Kidney transplant patients treated with belatacept-based regimens without depletional induction have higher rates of costimulation blockade resistant rejection (CoBRR). In contrast, belatacept effectively prevents rejection when used following T cell depletion. We longitudinally monitored T cell repertoires in 40 patients who received kidney allografts from living (n=30) or deceased (n=10) donors under alemtuzumab depletion followed by a belatacept and rapamycin maintenance regimen (ABR). Ten patients treated with non-depletional induction and a calcineurin inhibitor-based regimen were used as comparators. Using polychromatic flow cytometry, the phenotype of reconstituting T cells was assessed every 6 months for 36 months focusing specifically on markers of T cell proliferation, maturation, and costimulation. Alemtuzumab induction produced profound lymphopenia, evoking substantial homeostatic T cell proliferation characterized by increased intracellular Ki67 expression (p<0.05). Depleted patients were enriched significantly with naïve (CCR7⁺CD45RA⁺, CD57^–PD1^–, CD28⁺) CD4⁺ and CD8⁺ T cells compared to baseline (p<0.05). Alemtuzumab induction significantly reduced T cell subsets associated with belatacept resistance including CD8⁺CD2^hiCD28^–, CD4⁺CD28⁺CCR7^–CD45RA^–, and CD4⁺CD57⁺PD1^– cells when compared with baseline (p<0.05). The CD8⁺CD2^hiCD28⁺ and CD4⁺CD2^hiCD28⁺ subsets were also significantly decreased (p<0.05), and a reduced effector memory compartment (CCR7^–CD45RA^–) in CD8⁺CD2^hiCD28⁺ subset was observed post-depletion when compared with baseline (p<0.05). Control patients had no significant changes in their repertoire over the follow-up period. In summary, ABR regimen effectively prevents the repopulation of belatacept-resistant T cell subsets, and the de novo priming of reconstituted T cells results in proliferation of predominantly CD28⁺ naïve cells that are susceptible to belatacept. Our results demonstrate that alemtuzumab depletion followed by belatacept and rapamycin maintenance alters the immune profile of the recipient, producing a peripheral repertoire that is naïve, CD28⁺ and thus conceptually more conducive to control with belatacept-based therapy. This regimen warrants formal, prospective, comparative study.

CITATION INFORMATION: Gao Q., Mehta A., Guasch A., Stempora L., Kirk A., Xu H. Emergence of a Costimulation-Susceptible T Cell Repertoire Post-Alemtuzumab Induction Am J Transplant. 2017;17 (suppl 3).

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