulated. The article concludes that, thanks to regulatory requirements, this poly-centric system of public administration was more expensive than a state-run equivalent – and that this message has significance for recent reforms. In the course of the analysis, the narrowness of a ‘pure’ transaction cost perspective is demonstrated and common assumptions concerning distinctions between ‘the state and the market’ in administrative structures are drawn into question. The division of public administration into these two typologies is arguably based on a false dichotomy.

Notes: Far-reaching managerial changes to the public sector in the UK have been occurring in the last few years. Broadly described as the ‘new public management’ (Hood 1991, 1995) these changes have reached new levels of intensity ever since the Conservative Government came to power in 1979. The article argues that the government should be accountable for these changes but not in a way which simply justifies its actions to the body politic but rather by going beyond this to a complete critical evaluation to assess their merit and worth. It is this exposure which will provide its real accountability. This article addresses the contextual factors surrounding the possibility of conducting such a wide-ranging evaluation. It traces a range of different examples which highlight the resistance of the previous government to an open-ended evaluation tracing the sizeable investment in implementation rather than careful policy experimentation and evaluation that has occurred. Finally, and most importantly the article explores the constitutional position of the Comptroller and Auditor General (C&AG) and the National Audit Office (NAO) who could conduct the wide-ranging evaluation which is deemed necessary. The conclusion of the article is that there is a need for an evaluation and any resistance of the government could be overcome if the C&AG and NAO exercised their constitutional right to conduct an evaluation of the reforms.

Notes: In the build up to general elections there is invariably a wealth of discourse on constitutional and transitional issues and even on the efficiency and cost-effectiveness of the civil service, but rarely is there any debate on the manner in which politicians manage the government machine. This article seeks to address this deficiency. It examines the operational factors common to the core executive, assesses the problems usually associated with the government as an organization and reviews alternative solutions. Finally, it offers managerially oriented advice, reasoning that it is the role of policy analysts to prescribe and that it is irresponsible to ignore this function. it is clearly emphasized that management solutions are not synonymous with business solutions. The article draws on universal principles of management, seeking to avoid normative suggestions and concentrating instead on practical considerations. Those considerations include personnel selection, collective responsibility, leadership style, organizational structure and team mentality. The conclusion is that strong managerially based leadership should not be dismissed as incompatible with the political constraints placed upon Prime Ministers but rather it should e the predominant impulse.

Notes: This article contrasts the principles and prescriptions behind the UK model of utility regulation in the post–privatization period with its workings in actual practice, focusing in particular on the case of the telecommunications services industry as an exemplar of the broader picture.It diagnoses that the system has not evolved, as its primary architect (Littlechild) prescribed, into the rule – where feasible – of the competitive order in UK utility industries. Instead it has metamorphosed into a different system that Hayek termed ordered competition. The unintended consequences of this miscegenation are then evaluated.The conclusion is that a fundamental policy choice remains to be made as to the basic form of the system in the future: whether it should continue as a system of ordered competition as now, or whether it should become a regime characterized by open and effective competition (where feasible) as envisioned by Littlechild originally.

Notes: The purpose of this article is to describe and evaluate the public consultation exercises mounted by the Local Government Commission for England under its successive Chairmen, Sir John Banham and Sir David Cooksey. The Commission was evidently proud of this aspect of its work, emphasizing repeatedly its unprecedented nature: in itself an unremarkable claim in the context of British local government structural reviews. This article suggests that, in terms of quality and value for money, as opposed to sheer scale, the consultation programme - and particularly the three principal tranches of MORI residential surveys - was less laudable. The article examines each of these surveys: the stage one community identity polls, which might have contributed to the government’s intended ‘community index’, had the latter not previously been rejected by the Commission; the stage three option consultation surveys, the Banham Commission’s instrument for the hybridization of English local government, which prompted accusations of policymaking by opinion poll; and the stage three ‘re-review’ surveys for the Cooksey Commission, which had already indicated its disinclination to accord local public opinion any special weighting in its deliberations. The article attempts to summarize, in two key tables, both the results and the impact of the Commission’s public consultations, and in doing so to trace the progress of the review from an initially proposed 99 new unitary authorities, down to 50, then 38, and back up to the final total of 46.

Notes: Leach, Steve Davis, Howard and Associates Enabling or Disabling Local GovernmentMidwinter, Arthur Local government in Scotland

Notes: Abstract Precise regulation of major histocompatibility complex class II (MHC-II) gene expression plays a crucial role in the control of the immune response. A major breakthrough in the elucidation of the molecular mechanisms involved in MHC-II regulation has recently come from the study of patients that suffer from a primary immunodeficiency resulting from regulatory defects in MHC-II expression. A genetic complementation cloning approach has led to the isolation of CIITA and RFX5, two essential MHC-II gene transactivators. CIITA and RFX5 are mutated in these patients, and the wild-type genes are capable of correcting their defect in MHC-II expression. The identification of these regulatory factors has furthered our understanding of the molecular mechanisms that regulate MHC-II genes. CIITA was found to be a non-DNA binding transactivator that functions as a molecular switch controlling both constitutive and inducible MHC-II expression. The finding that RFX5 is a subunit of the nuclear RFX-complex has confirmed that a deficiency in the binding of this complex is indeed the molecular basis for MHC-II deficiency in the majority of patients. Furthermore, the study of RFX has demonstrated that MHC-II promoter activity is dependent on the binding of higher-order complexes that are formed by highly specific cooperative binding interactions between certain MHC-II promoter-binding proteins. Two of these proteins belong to families of which the other members, although capable of binding to the same DNA motifs, are probably not directly involved in the control of MHC-II expression. Finally, the facts that CIITA and RFX5 are both essential and highly specific for MHC-II genes make possible novel strategies designed to achieve immunomodulation via transcriptional intervention.

