Purpose: Costimulation blockade prolongs graft survival but does not induce tolerance in primates, and mechanisms of rejection are incompletely understood. Here we evaluate changes in the proportion of naïve, central memory, and effector memory T cell populations over time in a non-human primate (NHP) transplant model in the context of αCD28 or αCD40 immunomodulation.

Methods: Cynomolgus heterotopic (intraabdominal) cardiac transplant recipients were treated with either αCD28 (FR104, n=7) or αCD40 (2C10R4, n=5) for 90 days. Primary graft survival was defined by diminished pulse pressure or a drop in heart rate (by telemetry), and confirmed by histology. Peripheral blood CD4⁺ and CD8⁺ T cells were categorized as naïve (N: CD45RA⁺CD62L⁺ or CD95^–CD62L⁺ phenotype), central memory (CM: CD45RA^–CD62L⁺ or CD95⁺CD62L⁺), or effector memory (EM: CD45RA^+/-CD62L^– or CD95^+/-CD62L^–).

Results: Survival of grafts treated with αCD28 (median 164 days, 50 –179) or αCD40 (median 124 days, 89 –178) monotherapy was similar. CM CD4⁺ and CD8⁺ T cells were a low proportion and exhibited minimal changes in these treatment groups. Two EM distribution patterns were found at baseline, with either a low (n=4, CD45RA^+/-CD62L^–; mean: 38.5%, SD±4.6) or high (n=8, CD45RA^+/-CD62L^–; 69.5%±8.9; p=0.004) proportion of EM among CD3⁺CD8⁺ T cells. The proportion of T cell subsets was similar whether phenotyping was based on CD45RA or CD95. No correlation was observed between baseline CD8⁺ EM proportion and graft survival. The proportion of CD8⁺ EM increased significantly from baseline (56.5%±16.9) to time of rejection (73.4%±12.5; p=0.002) across all drugs and profiles, leading to a consistently inverted EM/N ratio a few weeks before rejection. Additionally, CD8⁺CD28^– T cell populations increased at time of rejection in 3 NHPs in the αCD28 cohort.

Conclusions: CD8⁺ effector T cells significantly increased before graft rejection. Specifically targeting this “escape” mechanism of co-stimulation independent effector T cells may help promote tolerance in transplantation.

CITATION INFORMATION: O'Neill N, Zhang T, Braileanu G, Sun W, Cheng X, Evans C, Pierson R, Azimzadeh A. Profiling of T Cell Subsets in a Primate Cardiac Transplant Model. Am J Transplant. 2016;16 (suppl 3).

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