Novel mechanism of rapamycin in GVHD: increase in interstitial regulatory T cells.
Rapamycin (RAPA) is an immunosuppressive drug that prevents and treats graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT). One possible mechanism for its efficacy is induction of tolerance, through increased number or enhanced survival of regulatory T cells. In our experiments, B10.D2 BM and splenocytes were injected into lethally irradiated BALB/cJ recipients. The mice received i.p. injections of either RAPA or vehicle control on days 1-28. There was a significant survival advantage in RAPA-treated mice. Evaluation of the skin biopsies showed a dense cellular infiltrate in RAPA-treated mice. Further characterization of these cells revealed a higher percentage of regulatory T cells characterized by FoxP3-positive cells in high-dose RAPA-treated mice as compared with controls on day 30. This effect appears to be dose dependent. When peripheral blood analysis for FoxP3-positive cells was performed, there was no significant difference observed in the RAPA-treated mice as compared with control mice. These data show a novel mechanism of rapamycin in GVHD, accumulation of regulatory T cells in the GVHD target tissue: the skin.
Palmer
J M
JM
Division of Cellular Therapy, BMT Duke University Medical Center, Durham, NC, USA. jpalmer@mcw.edu
Chen
B J
BJ
DeOliveira
D
D
Le
N-D
ND
Chao
N J
NJ
D000818:Animals; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D007422:Intestines / Q000276:immunology; D008099:Liver / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D020123:Sirolimus / Q000627:therapeutic use*; D012867:Skin / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020123:Sirolimus