The role of intracellular antigen processing for the induction of a selective graft-versus-leukemia effect without graft versus host disease

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Allogeneic stem cell transplantation is often the only curative treatment for patients with hematological malignancies. The replacement of the patient`s hematopoietic system by a healthy donor graft allows an immunological response of donor derived T-lymphocytes against residual malignant cells of the patient thereby leading to long-lasting remissions. This immune response, however, is not selectively directed against malignant patient cells, but may also attack and damage healthy non-hematopoietic cells of the patient leading to detrimental graft-versus-host disease. This side effect is often difficult to treat and is still the major cause for morbidity and mortality after allogeneic stem cell transplantation. A concerted separation of graft-versus-leukemia effect and graft-versus-host disease is so far not possible. One possibility to separate these two effects is to exploit CD4+ T-cells, since HLA class II molecules are only expressed on the hematopoietic system. However, during inflammation and cytokine release non-hematopoietic cells can also up-regulate HLA class II molecules. Recently, we could show that there are two subgroups of HLA class II restricted antigens. One group of antigens is presented on all HLA class II expressing cells and is independent of the expression of the non-classical HLA class II molecule HLA-DM. These antigens are called DM-resistant. The presentation of the other group of antigens is abolished by HLA-DM and only reconstituted by co-expression of HLA-DO. Those antigens are called DM-sensitive. Similar to the classical HLA class II molecules expression of HLA-DM is induced by cytokines such as interferon -gamma. HLA-DO in contrast is not up-reguated by inflammatory cytokines. Therefore, CD4+ T-cells directed against DM-sensitive antigens may allow induction of a selective graft-versus-leukemia effect without graft-versus-host disease. The first aim of this project is to analyze whether DM-sensitive antigens are capable of inducing a potent primary and secondary immune response in vivo. Further, we will investigate their potential in mediating graft-versus-tumor effect as well as the incidence of graft-versus-host disease as compared to DM-resistant antigens. On the long run this project should lay the basis for treating patients with hematological malignancies that undergo allogeneic stem cell transplantation with additional CD4+ donor lymphocytes directed against DM-sensitive antigens in order to induce a more potent anti-tumor immune response with reduced risk for graft-versus-host disease.