Notes: Abstract Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNFalpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGFbeta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNFalpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNFalpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNFalpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNFalpha at its apex. This led to the hypothesis that TNFalpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNFalpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNFalpha antibody have shown marked clinical benefit, verifying the hypothesis that TNFalpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNFalpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.

Notes: Abstract In contrast with the study of alphabeta T cells, that of gammadelta T cells is relatively recent and stems from the discovery of their rearranged genes, rather than from any knowledge of their biological function. Thus, experiments designed to characterize their specificity and function have drawn heavily on our knowledge of alphabeta T cells. During the past few years, many studies, especially with mice lacking either alphabeta or gammadelta T cells, have demonstrated that gammadelta T cells can contribute to immune competence, but they do so in a way that is distinct from alphabeta T cells. It is also evident that gammadelta T cells may not recognize antigen the same way as do alphabeta T cells. Analysis of three protein antigens-the murine MHC class II IEk, the nonclassical MHC T10/T22, and the Herpes virus glycoprotein gI-indicates that gammadelta T cell recognition does not require antigen processing and that the proteins are recognized directly. In all three cases, recognition by these T cell clones involves neither peptides bound to these proteins nor peptides derived from them. Moreover, a group of small phosphate-containing nonpeptide compounds derived from mycobacterial extracts has been found to stimulate a major population of human peripheral gammadelta T cells in a T cell receptor (TCR)-dependent manner. This indicates that gammadelta T cells can respond to ligands that are different from those of alphabeta T cells. Analysis of complementarity determining region (CDR3) length distributions of gamma and delta chains indicates that they are more similar to those of immunoglobulins than to TCR alpha and beta. This further supports the idea that gammadelta and alphabeta T cells recognize antigens differently and suggests that gammadelta T cells may be more like immunoglobulins in their recognition properties. gammadelta T cells share many cell surface proteins with alphabeta T cells and are able to secrete lymphokines and express cytolytic activities in response to antigenic stimulation. These, together with the results cited above, indicate that gammadelta T cells can mediate cellular immune functions without a requirement for antigen processing. Thus, pathogens, damaged tissues, or even B and T cells can be recognized directly, and cellular immune responses can be initiated without a requirement for antigen degradation or specialized antigen-presenting cells. This would give gammadelta T cells greater flexibility than the more classical type of alphabeta T cell-mediated cellular immunity.

Notes: Abstract The transcription factor NF-kappaB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-kappaB is through interactions with an inhibitor protein called IkappaB. Recent evidence confirms the existence of multiple forms of IkappaB that appear to regulate NF-kappaB by distinct mechanisms. NF-kappaB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-kappaB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IkappaB. Exciting new research has elaborated several important and unexpected findings that explain mechanisms involved in the activation of NF-kappaB. In the nucleus, NF-kappaB dimers bind to target DNA elements and activate transcription of genes encoding proteins involved with immune or inflammation responses and with cell growth control. Recent data provide evidence that NF-kappaB is constitutively active in several cell types, potentially playing unexpected roles in regulation of gene expression. In addition to advances in describing the mechanisms of NF-kappaB activation, excitement in NF-kappaB research has been generated by the first report of a crystal structure for one form of NF-kappaB, the first gene knockout studies for different forms of NF-kappaB and of IkappaB, and the implications for therapies of diseases thought to involve the inappropriate activation of NF-kappaB.

Notes: Abstract Naturally occurring genetic disorders of the immune system provide many models for the study of its development and function. In a way, their analysis complements the information provided by the generation of genetic defects in mice created using homologous recombination techniques. In this review, the recent findings made in three areas are focused upon deficiencies in T cell differentiation and in T lymphocyte activation, and on the control process of peripheral immune response.

Notes: Abstract This review deals with membrane Fc receptors (FcR) of the immunoglobulin superfamily. It is focused on the mechanisms by which FcR trigger and regulate biological responses of cells on which they are expressed. FcR deliver signals when they are aggregated at the cell surface. The aggregation of FcR having immunoreceptor tyrosine-based activation motifs (ITAMs) activates sequentially src family tyrosine kinases and syk family tyrosine kinases that connect transduced signals to common activation pathways shared with other receptors. FcR with ITAMs elicit cell activation, endocytosis, and phagocytosis. The nature of responses depends primarily on the cell type. The aggregation of FcR without ITAM does not trigger cell activation. Most of these FcR internalize their ligands, which can be endocytosed, phagocytosed, or transcytosed. The fate of internalized receptor-ligand complexes depends on defined sequences in the intracytoplasmic domain of the receptors. The coaggregation of different FcR results in positive or negative cooperation. Some FcR without ITAM use FcR with ITAM as signal transduction subunits. The coaggregation of antigen receptors or of FcR having ITAMs with FcR having immunoreceptor tyrosine-based inhibition motifs (ITIMs) negatively regulates cell activation. FcR therefore appear as the subunits of multichain receptors whose constitution is not predetermined and which deliver adaptative messages as a function of the environment.

