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Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells.


ABSTRACT: The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80/86 and CD154-CD40) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-co-stimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation.

SUBMITTER: Yuan X 

PROVIDER: S-EPMC2705547 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells.

Yuan Xueli X   Ansari M Javeed MJ   D'Addio Francesca F   Paez-Cortez Jesus J   Schmitt Isabella I   Donnarumma Michela M   Boenisch Olaf O   Zhao Xiaozhi X   Popoola Joyce J   Clarkson Michael R MR   Yagita Hideo H   Akiba Hisaya H   Freeman Gordon J GJ   Iacomini John J   Turka Laurence A LA   Glimcher Laurie H LH   Sayegh Mohamed H MH  

Proceedings of the National Academy of Sciences of the United States of America 20090615 26


The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-t  ...[more]

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