Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment option for patients with high-risk leukemia and lymphoma and for certain inherited or acquired hematopoietic deficiencies. Around half a million transplantations have been performed to date and approximately 30 million voluntary stem cell donors are currently registered world-wide. The curative potential of allo-HSCT is based on the replace¬ment of the patient´s hematopoiesis by hematopoietic stem cells derived from a healthy donor and the immunologic eradication of residual patient hematopoietic cells by co-transplanted lymphocytes. This graft-versus-hematopoiesis reaction is mainly mediated by alloreactive donor T cells that also attack malignant hematopoietic cells, thereby evoking potent graft-versus-leukemia / lymphoma (GvL) effects. Although allo-HSCT offers a unique chance to rescue patients with otherwise incurable hematologic malignancies, still around one quarter of allo-HSCT recipients develop disease relapse or progression after transplantation. Thus, there is an urgent need to better understand and ultimately strengthen GvL responses to prevent tumor escape. Yet, donor T cells can also attack solid organs, a transplant complication called graft-versus-host disease (GvHD) that can become life-threatening and in its acute form mainly affects skin, liver and gut. Therefore, it is the central goal of the TRR 221 to elucidate the immunological mechanisms of GvL and GvHD responses to increase the efficacy of allo-HSCT without increasing the risk for GvHD.To achieve this goal scientists of project area A analyzed new molecular targets and cellular pathways (e.g. T cell receptor & chimeric antigen receptor transfer, multifunctional antibodies, minor histocompatibility antigen-specific T cells) to augment GvL responses and assessed them in in vivo models (wherever reasonable) during the first funding period. In project area B involved scientists examined basic pathomechanisms of GvH-reactivity and develop new strategies for the prevention and/or therapy of this transplant complication. Here, the specific modulation of T cell signal transduction pathways is explored, regulatory molecular and cellular networks within innate and adaptive immune compartments are examined as well as GvHD-promoting co-factors, such as inflammatory pathways and microbiome alterations. Strategies aimed to strengthen GvL effects are always tested for their influence on GvHD and vice versa. The most promising strategies evolving from these studies shall be tested in future clinical trials to ultimately improve the safety and efficacy of allo-HSCT significantly.
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