The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model
Takuya Ueno, … , Nader Najafian, Mohamed H. Sayegh
Takuya Ueno, … , Nader Najafian, Mohamed H. Sayegh
Published January 2, 2008
Citation Information: J Clin Invest. 2008;118(2):742-751. https://doi.org/10.1172/JCI32451.
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Research Article

The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model

Abstract

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.

Authors

Takuya Ueno, Antje Habicht, Michael R. Clarkson, Monica J. Albin, Kazuhiro Yamaura, Olaf Boenisch, Joyce Popoola, Ying Wang, Hideo Yagita, Hisaya Akiba, M. Javeed Ansari, Jaeseok Yang, Laurence A. Turka, David M. Rothstein, Robert F. Padera, Nader Najafian, Mohamed H. Sayegh

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Figure 1

Prolongation of cardiac allograft survival by RMT1-10 is associated with a Th1-to-Th2 cytokine switch.

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Prolongation of cardiac allograft survival by RMT1-10 is associated with...
B6 hearts were transplanted into BALB/c wild-type, STAT4-, and STAT6-deficient recipients. (A) Treatment with RMT1-10 resulted in significant prolongation of allograft survival in wild-type recipients. (B) Both treated STAT4–/– and STAT6–/– recipients showed significant prolongation of graft survival compared with untreated mice. However, anti–TIM-1 mAb was significantly more effective in STAT4–/– mice. Using the ELISPOT assay, the frequency of cytokine-producing allospecific T cells was measured between days 10 and 12 after transplantation by stimulating splenocytes of BALB/c recipients of B6 heart allografts with irradiated B6 splenocytes. Administration of RMT1-10 decreased allospecific Th1 cytokines (C) and preserved the frequency of IL-5–producing alloreactive T cells (D). Data are representative of 3 independent experiments and indicate the mean of triplicate results in each experiment.