Notes: Abstract T helper lymphocytes can be divided into two distinct subsets of effector cells based on their functional capabilities and the profile of cytokines they produce. The Th1 subset of CD4+ T cells secretes cytokines usually associated with inflammation, such as IFN-gamma and TNF and induces cell-mediated immune responses. The Th2 subset produces cytokines such as IL-4 and IL-5 that help B cells to proliferate and differentiate and is associated with humoral-type immune responses. The selective differentiation of either subset is established during priming and can be significantly influenced by a variety of factors. One of these factors, the cytokine environment, has been put forward as the major variable influencing Th development and is already well reviewed by others. Instead, in the current review, we focus on some of the alternative approaches for skewing Th1/Th2 responses. Specifically, we discuss the effects on Th priming of (a) using altered peptide ligands as antigens, (b) varying the dose of antigen, and (c) altering costimulatory signals. The potential importance of each of these variables to influence immune responses to pathogens in vivo is discussed throughout.

Notes: Abstract Epstein-Barr virus (EBV) provides one of the most informative systems with which to study cytotoxic T lymphocyte (CTL) responses in humans. The virus establishes a highly immunogenic growth-transforming infection of B lymphocytes, associated with the coordinate expression of six virus-coded nuclear antigens (EBNAs 1, 2, 3A, 3B, 3C, -LP) and two latent membrane proteins (LMPs 1 and 2). This elicits both primary and memory CT8+ CTL responses that are markedly skewed toward HLA allele-specific epitopes drawn from the EBNA3A, 3B, 3C subset of latent proteins, with reactivities to other antigens being generally much less frequent. This heirarchy of immunodominance among the different latent proteins may at least partly reflect their differential accessibility to the HLA class I-processing pathway. Furthermore, CTLs to some of the immunodominant epitopes involve highly conserved T cell receptor (TCR) usage, a level of focusing which evidence suggests could have immunopathological consequences from cross-reactive recognition of other target structures. EBV is associated with a range of human tumors, and there is increasing interest in the possibility of targeting such malignancies using virus-specific CTLs. The dramatic reversal of EBV-driven lymphoproliferations in bone marrow transplant patients following CTL infusion demonstrates the potential of this approach, and here we discuss prospects for its extension to other EBV-positive tumors in which the immunodominant EBNA3A, 3B, 3C proteins are not expressed.

Notes: Abstract NK1 T cells are a specialized population of alpha/beta T cells that coexpress receptors of the NK lineage and have the unique potential to very rapidly secrete large amounts of cytokines, providing early help for effector cells and regulating the Th1 or Th2 differentiation of some immune responses. NK1 T cells express a restricted TCR repertoire made of an invariant TCR alpha chain, Valpha14-Jalpha281, associated with polyclonal Vbeta8, Vbeta7, and Vbeta2 TCR beta chains. NK1 T cells recognize the products of the conserved family of MHC class I-like CD1 genes, apparently in the absence of foreign antigens. Thus, this novel regulatory pathway, which straddles the innate and the adaptive immune systems, is unique in that its activation may not require associative recognition of antigen. Here, we review the specificity and function of mouse NK1 T cells, and we discuss the relationship of this lineage to mainstream T cells and NK cells.

Notes: Abstract Receptors for most interleukins and cytokines that regulate immune and hematopoietic systems belong to the class I cytokine receptor family. These molecules form multichain receptor complexes in order to exhibit high-affinity binding to, and mediate biological functions of, their respective cytokines. In most cases, these functional receptor complexes share common signal transducing receptor components that are also in the class I cytokine receptor family, i.e. gp130, common beta, and common gamma molecules. Interleukin-6 and related cytokines, interleukin-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1 are all pleiotropic and exhibit overlapping biological functions. Functional receptor complexes for this interleukin-6 family of cytokines share gp130 as a component critical for signal transduction. Unlike cytokines sharing common beta and common gamma chains that mainly function in hematopoietic and lymphoid cell systems, the interleukin-6 family of cytokines function extensively outside these systems as well, e.g. from the cardiovascular to the nervous system, owing to ubiquitously expressed gp130. Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. Although gp130 and its dimer partners possess no intrinsic tyrosine kinase domain, the dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. This paper reviews recent progress in the study of the interleukin-6 family of cytokines and gp130.

