IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection.

Published

Journal Article

Kidney transplant patients treated with belatacept without depletional induction experience higher rates of acute rejection compared to patients treated with conventional immunosuppression. Costimulation blockade-resistant rejection (CoBRR) is associated with terminally differentiated T cells. Alemtuzumab induction and belatacept/sirolimus immunotherapy effectively prevent CoBRR. We hypothesized that cells in late phases of differentiation would be selectively less capable than more naive phenotypes of repopulating postdepletion, providing a potential mechanism by which lymphocyte depletion and repopulation could reduce the risk of CoBRR. Lymphocytes from 20 recipients undergoing alemtuzumab-induced depletion and belatacept/sirolimus immunosuppression were studied longitudinally for markers of maturation (CCR7, CD45RA, CD57, PD1), recent thymic emigration (CD31), and the IL-7 receptor-α (IL-7Rα). Serum was analyzed for IL-7. Alemtuzumab induction produced profound lymphopenia followed by repopulation, during which naive IL-7Rα+ CD57- PD1- cells progressively became the predominant subset. This did not occur in a comparator group of 10 patients treated with conventional immunosuppression. Serum from depleted patients showed markedly elevated IL-7 levels posttransplantation. Sorted CD57- PD1- cells demonstrated robust proliferation in response to IL-7, whereas more differentiated cells proliferated poorly. These data suggest that differences in IL-7-dependent proliferation is one exploitable mechanism that distinguishes CoB-sensitive and CoB-resistant T cell populations to reduce the risk of CoBRR. (ClinicalTrials.gov - NCT00565773.).

Full Text

Duke Authors

Cited Authors

  • Xu, H; Bendersky, VA; Brennan, TV; Espinosa, JR; Kirk, AD

Published Date

  • March 2018

Published In

Volume / Issue

  • 18 / 3

Start / End Page

  • 720 - 730

PubMed ID

  • 29136317

Pubmed Central ID

  • 29136317

Electronic International Standard Serial Number (EISSN)

  • 1600-6143

Digital Object Identifier (DOI)

  • 10.1111/ajt.14589

Language

  • eng

Conference Location

  • United States