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.
Bibliographical noteFunding Information:
This work was supported by funding from Bristol-Myers Squibb, Non-Human Primate Transplant Tolerance Cooperative Study Group, NIH grant U19AI051731 and NIH grant P51OD11132 in support of Yerkes. DM was supported by NIH F30DK109665. WCW was supported by ASTS Fellowship. This work was also supported by National Institute of Diabetes and Digestive and Kidney DiseasesF30DK109665 and National Institute of Allergy and Infectious DiseasesU19AI051731 The authors would like to thank all collaborators at the Emory Transplant Center and at the Yerkes Primate Research Center, especially all veterinary technicians and pathology lab staff, as well as all collaborators at Bristol Myers-Squibb.
- animal models: nonhuman primate
- basic (laboratory) research/science
- fusion proteins and monoclonal antibodies: belatacept
- fusion proteins and monoclonal antibodies: costimulation molecule specific
- immunosuppression/immune modulation
- rejection: T cell mediated (TCMR)