Notes: At first one is very pleased at being invited to write a Prefatory Chapter, but as the delivery deadline draws closer one begins to think, "Oh my God! What on earth can I say that all but family members and few close friends will not find a great bore?" One solution is to write a scientific essay, but I concluded that that was a cop-out. I decided that perhaps the best tack to follow was to try to convey to the reader the personal characteristics I bring to my science and to other aspects of my professional career. The writing of this chapter has certainly convinced me that my particular background influenced what problems I chose to work on and how I approached their solution, but I hope that my results have a more ecumenical significance. There's been much written recently about how one's cultural background affects one's science, but I think that thesis can also be exaggerated. Science is a method of inquiry that by using certain guidelines permits rational individuals to observe Nature in a way that their findings will agree and have permanence. We shouldn't be diffident about defending that claim of objectivity.

Notes: Abstract CD40-CD154-mediated contact-dependent signals between B and T cells are required for the generation of thymus dependent (TD) humoral immune responses. CD40-CD154 interactions are however also important in many other cell systems. CD40 is expressed by a large variety of cell types other than B cells, and these include dendritic cells, follicular dendritic cells, monocytes, macrophages, mast cells, fibroblasts, and endothelial cells. CD40- and CD154-knockout mice and antibodies to CD40 and CD154 have helped to elucidate the role of the CD40-CD154 system in immune responses. Recently published studies indicate that CD40-CD154 interactions can influence T cell priming and T cell-mediated effector functions; they can also upregulate costimulatory molecules and activate macrophages, NK cells, and endothelia as well as participate in organ-specific autoimmune disease, graft rejection, and even atherosclerosis. This review focuses on the role of the CD40-CD154 system in the regulation of many newly discovered functions important in inflammation and cell-mediated immunity.

Notes: Abstract Immunological memory can be defined as the faster and stronger response of an animal that follows reexposure to the same antigen. By this definition, it is an operational property of the whole animal or the immune system. Memory cells express a different pattern of cell surface markers, and they respond in several ways that are functionally different from those of naive cells. Murine memory cells are CD44 high and low in the expression of activation markers such as CD25 (IL-2R), whereas human memory cells are CD45RA-, CD45RO+. In contrast to naive cells, memory cells secrete a full range of T cell cytokines and can be polarized to secrete particular restricted patterns of secretion for both CD4 and CD8 T cells. The requirements for the activation of memory cells for proliferation and cytokine production are not quite as strict as those of naive cells, but costimulation in the broad sense is required for optimum responses and for responses to suboptimum antigen concentrations. It would appear that memory cells can persist in the absence of antigenic stimulation and persist as nondividing cells. Reencounter with the same antigen can expand the population to a new, stable, higher level and generate a separate population of CD44 high effectors that may be required for protection, while competition from other antigens can drive it down to a lower stable level. It is unclear how or where memory cells arise, but once generated they have different pathways of recirculation and homing.

Notes: Abstract NK cells are regulated by opposing signals from receptors that activate and inhibit effector function. While positive stimulation may be initiated by an array of co-stimulatory receptors, specificity is provided by inhibitory signals transduced by receptors for MHC class I. Three distinct receptor families, Ly49, CD94/NKG2, and KIR, are involved in NK cell recognition of polymorphic MHC class I molecules. A common pathway of inhibitory signaling is provided by ITIM sequences in the cytoplasmic domains of these otherwise structurally diverse receptors. Upon ligand binding and activation, the inhibitory NK cell receptors become tyrosine phosphorylated and recruit tyrosine phosphatases, SHP-1 and possibly SHP-2, resulting in inhibition of NK cell-mediated cytotoxicity and cytokine expression. Recent studies suggest these inhibitory NK cell receptors are members of a larger superfamily containing ITIM sequences, the inhibitory receptor superfamily (IRS).

Notes: Abstract This review summarizes the clinical history and rationale for xenotransplantation; recent progress in understanding the physiologic, immunologic, and infectious obstacles to the procedure's success; and some of the strategies being pursued to overcome these obstacles. The problems of xenotransplantation are complex, and a combination of approaches is required. The earliest and most striking immunologic obstacle, that of hyperacute rejection, appears to be the closest to being solved. This phenomenon depends on the binding of natural antibody to the vascular endothelium, fixation of complement by that antibody, and finally, activation of the endothelium and initiation of coagulation. Therefore, these three pathways have been targeted as sites for intervention in the process. The mechanisms responsible for the next immunologic barrier, that of delayed xenograft/acute vascular rejection, remain to be fully elucidated. They probably also involve multiple pathways, including antibody and/or immune cell binding and endothelial cell activation. The final immunologic barrier, that of the cellular immune response, involves mechanisms that are similar to those involved in allograft rejection. However, the strength of the cellular immune response to xenografts is so great that it is unlikely to be controlled by the types of nonspecific immunosuppression used routinely to prevent allograft rejection. For this reason, it may be essential to induce specific immunologic unresponsiveness to at least some of the most antigenic xenogeneic molecules.

