Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells |
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| Authors: | Anne-Kathrin Hechinger Kristina Maas Christoph Dürr Franziska Leonhardt Gabriele Prinz Reinhard Marks Ulrike Gerlach Maike Hofmann Paul Fisch Jürgen Finke Hanspeter Pircher Robert Zeiser |
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| Institution: | 1.Division of Hematology and Oncology, Department of Medicine, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;2.Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany;3.Department of Pathology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;4.Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Germany;5.BIOSS Centre for Biological Signaling Studies, Freiburg, Germany |
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| Abstract: | Despite advances in immunosuppressive regimens, acute graft-versus-host disease remains a frequent complication of allogeneic hematopoietic cell transplantation. Pathogenic donor T cells are dependent on correct attachment of small GTPases to the cell membrane, mediated by farnesyl- or geranylgeranyl residues, which, therefore, constitute potential targets for graft-versus-host disease prophylaxis. A mouse model was used to study the impact of a farnesyl-transferase inhibitor and a geranylgeranyl-transferase inhibitor on acute graft-versus-host disease, anti-cytomegalovirus T-cell responses and graft-versus-leukemia activity. Treatment of mice undergoing allogeneic hematopoietic cell transplantation with farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor reduced the histological severity of graft-versus-host disease and prolonged survival significantly. Mechanistically, farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor treatment resulted in reduced alloantigen-driven expansion of CD4 T cells. In vivo treatment led to increased thymic cellularity and polyclonality of the T-cell receptor repertoire by reducing thymic graft-versus-host disease. These effects were absent when squalene production was blocked. The farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor did not compromise CD8 function against leukemia cells or reconstitution of T cells that were subsequently responsible for anti-murine cytomegalovirus responses. In summary, we observed an immunomodulatory effect of inhibitors of farnesyl-transferase and geranylgeranyl-transferase on graft-versus-host disease, with enhanced functional immune reconstitution. In the light of the modest toxicity of farnesyl-transferase inhibitors such as tipifarnib in patients and the potent reduction of graft-versus-host disease in mice, farnesyl-transferase and geranylgeranyl-transferase inhibitors could help to reduce graft-versus-host disease significantly without having a negative impact on immune reconstitution. |
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