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  • 1
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    Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-07-31
    Description: Treatment-resistant Lyme arthritis is associated with immune reactivity to outer surface protein A (OspA) of Borrelia burgdorferi, the agent of Lyme disease, and the major histocompatibility complex class II allele DRB1*0401. The immunodominant epitope of OspA for T helper cells was identified. A homology search revealed a peptide from human leukocyte function-associated antigen-1 (hLFA-1) as a candidate autoantigen. Individuals with treatment-resistant Lyme arthritis, but not other forms of arthritis, generated responses to OspA, hLFA-1, and their highly related peptide epitopes. Identification of the initiating bacterial antigen and a cross-reactive autoantigen may provide a model for development of autoimmune disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gross, D M -- Forsthuber, T -- Tary-Lehmann, M -- Etling, C -- Ito, K -- Nagy, Z A -- Field, J A -- Steere, A C -- Huber, B T -- R01 AR20358/AR/NIAMS NIH HHS/ -- New York, N.Y. -- Science. 1998 Jul 31;281(5377):703-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Tufts University, Boston, MA 02111 USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9685265" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Algorithms ; Amino Acid Sequence ; Animals ; Antigen Presentation ; Antigens, Surface/immunology/metabolism ; Arthritis, Reactive/drug therapy/*immunology ; Autoantigens/*immunology ; Autoimmune Diseases/*immunology ; Bacterial Outer Membrane Proteins/immunology/metabolism ; Bacterial Vaccines ; Borrelia burgdorferi Group/immunology ; Child ; Cross Reactions ; Female ; HLA-DR Antigens/genetics/immunology/metabolism ; HLA-DRB1 Chains ; Humans ; Immunodominant Epitopes ; *Lipoproteins ; Lyme Disease/drug therapy/*immunology ; Lymphocyte Function-Associated Antigen-1/chemistry/*immunology/metabolism ; Male ; Mice ; Mice, Transgenic ; Molecular Sequence Data ; Synovial Fluid/immunology ; T-Lymphocytes, Helper-Inducer/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Umbilical Cord Blood (UCB) Graft T-Cells Correlate with Myeloid Recovery in Adults with Hematologic Malignancies Treated with Reduced Intensity Conditioning (RIC) and Single Unit Infusion. (2006)
    American Society of Hematology
    Details
    Publication Date: 2006-11-16
    Description: Experience with unrelated allogeneic UCB stem cell transplantation in the non-myeloablative setting is limited because of concerns of graft failure due to limited cell content. Dual UCB graft infusion has been explored to overcome cell dose limitations, but influence on engraftment is unclear. This single institution phase I trial examined RIC followed by single UCB transplantation for patients unable to tolerate fully myeloablative regimens and lacking a matched adult donor. Conditioning consisted of TBI 200 cGy, fludarabine 175 mg/m², cyclophosphamide 2 gm/m², ATG 60 mg/kg. Trial design specified selection of UCB grafts to be matched at 4/6 HLA loci or better with one unit infused if cryopreserved nucleated cell dose exceeded 2.5 x 107/kg recipient weight. If no adequate single UCB unit to meet these criteria was available, study patients received 2 UCB units containing a combined cell dose exceeding 1.5 x 107/kg. Grafts were analyzed via flow cytometry post thaw for stem cell and lymphocyte expression of surface antigens, among them CD4, CD8, CD7, CD34, CD38, CD45RA, CD45RO. 23 patients have been enrolled, the majority diagnosed with AML (n=17). Median age was 47 (range 25–68) years. Single UCB units meeting stated criteria were identified for all but one study patient, who was excluded from graft analysis. The time to engraftment was measured from the date of transplantation to the date of 3 successive days ANC≥500/μL attained. In addition, we assessed time to peripheral blood donor lymphocyte chimerism ≥ 60%. Patients were censored at the date of last follow-up or the date of death. 94% (95%CI: 77-.99%) of patients achieved ANC≥500/μL by T+36 with median of 26.5 ( range 11–55) days. 68% (95%CI: 48–85%) of patients (n=15) achieved 〉60% donor derived chimerism by median of 22 (range 14–35) days. Median cryopreserved and infused total nucleated cell dose was 2.85 x 107 and 2.5 x 107 cells/kg, respectively. Median infused CD34 cell dose was 1.71 (range 0.21–5.39) x 105 cells/kg. By univariate analysis the dose of infused UCB graft T-cells including CD4 and CD8 T-cells co-expressing CD45RO, and CD34 stem cells co-expressing CD7 and CD38 correlated with neutrophil recovery, p=0.046, 0.008, and 0.033, respectively. Median overall survival at this early interim analysis has not been reached; with 86% and 65% survival at 3 and 24 months, respectively. Event free survival is 78% and 44.5% at 3 and 24 months, respectively. In summary, in this heavily pretreated group of advanced age patients, RIC and single unit unrelated allogeneic UCB stem cell transplantation is safe. Identification of a single UCB graft of HLA match 4/6 meeting cell dose requirement 2.5x107/kg is identified in the vast majority of full size adult patients. Engraftment and survival rates are higher than reported in single UCB transplants following administration of myeloablative regimens and similar to recent reports for RIC with double UCB graft infusion. The potential benefit of infusion of 1 vs. 2 UCB units after RIC in adult patients remains to be fully evaluated.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 3
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    Cytokine Production and Proliferation in Mixed Lymphocyte Culture (MLC) May Predict Donor Engraftment in Adult Recipients of Multiple Umbilical Cord Blood (UCB) Unit Transplantation. (2004)
    American Society of Hematology