Notes: Abstract Covalent attachment of activated complement C3 (C3d) to antigen links innate and adaptive immunity by targeting antigen to follicular dendritic cells (FDC) and B cells via specific receptors CD21 and CD35. Recent characterization of knockout mice deficient in complement components C3, C4, or the receptors CD21 and CD35 as well as biochemical studies of the CD21/CD19/Tapa-1 coreceptor on B cells have helped to elucidate the mechanism of complement regulation of both B-1 and B-2 lymphocytes. Interestingly, natural antibody of the adaptive immune system provides a major recognition role in activation of the complement system, which in turn enhances activation of antigen-specific B cells. Enhancement of the primary and secondary immune response to T-dependent antigens is mediated by coligation of the coreceptor and the B cell antigen receptor, which dramatically increases follicular retention and B cell survival within the germinal center. Most recent evidence suggests that complement also regulates elimination of self-reactive B cells, as breeding of mice that are deficient in C4 or CD21/CD35 with the lupus-prone strain of lpr mice demonstrates an exacerbation of disease due to an increase in autoantibodies.

Notes: Work done in the late 1950s and in the 1960s revealed the role of the thymus in virus-induced leukemia in mice. Thymectomizing mice at birth to test whether the virus first multiplied in thymus tissue and then spread elsewhere ultimately led to the conclusion that the thymus was essential to the normal development of the immune system. Subsequent testing to try to understand how the thymus contributes to the pool of immunocompetent lymphocytes opened a new chapter in immunology and required a reappraisal of many immunological phenomena and an understanding of the molecular interactions that take place during cell-to-cell interactions.

Notes: Abstract Interleukin-15 (IL-15) is a 14- to 15-kDa member of the 4 alpha-helix bundle family of cytokines. IL-15 expression is controlled at the levels of transcription, translation, and intracellular trafficking. In particular, IL-15 protein is posttranscriptionally regulated by multiple controlling elements that impede translation, including 12 upstream AUGs of the 5' UTR, 2 unusual signal peptides, and the C-terminus of the mature protein. IL-15 uses two distinct receptor and signaling pathways. In T and NK cells the IL-15 receptor includes IL-2/15Rbeta and gammac, subunits, which are shared with IL-2, and an IL-15-specific receptor subunit, IL-15Ralpha. Mast cells respond to IL-15 with a receptor system that does not share elements with the IL-2 receptor but uses a novel 60- to 65-kDa IL-15RX subunit. In mast cells IL-15 signaling involves Jak2/STAT5 activation rather than the Jak1/Jak3 and STAT5/STAT3 system used in activated T cells. In addition to its other functional activities in immune and nonimmune cells, IL-15 plays a pivotal role in the development, survival, and function of NK cells. Abnormalities of IL-15 expression have been described in patients with rheumatoid arthritis or inflammatory bowel disease and in diseases associated with the retroviruses HIV and HTLV-I. New approaches directed toward IL-15, its receptor, or its signaling pathway may be of value in the therapy of these disorders.

Notes: Abstract Natural killer (NK) cells are populations of lymphocytes that can be activated to mediate significant levels of cytotoxic activity and produce high levels of certain cytokines and chemokines. NK cells respond to and are important in defense against a number of different infectious agents. The first indications for this function came from the observations that virus-induced interferons alpha/beta (IFN-alpha and -beta) are potent inducers of NK cell-mediated cytotoxicity, and that NK cells are important contributors to innate defense against viral infections. In addition to IFN-alpha/beta, a wide range of other innate cytokines can mediate biological functions regulating the NK cell responses of cytotoxicity, proliferation, and gamma interferon (IFN-gamma) production. Certain, but not all, viral infections induce interleukin 12 (IL-12) to elicit NK cell IFN-gamma production and antiviral mechanisms. However, high levels of IFN-alpha/beta appear to be unique and/or uniquely dominant in the context of viral infections and act to regulate other innate responses, including induction of NK cell proliferation in vivo and overall negative regulation of IL-12 production. A detailed picture is developing of particular innate cytokines activating NK cell responses and their consorted effects in providing unique endogenous milieus promoting downstream adaptive responses, most beneficial in defense against viral infections.

Notes: Abstract Four members of the tumor necrosis factor (TNF) ligand family, TNF-alpha, LT-alpha, LT-beta, and LIGHT, interact with four receptors of the TNF/nerve growth factor family, the p55 TNF receptor (CD120a), the p75 TNF receptor (CD120b), the lymphotoxin beta receptor (LTbetaR), and herpes virus entry mediator (HVEM) to control a wide range of innate and adaptive immune response functions. Of these, the most thoroughly studied are cell death induction and regulation of the inflammatory process. Fas/Apo1 (CD95), a receptor of the TNF receptor family activated by a distinct ligand, induces death in cells through mechanisms shared with CD120a. The last four years have seen a proliferation in knowledge of the proteins participating in the signaling by the TNF system and CD95. The downstream signaling molecules identified so far-caspases, phospholipases, the three known mitogen activated protein (MAP) kinase pathways, and the NF-kappaB activation cascade-mediate the effects of other inducers as well. However, the molecules that initiate these signaling events, including the death domain- and TNF receptor associated factor (TRAF) domain-containing adapter proteins and the signaling enzymes associated with them, are largely unique to the TNF/nerve growth factor receptor family.

