Belatacept‐Resistant Rejection Is Associated With CD28+ Memory CD8 T Cells. Issue 9 (11th July 2017)

• Record Type: Journal Article
• Authors: Mathews, D. V.; Wakwe, W. C.; Kim, S. C.; Lowe, M. C.; Breeden, C.; Roberts, M. E.; Farris, A. B.; Strobert, E. A.; Jenkins, J. B.; Larsen, C. P.; Ford, M. L.; Townsend, R.; Adams, A. B.
• Is Part Of: American journal of transplantation. Volume 17:Issue 9(2017)
• Page Start: 2285
• Page End: 2299
• Publication Date: 2017-07-11
• Subjects: basic (laboratory) research/science -- immunosuppression/immune modulation -- immunobiology -- animal models: nonhuman primate -- costimulation -- immunosuppressant -- fusion proteins and monoclonal antibodies: belatacept -- fusion proteins and monoclonal antibodies: costimulation molecule specific -- rejection: T cell mediated (TCMR); Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.14349
• Languages: English
• ISSNs: 1600-6135

Abstract

Abstract : Recently, newer therapies have been designed to more specifically target rejection in an effort to improve efficacy and limit unwanted toxicity. Belatacept, a CD28‐CD80/86 specific reagent, is associated with superior patient survival and graft function compared with traditional therapy, but its adoption as a mainstay immunosuppressive therapy has been tempered by increased rejection rates. It is essential that the underlying mechanisms associated with this rejection be elucidated before belatacept is more widely used. To that end, we designed a study in a nonhuman primate kidney transplant model where animals were treated with either a belatacept‐ or a tacrolimus‐based immunosuppressive regimen. Interestingly, we found that elevated pretransplant frequencies of CD28 + CD8 + TEMRA cells are associated with rejection on belatacept but not tacrolimus treatment. Further analysis showed that the CD28 + CD8 + TEMRA cells rapidly lose CD28 expression after transplant in those animals that go on to reject with the allograft infiltrate being predominantly CD28 − . These data suggest that CD28 + memory T cells may be resistant to belatacept, capable of further differentiation including loss of CD28 expression while maintaining effector function. The unique signaling requirements of CD28 + memory T cells provide opportunities for the development of targeted therapies, which may synergize with belatacept to prevent costimulation‐independent rejection. Abstract : This study identifies increased frequency of CD28+ memory T cells as a pretransplant predictor of belatacept‐ resistant rejection in a nonhuman primate renal transplant model. See the companion article by Cortes‐Cerisuelo et al (page 2350 ) and an editorial by Wekerle (page 2235 ).