The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model.
T cell Ig mucin 1 (TIM-1) plays an important role in regulating immune responses in autoimmune and asthma models, and it is expressed on both Th1 and Th2 cells. Using an antagonistic TIM-1-specific antibody, we studied the role of TIM-1 in alloimmunity. A short course of TIM-1-specific antibody monotherapy prolonged survival of fully MHC-mismatched vascularized mouse cardiac allografts. This prolongation was associated with inhibition of alloreactive Th1 responses and preservation of Th2 responses. TIM-1-specific antibody treatment was more effective in Th1-type cytokine-deficient Stat4(-/-) recipients as compared with Th2-type cytokine-deficient Stat6(-/-) recipients. Subtherapeutic doses of rapamycin plus TIM-1-specific antibody resulted in allograft acceptance and prevented the development of chronic allograft vasculopathy. Allograft survival via this treatment was accompanied by a Th1- to Th2-type cytokine switch. Depletion of natural Tregs abrogated the graft-protecting effect of the TIM-1-specific antibody. Importantly, CD4(+)CD25(+) Tregs obtained from long-term survivors had enhanced regulatory activity as compared with naive CD4(+)CD25(+) Tregs. Consistent with this, TIM-1-specific antibody treatment both preserved Tregs and prevented the expansion of alloreactive effector Th1 cells in an alloreactive TCR transgenic adoptive transfer model. These studies define previously unknown functions of TIM-1 in regulating alloimmune responses in vivo and may provide a novel approach to promoting transplantation tolerance.
Ueno
Takuya
T
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Habicht
Antje
A
Clarkson
Michael R
MR
Albin
Monica J
MJ
Yamaura
Kazuhiro
K
Boenisch
Olaf
O
Popoola
Joyce
J
Wang
Ying
Y
Yagita
Hideo
H
Akiba
Hisaya
H
Ansari
M Javeed
MJ
Yang
Jaeseok
J
Turka
Laurence A
LA
Rothstein
David M
DM
Padera
Robert F
RF
Najafian
Nader
N
Sayegh
Mohamed H
MH
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D000072596:Hepatitis A Virus Cellular Receptor 1; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008212:Lymphocyte Depletion; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D020123:Sirolimus / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology*
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D016207:Cytokines; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D020123:Sirolimus