Notes: Abstract Exciting breakthroughs in the last two years have begun to elucidate the structural basis of cellular immune recognition. Crystal structures have been determined for full-length and truncated forms of alphabeta T cell receptor (TCR) heterodimers, both alone and in complex with their peptide-MHC (pMHC) ligands or with anti-TCR antibodies. In addition, a truncated CD8 coreceptor has been visualized with a pMHC. Aided in large part by the substantial body of knowledge accumulated over the last 25 years on antibody structure, a number of general conclusions about TCR structure and its recognition of antigen can already be derived from the relatively few TCR structures that have been determined. Small, but important, variations between TCR and antibody structures bear on their functional differences as well as on their specific antigen recognition requirements. As observed in antibodies, canonical CDR loop structures are already emerging for some of the TCR CDR loops. Highly similar docking orientations of the TCR Valpha domains in the TCR/pMHC complex appear to play a primary role in dictating orientation, but the Vbeta positions diverge widely. Similar TCR contact positions, but whose exact amino acid content can vary, coupled with relatively poor interface shape complementarity, may explain the flexibility and short half-lives of many TCR interactions with pMHC. Here we summarize the current state of this field, and suggest that the knowledge gap between the three-dimensional structure and the signaling function of the TCR can be bridged through a synthesis of molecular biological and biophysical techniques.

Notes: Abstract In B lymphocytes, a signaling complex that contributes to cell fate decisions is the B cell antigen receptor (BCR). Data from knockout experiments in cell lines and mice have revealed distinct functions for the intracellular protein tyrosine kinases (Lyn, Syk, Btk) in BCR signaling and B cell development. Combinations of intracellular signaling pathways downstream of these PTKs determine the quality and quantity of BCR signaling. For example, concerted actions of the PLC-gamma2 and PI3-K pathways are required for proper calcium responses. Similarly, the regulation of ERK and JNK responses involves both PLC-gamma2 and GTPases pathways. Since the immune response in vivo is regulated by alteration of these signaling outcomes, achieving a precise understanding of intracellular molecular events leading to B lymphocyte proliferation, deletion, anergy, receptor editing, and survival still remains a challenge for the future.

Notes: Abstract Phagocytosis of pathogens by macrophages initiates the innate immune response, which in turn orchestrates the adaptive response. In order to discriminate between infectious agents and self, macrophages have evolved a restricted number of phagocytic receptors, like the mannose receptor, that recognize conserved motifs on pathogens. Pathogens are also phagocytosed by complement receptors after relatively nonspecific opsonization with complement and by Fc receptors after specific opsonization with antibodies. All these receptors induce rearrangements in the actin cytoskeleton that lead to the internalization of the particle. However, important differences in the molecular mechanisms underlying phagocytosis by different receptors are now being appreciated. These include differences in the cytoskeletal elements that mediate ingestion, differences in vacuole maturation, and differences in inflammatory responses. Infectious agents, such as M. tuberculosis, Legionella pneumophila, and Salmonella typhimurium, enter macrophages via heterogeneous pathways and modify vacuolar maturation in a manner that favors their survival. Macrophages also play an important role in the recognition and clearance of apoptotic cells; a notable feature of this process is the absence of an inflammatory response.

Notes: Abstract The immune system relies on cell death to maintain lymphoid homeostasis and avoid disease. Recent evidence has indicated that the caspase family of cysteine proteases is a central effector in apoptotic cell death and is absolutely responsible for many of the morphological features of apoptosis. Cell death, however, can occur through caspase-independent and caspase-dependent pathways. In the case of cells that are irreversibly neglected or damaged, death occurs even in the absence of caspase activity. In contrast, healthy cells require caspase activation to undergo cell death induced by surface receptors. This review summarizes the current understanding of these two pathways of cell death in the immune system.

Notes: Abstract The discovery that genes in the major histocompatibility complex (MHC) play an important role in the immune response depended on the chance interaction of several unrelated events. The first, and most important, was the decision by Michael Sela to synthesize a series of branched, multichain, synthetic polypeptides based on a backbone of poly-l-lysine. The prototype compound, (T,G)-A-L, was tipped with short random sequences of tyrosine and glutamic acid. This resulted in a restricted range of antigenic determinants composed of only two or three amino acids with a variable length-ideal for binding to the peptide binding groove of MHC class II molecules. The second was the decision by John Humphrey to immunize various strains of rabbits with this synthetic polypeptide. Two of these rabbit strains showed very large quantitative differences in antibody response to (T,G)-A-L. In transferring this system to inbred mouse strains, the third bit of good fortune was the availability at the National Institute of Medical Research, in Mill Hill (London), of the CBA (H2k) and C57 (H2b) strains. The H2b haplotype is the only one mediating a uniform high antibody response to (T,G)-A-L. The fourth critical ingredient was the availability of numerous congenic and H2 recombinant inbred strains of mice produced earlier by Snell, Stimpfling, Shreffler, and Klein. A search for congenic pairs of mice expressing the responder and nonresponder H2 haplotypes on the same background revealed that these strains responded as a function of their H2 haplotype, not of their inbred background. Extensive studies in a variety of inbred strains carrying recombinant H2 haplotypes, as well as a four-point linkage cross, mapped immune response to (T,G)A-L within the murine MHC, between the K and Ss loci. The demonstration that stimulation in the mixed lymphocyte reaction (MLR) mapped to the same region quickly led to attempts to produce antisera in congenic H2 recombinant strain combinations. These antisera identified I-region associated (Ia) antigens. Immunoprecipitation and blocking studies showed that the gene products controlling specific immune responses, the mixed lymphocyte reaction, and the structure of Ia antigens were one and the same-now designated as the I-A MHC class II molecules. These antisera and inbred strains enabled Unanue to demonstrate the peptide binding function of class II MHC molecules.

