Recent studies have showed correlation between CD4⁺CD57⁺PD1^– cells and costimulation blockade resistant rejection (CoBRR) in patients treated with belatacept without depletional induction. We have recently reported that alemtuzumab induction and belatacept/ sirolimus-based maintenance effectively prevents CoBRR. We have therefore investigated the dynamics, phenotypes, and antigen specificity of reconstituting CD57⁺ cells in patients treated with this regimen. Peripheral blood mononuclear cells collected from 20 patients before and serially after transplantation were assessed by flow cytometry focused, specifically focusing on CD57 expressing T cells, interrogating markers of memory (CCR7/CD45RA classification) and differentiation (IL-7R, a receptor required for homeostatic repopulation). Cells collected from 9 patients were stimulated with specific donor antigens and analyzed by intracellular cytokine staining to detect dual (TNF-α/IFN-γ) cytokine producers. Early post-depletion, depletion-resistant T cells were characterized as being phenotypically memory cells (CCR7-CD45RA- effector and CCR7-CD45RA+ terminally differentiated effector memory cells), with CD57⁺ PD1^–, CD57⁺PD1⁺, and CD57^–PD1⁺ subsets present. However, as homeostatic repopulation occurred, this was almost exclusively CD4⁺ and CD8⁺ CD57^–PD1^– T cells. This produced a repopulating repertore enrisched for CD57^–PD1^– T cells (p<0.05). In contrast, patients treated with conventional immunosuppression did not show reduction of CD57⁺ cells posttransplantation. Interestingly, CD57^– but not CD57⁺ T cells were predominantly positive for IL7R, perhaps explaining the mechanism for CD57^– T cell selective expansion. Preoperatively, allospecific T cells (defined as dual cytokine producers following allostimulation) were predominantly memory cells characterized as being CD57+ and/or PD1+. The frequency of dual cytokine producers in these patients decreased posttransplantation commensurate with the emergence of a CD57^– repertoire. In summary, patients receiving alemtuzumab induction and belatacept/sirolimus-based immunosuppression demonstrate increased repopulating CD57^–PD1^– cells predominantly expressing IL-7R, a change not seen in conventionally treated patients. This unique repertoire enriched for CD57^–PD1^– cells may be permissive for control of costimulation blockade-resistant allograft rejection.

CITATION INFORMATION: Xu H, Feng F, Kirk A. Investigating Posttransplant Allo-Donor Specific CD57⁺ Cells in Patients with Alemtuzumab Induction and Belatacept-Based Regimen. Am J Transplant. 2016;16 (suppl 3).

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