Project Details
Projekt
Human cytomegalovirus-mediated modulation of leukemia and its immune control by donor T cell alloreactivity to HLA-DPB1 after hematopoietic stem cell transplantation
Subject Area
Hematology, Oncology
Virology
Virology
Term
from 2019 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 423291167
Human cytomegalovirus (HCMV) is a prototypical β-herpesvirus with important clinical relevance, especially for immunosuppressed patients like individuals receiving allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy for leukemia. In this setting, HCMV reactivation has been shown to impact both immune reconstitution and the risk of developing graft versus host disease (GvHD) or relapse after transplantation. Three novel, mutually non-exclusive hypotheses to explain these clinical observations will be explored during the proposed project, through the synergistic effort of the two PIs who will contribute their complementary expertise in the immunobiology of HSCT and cytomegaloviruses, respectively: 1) Heterologous immunity by HCMV-specific CD4+ T cell receptors (TCR) cross-recognizing HLA-DPB1 alloantigens (mainly PI Fleischhauer). HCMV-specific and HLA-DPB1 alloreactive CD4+ T cell cultures will be independently obtained from donors of HLA-DPB1-mismatched unrelated HSCT at UK-Essen. Their TCR CDR3 sequences will be determined by next generation sequencing. TCR with identical CDR3 sequences identified in both cultures are indicative of heterologous immunity and will be longitudinally traced in the patient with or without acute GvHD or leukemia relapse after transplantation. 2) HCMV-encoded proteins modulating the immunogenicity of allogeneic HLA-DPB1 (PI Fleischhauer and Trilling). An available library of expression vectors covering the canonical HCMV proteins will be introduced individually into single HLA-DP expressing model cell lines, to test the gene-specific impact on allorecognition by HLA-DPB1-specific CD4+ T cells. Identified candidate genes will be characterized concerning their effects on HLA-DPB1 expression and processing upon ectopic expression as well as in the context of HCMV infection. 3) Cellular and viral determinants of the HCMV-induced impairment of leukemic cell proliferation (mainly PI Trilling). To identify and characterize the mediators of previously observed anti-proliferative effects elicited by inactivated HCMV particles on acute myeoloid leukemia (AML) cells, a series of biochemical and immunological assays as well as inhibition studies will be conducted to test the hypothesis that HCMV triggers a suicidal innate immune response after contact with AML cells, and to identify the responsible factors. Together, the new insights into the immunobiology of T cell alloreactivity, HCMV and leukemia expected from this project will have potential translational implications in cellular therapy.
DFG Programme
Research Grants