Notes: Abstract Ligation of the T cell antigen receptor (TCR) stimulates protein tyrosine kinases (PTKs), which regulate intracellular calcium and control the activity of protein kinase C (PKC) isozymes. PTKs activated by antigen receptors and costimulatory molecules also couple to phosphatidylinositol-3 kinase (PI3K) and control the activity of Ras- and Rho-family GTPases. T cell signal transduction is triggered physiologically by antigen in the context of antigen presenting cells (APC). The formation of stable and prolonged contacts between T cells and APCs is not neccessary to initiate T cell signaling but is required for effective T cell proliferation and differentiation. The stabilization of the T cell/ APC conjugate is regulated by intracellular signals induced by antigen receptors and costimulators. These coordinate the regulation of the actin and microtubule cytoskeleton and organize a specialized signaling zone that allows sustained TCR signaling.

Notes: Abstract The potential to harness the potency and specificity of the immune system underlies the growing interest in cancer immunotherapy. One such approach uses bone marrow-derived dendritic cells, phenotypically distinct and extremely potent antigen-presenting cells, to present tumor-associated antigens and thereby generate tumor-specific immunity. Support for this strategy comes from animal studies that have demonstrated that dendritic cells, when loaded ex vivo with tumor antigens and administered to tumor-bearing hosts, can elicit T cell-mediated tumor destruction. These observations have led to clinical trials designed to investigate the immunologic and clinical effects of antigen-loaded dendritic cells administered as a therapeutic vaccine to patients with cancer. In the design and conduct of such trials, important considerations include antigen selection, methods for introducing the antigen into MHC class I and II processing pathways, methods for isolating and activating dendritic cells, and route of administration. Although current dendritic cell-based vaccination methods are cumbersome, promising results from clinical trials in patients with malignant lymphoma, melanoma, and prostate cancer suggest that immunotherapeutic strategies that take advantage of the antigen presenting properties of dendritic cells may ultimately prove both efficacious and widely applicable to human tumors.

Notes: Abstract Allergic diseases affect approximately one third of the general population. This class of disease, characterized by elevated serum IgE levels and hypersensitivity to normally innocuous antigen, can manifest in practically any mucosal tissue or as a systemic response. A few examples of serious allergic diseases include asthma, dermatitis, bee sting allergy, food allergy, conjunctivitis, and severe systemic anaphylaxis. Taken together, allergic diseases constitute one of the major problems of modern day medicine. A considerable portion of the healthcare budget is expended in the treatment of allergic disease, and morbidity rates of inner city asthmatics are rising steadily. Due to the enormity of the problem, there has been a worldwide effort to identify factors that contribute to the etiology of allergic diseases. Epidemiologic studies of multigeneration families and large numbers of twins clearly indicate a strong genetic component to atopic diseases. At least two independently segregating diseasesusceptibility genes are thought to come together with environmental factors to result in allergic inflammation in a particular tissue. On the basis of the strong genetic studies, multiple groups have attempted to identify disease-susceptibility genes via either a candidate gene approach or by genome-wide scans. Both of these approaches have implicated multiple regions in the human and mouse genomes, which are currently being evaluated as harboring putative atopy genes.

Notes: Abstract The human thymus is a complex chimeric organ comprised of central (thymic epithelial space) and peripheral (perivascular space) components that functions well into adult life to produce naive T lymphocytes. Recent advances in identifying thymic emigrants and development of safe methods to study thymic function in vivo in adults have provided new opportunities to understand the role that the human thymus plays in immune reconstitution in aging, in bone marrow transplantation, and in HIV-1 infection. The emerging concept is that there are age-dependent contributions of thymic emigrants and proliferation of postthymic T cells to maintain the peripheral T cell pool and to contribute to T cell regeneration, with the thymus contributing more at younger ages and peripheral T cell expansion contributing more in older subjects. New studies have revealed a dynamic interplay between postnatal thymus output and peripheral T cell pool proliferation, which play important roles in determining the nature of immune reconstitution in congenital immunodeficiency diseases, in bone marrow transplantation, and in HIV-1 infection. In this paper, we review recent data on human postnatal thymus function that, taken together, support the notion that the human thymus is functional well into the sixth decade and plays a role throughout life to optimize human immune system function.

