Transplant patients treated with belatacept without depletional induction show high rates of costimulation blockade resistant rejection (CoBRR); this has been associated with CD57+ T cells. In contrast, alemtuzumab induction effectively prevents CoBRR, particular when belatacept is used with sirolimus. We sought to examine the presence of CD57+ cells in depleted patients compared with non-depleted patients and to identify a potential mechanism by which depletion eliminates CoBRR. PBMCs collected from 20 kidney recipients that received alemtuzumab depletion and belatacept/sirolimus maintenance regimen and 10 patients treated with conventional regimen were FACS analyzed for markers of maturation (CCR7, CD45RA), senescence (CD57), exhaustion (PD1), and IL-7 receptor (IL-7R). Serum was analyzed for IL-7 by ELISA. Proliferation of purified CD57-PD1- and CD57+ and/or PD1+ cells in response to IL-7 was determined by intra-vital dye dilution measured by FACS. Profound lymphocyte depletion was observed post alemtuzumab induction. The depletion-resistant cells were effector (CCR7-CD45RA-) or terminally differentiated effector memory (CCR7-CD45RA+) cells. During homeostatic reconstitution, the CD4+ and CD8+ CD57-PD1- cells became the predominant subset characterized as naïve cells (CCR7+CD45RA+) expressing IL-7R. In contrast, patients treated with conventional regimen did not show expansion of CD57-PD1- cells. CD57-PD1- cells demonstrated robust proliferation in response to IL-7 (CD4+ cells, 77.5±10.5%; CD8+ cells, 95.3±3.8%), while CD57+ and/or PD1+ cells proliferated poorly in response to IL-7 (CD4+ cells: 10.1±3.3%; CD8+ cells, 6.4±3%; p<0.0001). Accordingly, CD57-PD1- cells were verified to express higher IL-7R than CD57+ and/or PD1+ cells (p<0.05). Preoperatively, patient serum demonstrated barely detectable IL-7. In contrast, serum IL-7 levels were increased significant (p<0.009) within 12 months post-depletion. In summary, patients receiving alemtuzumab induction and a belatacept/sirolimus regimen demonstrate increased IL-7 production and repopulate with predominantly CD57^–PD1^– naïve cells expressing the IL-7R, a change not seen in conventionally treated patients. As CD57+ cells lack the IL-7 receptor, this may provide costimulation sensitive CD57^–PD1^– naïve cells with a selective advantage during homeostatic repopulation and lead to a post depletional repertoire that is more easily controlled with belatacept.

CITATION INFORMATION: Xu H, Brennan T, Kirk A. IL-7 Receptor Heterogeneity as a Mechanism for Repertoire Change During Post-Depletional Homeostatic Proliferation and Its Relation to Costimulation Blockade Resistant Rejection. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress