Belatacept offers highly specific costimulation blockade to prevent recipient alloimmune responses with reduced toxicity. However, when applied with nondepletional induction therapy belatacept-based regimens have higher rates of acute rejection (AR). We have recently reported favorably low AR rates when using alemtuzumab depletion followed by belatacept-sirolimus based therapy, and now present mechanistic analysis from this trial. Using polychromatic flow cytometry, we longitudinally characterized the phenotype of reconstituting lymphocytes from 20 patients, and assessed their functional responses to donor-specific, third-party, and viral antigens using intracellular cytokine staining and CFSE-based lymphocyte proliferation assays. Ten patients treated with non-depletional induction and calcineurin inhibitor (CNI)-based regimen were used as controls. Lymphocyte reconstitution post-depletion ensued through a burst of homeostatic T-cell activation (CD69+, CD38+/HLA-DR+) and proliferation (Ki67+) that was not seen in non-depleted patients. Following reconstitution, depleted patients were enriched for naïve T (CCR7+CD45RA+) and B cell (CD27-IgD+) subsets and had reduced memory compartments and diminished belatacept-resistant CD2hiCD28- T-cell subsets. Control patients had no significant changes in repertoire over the follow-up period. The allo-specific triple-cytokine (TNF-α/IFN-γ/IL-2) producing memory T cells in patients treated with alemtuzumab demonstrated hyporesponsiveness to donor-specific but not third-party alloantigens, with intact protective responses against CMV and EBV. The de novo priming of reconstituted naïve T cells resulted in proliferation of predominantly CD28 expressing T cells that were susceptible to belatacept. These 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.

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