Notes: Abstract Antibodies can completely suppress or enhance the antibody response to their specific antigen by several hundredfold. Immunoglobulin M (IgM) enhances antibody responses via the complement system, and complement activation by IgM probably starts the chain of events leading to antibody responses to suboptimal antigen doses. IgG can enhance primary antibody responses in the absence of the complement system and seems to be dependent on Fc receptors for IgG (FcgammaRs). IgE enhances antibody responses via the low-affinity receptor for IgE (FcepsilonRII/CD23). The precise effector mechanisms that cause enhancement are not known, but direct B-cell signaling, antigen presentation, and increased follicular localization are all possibilities. IgG, IgE, and IgM may also suppress antibody responses when used in certain immunization regimes, and it seems reasonable that an important mechanism behind suppression is the masking of antigenic epitopes by antibodies. In addition, FcgammaRIIB, which contains a cytoplasmic inhibitory motif, acts as a negative regulator of antibody responses. This receptor, however, may prevent the antibody responses from exceeding a certain level rather than causing complete suppression.

Notes: Abstract Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Notes: Abstract The development and widespread use of vaccines against infectious agents have been a great triumph of medical science. One reason for the success of currently available vaccines is that they are capable of inducing long-lived antibody responses, which are the principal agents of immune protection against most viruses and bacteria. Despite these successes, vaccination against intracellular organisms that require cell-mediated immunity, such as the agents of tuberculosis, malaria, leishmaniasis, and human immunodeficiency virus infection, are either not available or not uniformly effective. Owing to the substantial morbidity and mortality associated with these diseases worldwide, an understanding of the mechanisms involved in generating long-lived cellular immune responses has tremendous practical importance. For these reasons, a new form of vaccination, using DNA that contains the gene for the antigen of interest, is under intensive investigation, because it can engender both humoral and cellular immune responses. This review focuses on the mechanisms by which DNA vaccines elicit immune responses. In addition, a list of potential applications in a variety of preclinical models is provided.

Notes: Abstract Physical detection of antigen-specific CD4 T cells has revealed features of the in vivo immune response that were not appreciated from in vitro studies. In vivo, antigen is initially presented to naive CD4 T cells exclusively by dendritic cells within the T cell areas of secondary lymphoid tissues. Anatomic constraints make it likely that these dendritic cells acquire the antigen at the site where it enters the body. Inflammation enhances in vivo T cell activation by stimulating dendritic cells to migrate to the T cell areas and display stable peptide-MHC complexes and costimulatory ligands. Once stimulated by a dendritic cell, antigen-specific CD4 T cells produce IL-2 but proliferate in an IL-2-independent fashion. Inflammatory signals induce chemokine receptors on activated T cells that direct their migration into the B cell areas to interact with antigen-specific B cells. Most of the activated T cells then die within the lymphoid tissues. However, in the presence of inflammation, a population of memory T cells survives. This population is composed of two functional classes. One recirculates through nonlymphoid tissues and is capable of immediate effector lymphokine production. The other recirculates through lymph nodes and quickly acquires the capacity to produce effector lymphokines if stimulated. Therefore, antigenic stimulation in the presence of inflammation produces an increased number of specific T cells capable of producing effector lymphokines throughout the body.

Notes: Abstract Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNFalpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNFalpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNFalpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNFalpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activcity of TNFalpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNFalpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNFalpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.

Notes: Abstract Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3zeta, FcRIgamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCRdull phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.

Notes: Abstract Elevation of intracellular free Ca2+ is one of the key triggering signals for T-cell activation by antigen. A remarkable variety of Ca2+ signals in T cells, ranging from infrequent spikes to sustained oscillations and plateaus, derives from the interactions of multiple Ca2+ sources and sinks in the cell. Following engagement of the T cell receptor, intracellular channels (IP3 and ryanodine receptors) release Ca2+ from intracellular stores, and by depleting the stores trigger prolonged Ca2+ influx through store-operated Ca2+ (CRAC) channels in the plasma membrane. The amplitude and dynamics of the Ca2+ signal are shaped by several mechanisms, including K+ channels and membrane potential, slow modulation of the plasma membrane Ca2+-ATPase, and mitochondria that buffer Ca2+ and prevent the inactivation of CRAC channels. Ca2+ signals have a number of downstream targets occurring on multiple time scales. At short times, Ca2+ signals help to stabilize contacts between T cells and antigen-presenting cells through changes in motility and cytoskeletal reorganization. Over periods of minutes to hours, the amplitude, duration, and kinetic signature of Ca2+ signals increase the efficiency and specificity of gene activation events. The complexity of Ca2+ signals contains a wealth of information that may help to instruct lymphocytes to choose between alternate fates in response to antigenic stimulation.

Notes: Abstract B cell development is a highly regulated process whereby functional peripheral subsets are produced from hematopoietic stem cells, in the fetal liver before birth and in the bone marrow afterward. Here we review progress in understanding some aspects of this process in the mouse bone marrow, focusing on delineation of the earliest stages of commitment, on pre-B cell receptor selection, and B cell tolerance during the immature-to-mature B cell transition. Then we note some of the distinctions in hematopoiesis and pre-B selection between fetal liver and adult bone marrow, drawing a connection from fetal development to B-1/CD5+ B cells. Finally, focusing on CD5+ cells, we consider the forces that influence the generation and maintenance of this distinctive peripheral B cell population, enriched for natural autoreactive specificities that are encoded by particular germline VH-VL combinations.