    Details
    Publication Date: 2004-11-16
    Description: Limited cell dose within a single UCB graft provides the rationale for multiple UCB unit transplantation. Our single institution phase I study testing the safety and efficacy of multiple UCB unit infusion targeted a nucleated cell dose of minimum ≥ 5x107cells/kg, and patients were transplanted with 3-5 unrelated UCB units. Seven adult patients (median 56 years; range 20–69) with advanced hematologic malignancies (4 AML, 1 ALL, 2 NHL) were enrolled and treated with non-myelablative conditioning including Fludarabine 150mg/m2, Cyclophosphamide 2gm/m2, and ATGAM 60mg/kg. UCB grafts were not T-depleted. All UCB units were 1-2 HLA antigen mismatched with the patient, and HLA matching between units was not required. The patients were transplanted sequentially and received a median infused total nucleated cell dose: 5.4x107/kg (range 4.2–8.9), CD3+: 1.4x107/kg (range 1.4–3.4), and CD34+: 2.2x105/kg (range 1.9–5.3). Three of the 7 patients demonstrated UCB donor engraftment while 3 patients had autologous recovery, and one patient died prior to engraftment (day=56). Mixed lymphocyte culture (MLC) was performed including proliferation and cytokine production in order to evaluate impact of graft-graft and patient-graft immune reactivity on donor engraftment. Cryogenically preserved pre-transplant patient and corresponding UCB graft samples were thawed for MLC with readouts including proliferation (CFSE staining) and cytokine production (cytometric bead assay-CBA)(Becton Dickinson, Franklin Lakes, NJ) including pro-inflammatory TH1 cytokines (IFN-γ, TNF-α, IL-2) and anti-inflammatory TH2 cytokines (IL-10, IL-5, IL-4). We hypothesize that increased proliferation and a strong TH1 response may be detrimental to engraftment which was confirmed by preliminary analysis (n=4). We observed higher rates of proliferation as well as higher TH1 cytokine production within the MLC of patients who did not attain donor engraftment. Table 1: TH1 Cytokine Output and Proliferation of Patient and Graft Mixed Lymphocyte Cultures Patient Number Number of UCB Units Donor Engraftment IFNγ(pg/mL) TNFα (pg/mL) IL-2(pg/mL) % Proliferation Pt #1 5 No 940 226 79 16 Pt #2 3 No 234 56 46 20 Pt #3 3 Yes 32
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 4
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    Umbilical Cord Blood Derived CD133+ Hematopoietic Stem Cells Are Defective Antigen Presenting Cells (APC), Lack Expression of Co-Stimulatory Receptors, and Generate TH2 T-Lymphocyte Responses In Vitro. (2006)
    American Society of Hematology
    Details
    Publication Date: 2006-11-16
    Description: Early clinical studies have demonstrated benefit in patients receiving cellular therapy utilizing bone marrow derived (BM)-CD133+ hematopoietic stem cells (HSC) for treatment of cardiovascular disease. Umbilical cord blood (UCB) is a potential source of CD133+ cells for use as an allogeneic cell source for therapeutic angiogenesis, however, the benefits must be weighed against potential adverse immunologic responses. We tested the hypothesis that allogeneic CD133+ cells derived from UCB may be defective as professional antigen-presenting-cells (APC) and thus may mediate TH2 T-cell immune response. CD133+ cells were isolated from UCB mononuclear cells (MNC) by magnetic autoMACs bead selection (Miltenyi Biotech, Auburn CA) and analyzed for purity and surface expression of MHC and co-stimulatory antigens by flow cytometry. We have demonstrated induced immune reactivity by mixed lymphocyte reactions (MLR) using healthy adult peripheral blood MNC as responders stimulated by irradiated CD133+ from UCB and BM (ratio 3:1) with both 3H-thymidine and CFSE staining. Surface expression of both MHC class I (57.6±17.2%) and MHC class II (66.5±12.5%) are present on the majority of UCB CD133+ cells. To test the ability of CD133+ cells to function as APC, a modified MLR was performed. Briefly, isolated UCB CD133+ cells were cultured for 96h in the presence of adult peripheral blood (AB) derived-MNC or isolated CD3 AB T-cells as responders at a 3:1 ratio (responder:effector) in RPMI 1640 supplemented with 10% FBS and 1% L-glutamine. CD133+ cells induced proliferation in both non-selected AB MNC (21.7±6.4e3cpm) and selected AB T-cell (85.6±15.1e3 cpm) cultures as measured by 3H-thymidine incorporation. UCB CD133+ cells were noted to lack surface expression of co-stimulatory antigens including: CD40 (0.93±1.0%), CD80 (0.85±0.15%), and CD86 (0.88±0.64%). Because primary T-cell receptor stimulation in the absence of a co-stimulatory response is known to induce TH2 responses we compared UCB MNC and CD133+ derived from the same unit as stimulators for responding HLA mismatched allogeneic AB MNC. Preliminary results demonstrate elevated levels of IL-4 and IL-10 produced by responder AB MNC stimulated by CD133+ cells as compared to UCB MNC, with measured increases of 964±538pg/mL (IL-10) and 141±45.7pg/mL (IL-4). In conclusion, though CD133+ cells derived from UCB express both MHC class I and II they lack surface expression of co-stimulatory receptors, and are defective as professional APC. Additionally, UCB CD133+ cells induce elevated levels of IL-4 and IL-10 by responding allogeneic adult MNC in modified mixed lymphocyte in vitro cultures. MNC stimulation by selected UCB CD133+ cells elicit elevated levels of tolerance-associated cytokines IL-4 and IL-10 as compared to UCB MNC used as stimulator cells. Taken together, UCB CD133 lack co-stimulatory receptor expression and elicit TH2 T-lymphocyte responses, and may allow for immune tolerance responses when used as a source of allogeneic stem cells for therapeutic use in vasculogenesis.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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