We reported that alemtuzumab induction followed by belatacept-sirolimus based immunosuppression effectively prevents costimulation blockade resistant rejection (CoBRR). This study investigates the phenotypic characteristics of repopulating T cells post-depletion, specifically examining recent thymic emigrants (RTEs) and T cells from the mesentery.

The T cell repopulation of 20 patients treated with alemtuzumab induction followed by a belatacept/sirolimus based regimen was analyzed for 36 months post-transplantation by flow cytometry. The CD4⁺ and CD8⁺ RTEs were defined as CD31 expressing cells, while mesenteric T cells were characterized by surface expression of CD103. Naïve and memory phenotypes were defined using CCR7/CD45RA as follows: T_C (CCR7⁺CD45RA^–), T_naive (CCR7⁺CD45RA⁺), T_EMRA (CCR7^–CD45RA⁺), and T_EM (CCR7^–CD45RA^–).

Lymphocyte depletion was achieved post-transplantation using alemtuzumab induction. A significant increase of CD4⁺ RTEs (43±23 to 72±26.4%, p=0.0001) during post-depletion homeostatic proliferation was observed when compared to baseline levels (28.69±12.75%); the phenotype of these RTEs was primarily T_naive cells. In contrast, non-RTE CD4⁺ cells were significantly reduced post-transplantation (p=0.0001). Prior to transplant, CD8⁺ cells were predominantly CD31⁺ (77.73±9.7%) characterized largely as T_EMRA (33.5±14.2%) and T_EM cells (31.95±13.17%). The frequency of CD31⁺CD8⁺ cells increased above baseline significantly post-transplantation (82.2±23.7 to 90.8±10.5%); this persisted 36 months. Initially, CD8⁺CD31⁺ cells were largely T_EMRA cells in the first 2 months. However, thereafter T_naive cells increased as the predominant subset (p=0.0074). In contrast, the frequency of CD8⁺CD31⁺ T_EM cells were reduced (p=0.007). Unlike RTEs, CD4⁺CD103⁺ and CD8⁺CD103⁺ cells were resistant to depletional induction and had increased during early repopulation returning to baseline levels by 6 months post-transplant. However, a large proportion of CD8⁺CD103⁺ cells were T_naive cells during repopulation.

In summary, patients treated with alemtuzumab induction followed by belatacept/sirolimus maintenance immunosuppression demonstrate remarkable CD31⁺ RTEs repopulation primarily of T_naive cells. Although mesenteric T cells appear to be resistant to depletional induction, the CD8⁺CD103⁺ cells are largely T_naive cells. This unique repertoire of RTEs are CD28+ and thus may be sensitive targets for belatacept in controlling the CoBRR after depletional induction.

CITATION INFORMATION: Bendersky V, Xu H, Kirk A. Evaluating T Cell Repopulation Post Alemtuzumab Induction with a Belatacept-Based Regimen. Am J Transplant. 2017;17 (suppl 3).

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