Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells.
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.
Division of Hematology and Oncology, Department of Medicine, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
Anne-Kathrin
AK
Hechinger
Kristina
K
Maas
Christoph
C
Dürr
Franziska
F
Leonhardt
Gabriele
G
Prinz
Reinhard
R
Marks
Ulrike
U
Gerlach
Maike
M
Hofmann
Paul
P
Fisch
Jürgen
J
Finke
Hanspeter
H
Pircher
Robert
R
Zeiser
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054876:Prenylation / Q000187:drug effects / Q000502:physiology*; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology*; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D015363:Quinolones; C402769:tipifarnib