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IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection.
Am J Transplant. 2018 03; 18(3):720-730.AJ

Abstract

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.).

Authors+Show Affiliations

Department of Surgery, Duke University Medical Center, Durham, NC, USA.Department of Surgery, Duke University Medical Center, Durham, NC, USA.Department of Surgery, Duke University Medical Center, Durham, NC, USA.Department of Surgery, Duke University Medical Center, Durham, NC, USA.Department of Surgery, Duke University Medical Center, Durham, NC, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

29136317

Citation

Xu, He, et al. "IL-7 Receptor Heterogeneity as a Mechanism for Repertoire Change During Postdepletional Homeostatic Proliferation and Its Relation to Costimulation Blockade-resistant Rejection." American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, vol. 18, no. 3, 2018, pp. 720-730.
Xu H, Bendersky VA, Brennan TV, et al. IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection. Am J Transplant. 2018;18(3):720-730.
Xu, H., Bendersky, V. A., Brennan, T. V., Espinosa, J. R., & Kirk, A. D. (2018). IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 18(3), 720-730. https://doi.org/10.1111/ajt.14589
Xu H, et al. IL-7 Receptor Heterogeneity as a Mechanism for Repertoire Change During Postdepletional Homeostatic Proliferation and Its Relation to Costimulation Blockade-resistant Rejection. Am J Transplant. 2018;18(3):720-730. PubMed PMID: 29136317.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection. AU - Xu,He, AU - Bendersky,Victoria A, AU - Brennan,Todd V, AU - Espinosa,Jaclyn R, AU - Kirk,Allan D, Y1 - 2017/12/12/ PY - 2017/06/09/received PY - 2017/10/08/revised PY - 2017/11/04/accepted PY - 2017/11/15/pubmed PY - 2019/11/13/medline PY - 2017/11/15/entrez KW - basic (laboratory) research/science KW - clinical research/practice KW - cytokines/cytokine receptors KW - immunobiology KW - immunosuppressant - fusion proteins and monoclonal antibodies: belatacept KW - immunosuppressant - mechanistic target of rapamycin: sirolimus KW - immunosuppression/immune modulation KW - immunosuppressive regimens - induction KW - kidney transplantation/nephrology KW - lymphocyte biology: differentiation/maturation SP - 720 EP - 730 JF - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons JO - Am. J. Transplant. VL - 18 IS - 3 N2 - 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.). SN - 1600-6143 UR - https://www.unboundmedicine.com/medline/citation/29136317/IL_7_receptor_heterogeneity_as_a_mechanism_for_repertoire_change_during_postdepletional_homeostatic_proliferation_and_its_relation_to_costimulation_blockade_resistant_rejection_ L2 - https://doi.org/10.1111/ajt.14589 DB - PRIME DP - Unbound Medicine ER -