In the Collaborative Research Centre Transregio 221 scientists of the Universities and the University Hospitals Regensburg, Erlangen and Würzburg search for innovative immunotherapeutic methods to significantly improve allogeneic hematopoietic stem-cell transplantation. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment option for patients with high-risk leukemia and lymphoma and for some inherited or acquired hematopoietic deficiencies. Around half a million transplantations have been performed to date and approximately 28 million voluntary stem cell donors are currently registered world-wide. The curative potential of allo-HSCT is based on the replacement 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 and affects also 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. However, GvL-promoting strategies carry the inherent risk of inducing graft-versus-host disease (GvHD), where donor T cells attack and damage non-hematopoietic tissues. The efficient prevention and treatment of severe GvHD is a pivotal prerequisite to benefit from allo-HSCT and its potent GvL effects. Hence, the elucidation of basic mechanisms in tissue-directed graft-versus-host responses is essential to reduce the high treatment-related morbidity and mortality in allo-HSCT. GvHD-free allo-HSCT is then an ideal immunotherapy platform to boost GvL responses for the cure of patients, including those with residual disease or relapse after transplantation. [...]