Belatacept-based maintenance regimens prevent acute allograft rejection following alemtuzumab induction, and patients so treated maintain intact anti-CMV and -EBV T cell immune responses without viral reaction posttransplantation. However, a transient BK viremia is detected in ~50% patients within the first year, suggesting impaired BK-specific immunity. We therefore investigated the BKV-specific T cell responses posttransplantation in patients receiving this novel regimen (n=7). Peripheral blood mononuclear cells (PBMC) collected from patients were stimulated with BK VP1, VP2, and large T antigen peptide pools and CMV-pp65 peptides followed by intracellular cytokine staining (ICCS) to detect cytokine producers (TNF-α and IFN-γ), and the cytokine producers were interrogated for markers of memory (CCR7/CD45RA classification) and costimulation (CD28). Alemtuzumab induction lead to profound lymphocyte depletion, and the repopulation of CD4+ cells was particularly delayed. 6 of 7 patients demonstrated cytokine-producing CD4⁺ (TNF-α⁺IFN-γ⁺ 0.312±0.16%, TNF-α⁺IFN-γ^– 0.685±0.425%) and CD8⁺ cells (TNF-α⁺IFN-γ⁺ 0.024±0.008%, TNF-α⁺IFN-γ^– 0.714±0.593%) after viral peptide stimulation. CMV-specific T cells demonstrated upregulation of TNF-α⁺IFN-γ⁺ (CD4⁺ cells 1.35±0.94%, CD8⁺ cells 0.55±0.22%) and TNF-α⁺IFN-γ^– (CD4⁺ cells 1.093±0.669%, CD8⁺ cells 0.124±0.048%) production. A large fraction of BKV-specific CD8⁺ cells was negative for CD28. In contrast, CD4⁺ cells demonstrated low frequency of CD28⁺ cells in TNF-α⁺IFN-γ⁺ (42.6±12%) or TNF-α⁺IFN-γ^– (32.3±9.2%) producers. The dual and single cytokine producers were largely memory cells (CCR7⁺CD45RA^–, CCR7^–CD45RA⁺, CCR7^–CD45RA^–) which were similar to CMV-specific cytokine producers after viral peptide stimulation. In summary, anti-BKV T cell responses in patients with transient BK viremia after undergoing depletional induction and belatacept-based maintenance immunosuppression remain active post- repopulation. Unlike CD4⁺ BKV specific cells, CD8⁺ BKV-specific cells are phenotypically memory cells that lack costimulatory molecule CD28 expression. These data suggest that BK reactivation is directly associated with depletional induction, rather than being a specific effect of belatacept, and following repopulation, BKV specific protective immunity remains intact.

CITATION INFORMATION: McRae M, How T, Kirk A, Xu H. Evaluating Posttransplant BKV-Specific T Cell Responses in Patients with Alemtuzumab Induction and Belatacept-Based Regimen. Am J Transplant. 2016;16 (suppl 3).

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