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Characterisation of pathogenic memory T and B cells prior to and after transplantation

Prof. Volk (first supervisor), Prof. Radbruch (second supervisor), Prof. Sawitzki (Mentor); Charité and DRFZ

Achieving long-term, drug-free graft acceptance is still an unsolved problem in clinical transplantation. Barriers to transplantation tolerance are a specific immune memory already acquired in adult human patients and heterologous immunity. Preformed allo-specific and bystander memory T and B cells are thought to elicit or boost acute rejections early after transplantation. Early elimination of pathogenic memory T and B cells should decrease the frequency of acute rejections and thereby contribute to improved long term graft function. Furthermore, a specific elimination of these cells would also enable inclusion of high risk patients into tolerance induction or drug weaning protocols and subsequently allow a better in vivo performance of e.g. transferred regulatory T cells. So far, there are no treatment options which enable specific elimination of pathogenic memory T cells. Furthermore, there exist only little information about their generation, survival and their pathogenesis.
In an ongoing clinical trial we have examined peripheral CD4+ and CD8+ T cell subpopulations in samples of liver transplant patients prior to and at frequent intervals after transplantation. We analysed the frequency of regulatory T cells (CD25highCD127low), naïve T cells (CD45RO-CD62L+) and memory populations (central memory, effector memory, TEMRA. Interestingly, we detected a significantly elevated frequency of CD4+CD45RO-CD62L- terminal differentiated effector memory T cells (TEMRA) prior to and early after transplantation in patients developing acute rejections within the first 6 months after transplantation.
Following these initial results we have initiated a project in which we use a global gene profiling approach to determine selective mRNA expression pattern of surface molecules in CD4+CD45RO-CD62L- TEMRA cells we intend to identify new targets for a specific elimination of such pathogenic memory T cells. Once we have identified such targets their therapeutic potential will be later tested using in vitro and in vivo assays (humanized mouse).
Within the project we also want to determine the stability and antigen specificity of CD4+ TEMRA cells. In order to better understand the generation, survival and effector function of pathogeneic memory T and B cells, additional studies in experimental rat kidney transplant models (acute and chronic cellular and humoral rejections) will accompany the experiments on human samples.

References
Sawitzki B, Reinke P, Volk HD, Wood K, Turka LA. Autoimmunity and transplantation: a meeting at the crossroads in Berlin. Nat Immunol. 2008;9:447-9.

Kreijveld E, Koenen HJ, van Cranenbroek B, van Rijssen E, Joosten I, Hilbrands LB. Immunological monitoring of renal transplant recipients to predict acute allograft rejection following the discontinuation of tacrolimus. PLoS One. 2008;3:e2711.