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Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients.
Am J Transplant. 2016 Feb; 16(2):550-64.AJ

Abstract

Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation-resistant T cells. In this study, we report control of costimulation-resistant rejection when belatacept was combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, belatacept and rapamycin (ABR) regimen controls belatacept-resistant rejection, we studied 20 ABR-treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third-party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester-based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28(+) naïve cells, notably diminished in belatacept-resistant CD28(-) memory subsets and depleted of polyfunctional donor-specific T cells but able to respond to third-party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets-changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28(+) T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy.

Authors+Show Affiliations

Department of Surgery, Duke University School of Medicine, Durham, NC.Department of Surgery, Duke University School of Medicine, Durham, NC.Emory Transplant Center, Emory University, Atlanta, GA.Emory Transplant Center, Emory University, Atlanta, GA.Emory Transplant Center, Emory University, Atlanta, GA.Emory Transplant Center, Emory University, Atlanta, GA.Department of Surgery, Duke University School of Medicine, Durham, NC.Department of Surgery, Duke University School of Medicine, Durham, NC. Emory Transplant Center, Emory University, Atlanta, GA.

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

26436448

Citation

Xu, H, et al. "Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients." American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, vol. 16, no. 2, 2016, pp. 550-64.
Xu H, Samy KP, Guasch A, et al. Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients. Am J Transplant. 2016;16(2):550-64.
Xu, H., Samy, K. P., Guasch, A., Mead, S. I., Ghali, A., Mehta, A., Stempora, L., & Kirk, A. D. (2016). Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 16(2), 550-64. https://doi.org/10.1111/ajt.13469
Xu H, et al. Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients. Am J Transplant. 2016;16(2):550-64. PubMed PMID: 26436448.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients. AU - Xu,H, AU - Samy,K P, AU - Guasch,A, AU - Mead,S I, AU - Ghali,A, AU - Mehta,A, AU - Stempora,L, AU - Kirk,A D, Y1 - 2015/10/05/ PY - 2015/05/08/received PY - 2015/07/09/revised PY - 2015/07/17/accepted PY - 2015/10/6/entrez PY - 2015/10/6/pubmed PY - 2016/11/12/medline KW - basic (laboratory) research / science KW - clinical research / practice KW - fusion proteins and monoclonal antibodies: alemtuzumab KW - fusion proteins and monoclonal antibodies: belatacept KW - immune regulation KW - immunobiology KW - immunosuppressant KW - immunosuppression / immune modulation KW - kidney transplantation / nephrology KW - lymphocyte biology: differentiation / maturation KW - mechanistic target of rapamycin (mTOR) SP - 550 EP - 64 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 - 16 IS - 2 N2 - Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation-resistant T cells. In this study, we report control of costimulation-resistant rejection when belatacept was combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, belatacept and rapamycin (ABR) regimen controls belatacept-resistant rejection, we studied 20 ABR-treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third-party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester-based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28(+) naïve cells, notably diminished in belatacept-resistant CD28(-) memory subsets and depleted of polyfunctional donor-specific T cells but able to respond to third-party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets-changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28(+) T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy. SN - 1600-6143 UR - https://www.unboundmedicine.com/medline/citation/26436448/Postdepletion_Lymphocyte_Reconstitution_During_Belatacept_and_Rapamycin_Treatment_in_Kidney_Transplant_Recipients_ L2 - https://doi.org/10.1111/ajt.13469 DB - PRIME DP - Unbound Medicine ER -