Ex vivo rapamycin generates donor Th2 cells that potently inhibit graft-versus-host disease and graft-versus-tumor effects via an IL-4-dependent mechanism.
Rapamycin (sirolimus) inhibits graft-vs-host disease (GVHD) and polarizes T cells toward Th2 cytokine secretion after allogeneic bone marrow transplantation (BMT). Therefore, we reasoned that ex vivo rapamycin might enhance the generation of donor Th2 cells capable of preventing GVHD after fully MHC-disparate murine BMT. Using anti-CD3 and anti-CD28 costimulation, CD4+ Th2 cell expansion was preserved partially in high-dose rapamycin (10 microM; Th2.rapa cells). Th2.rapa cells secreted IL-4 yet had reduced IL-5, IL-10, and IL-13 secretion relative to control Th2 cells. BMT cohorts receiving wild-type (WT) Th2.rapa cells, but not Th2.rapa cells generated from IL-4-deficient (knockout) donors, had marked Th2 skewing post-BMT and greatly reduced donor anti-host T cell alloreactivity. Histologic studies demonstrated that Th2.rapa cell recipients had near complete abrogation of skin, liver, and gut GVHD. Overall survival in recipients of WT Th2.rapa cells, but not IL-4 knockout Th2.rapa cells, was constrained due to marked attenuation of an allogeneic graft-vs-tumor (GVT) effect against host-type breast cancer cells. Delay in Th2.rapa cell administration until day 4, 7, or 14 post-BMT enhanced GVT effects, moderated GVHD, and improved overall survival. Therefore, ex vivo rapamycin generates enhanced donor Th2 cells for attempts to balance GVHD and GVT effects.
Foley
Jason E
JE
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jung
Unsu
U
Miera
Angel
A
Borenstein
Todd
T
Mariotti
Jacopo
J
Eckhaus
Michael
M
Bierer
Barbara E
BE
Fowler
Daniel H
DH
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D006086:Graft vs Host Disease / Q000517:prevention & control*; D020350:Graft vs Tumor Effect / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects / Q000502:physiology*; D014019:Tissue Donors
D007166:Immunosuppressive Agents; D015847:Interleukin-4; D020123:Sirolimus