ALBERT

Description: Genetic polymorphisms of various donor and host genes have been found to be associated risk factors for graft versus host disease and transplant related mortality. Most of these genes are involved in the regulation of immune response and inflammatory reactions towards pathogens. The heme oxygenase (HO) protein is the rate limiting enzyme in heme degradation to biliverdin, free iron and carbon monoxide. Its inducible form I (HO-I) is constitutively expressed in the spleen due to the abundance of its substrate. It is inducible in a wide range of tissues upon exposure to cellular stress factors such as irradiation, bacterial lipopolysaccharide, proinflammatory cytokines and heat shock. Further, HO-I is involved in regulating inflammatory response and has been described as a “protective gene” in solid organ transplantation. In man the promoter region of HO-I displays length polymorphism due to a variable number of gt repeats within a 500bp region upstream of the TATA box. Individuals exhibiting 25 or less gt repeats express HO-I upon cellular stress at a higher level than individuals with more than 30 gt repeats. We retrospectively analysed length polymorphisms of 92 donor and host pairs undergoing allogeneic stem cell transplantation for various malignancies. We show here that donor promoter length polymorphism leading to low expression of HO-1 (〉30 gt repeats) is associated with improved overall survival, relative to donors with ≤ 30 repeats (80.6% versus 54.4%, p=0.023). When subgrouped, having HLA identical siblings as donors had no influence on outcome (see figure below, right panel) whereas having matched unrelated donors strongly influenced overall survival (82.6 vs. 44.2%, p=0.015). Combination of high HO-1 expressing unrelated donors and high expressing hosts displayed a 27.8% survival (left panel, solid line vs.81.3% for individuals with one allele 〉30 repeats dotted line). Polymorphisms of the recipient HO-1 genes did not influence outcome after transplantation. When matched unrelated donors were used, the incidence of grade III gut GvHD was significantly higher when (p=0.032) and overall GvHD (≥ grade III) displayed a trend towards significance (p=0.098). Transplant related mortality was strongly influenced by having a donor who expresses HO-1 at a high level upon cellular stress (p=0.006). In a multivariate Cox regression analysis of pretransplant factors such as age, disease stage, sibling/unrelated donor etc. polymorphism in the donor HO-1 gene had a significant influence on overall survival (p=0.027). These data suggest a role for HO-I in GvHD pathophysiology and a possible role for HO-1 as a non MHC risk factor for unrelated transplantation. Figure Figure

Description: DF is a polydisperse mixture of single-stranded polydeoxyribunucleotides which is successfully used in the treatment of hepatic veno-occlusive disease and other endothelial disorders. Recent pre-clinical evidence suggests that DF might also have anti-neoplastic properties. We addressed the question whether this might be due to the prevention of tumor blood vessel formation (angiogenesis). The anti-angiogeneic potential of DF was tested in vitro (Matrigel™ tube formation and aortic ring assay) and in vivo (dorsal skin-fold chamber model). Our results show that DF quantitatively (100%) blocks tube formation of trans-differentiated human endothelial-like cells (ELC) at concentrations corresponding to pharmacologic DF blood levels (100 μg/mL). Similarly, the sprouting of rat aorta endothelial cells in Matrigel™ was prevented by nearly 100%, when DF was applied on a daily basis. In vivo tumor angiogenesis in a human gastric cancer (TMK-1) grown in skin-fold chambers (nude mice) was also attenuated on day 5 by DF, as measured by microvascular density. Although the exact mechanism of DF action remains to be elucidated, initial Western blotting results show that DF reduces phosphorylation-activation of p70S6 kinase, which is a key target in the PI3K/Akt/mTOR signaling pathway linked to endothelial cell and pericyte proliferation and activation. Taken together, our data suggest that while DF is known for its endothelium-protecting function, it also inhibits tumor blood vessel formation, and thus should be considered for further testing as an anticancer agent.