The Allo- and Viral-Specific Immunosuppressive Effect of Belatacept, but Not Tacrolimus, Attenuates With Progressive T Cell Maturation

• Type of Material: Article
• Authors: H. Xu, Emory University; Sebastian Perez, Emory University; J. Cheeseman, Emory University; Aneesh Mehta, Emory University; Allan Kirk, Emory University
• Language: English
• Date: 2014-02-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2014 The American Society of Transplantation and the American Society of Transplant Surgeons.
• Final Published Version (URL): http://dx.doi.org/10.1111/ajt.12574
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 14
• Issue: 2
• Start Page: 319
• End Page: 332
• Grant/Funding Information: This work was funded in part by grants from the US Food and Drug Administration (1R01 FD003539-01; ADK), the National Institutes of Health (1R01 AI097423; ADK), the Georgia Research Alliance, and the Roche Organ Transplant Research Foundation grant (346678023; HX).
• Keywords: Transplantation; Surgery; DIFFERENTIATION; Science & Technology; cytomegalovirus; BLOCKADE; DISEASE; Life Sciences & Biomedicine; T cell maturation; calcineurin inhibitor; ALLOGRAFT SURVIVAL; memory T cells; VIRUS; Belatacept; IMMUNITY; costimulation blockade
• Research Categories: Health Sciences, General; Health Sciences, Medicine and Surgery

Abstract

Tacrolimus impairs allo- and viral-specific T cell responses. Belatacept, a costimulation-based alternative to tacrolimus, has emerged with a paradoxical picture of less complete control of alloimmunity with concomitant impaired viral immunity limited to viral-naïve patients. To reconcile these signatures, bulk population and purified memory and naïve lymphocytes from cytomegalovirus (CMV)-seropositive (n = 10) and CMV-seronegative (n = 10) volunteers were studied using flow cytometry, interrogating proliferation (carboxyfluorescein succinimidyl ester dilution) and function (intracellular cytokine staining) in response to alloantigens or CMV-pp-65 peptides. As anticipated, T cells from CMV-experienced, but not naïve, individuals responded to pp-65 with a small percentage of their repertoire (<2.5%) consisting predominantly of mature, polyfunctional (expressing interferon gamma, tumor necrosis factor alpha and IL-2) T effector memory cells. Both CMV naïve and experienced individuals responded similarly to alloantigen with a substantially larger percentage of the repertoire (up to 48.2%) containing proportionately fewer polyfunctional cells. Tacrolimus completely inhibited responses of CMV- and allo-specific T cells regardless of their maturation. However, belatacept's effects were decreasingly evident in increasingly matured cells, with minimal effect on viral-specific triple cytokine producers and CD28-negative allo-specific cells. These data indicate that belatacept's immunosuppressive effect, unlike tacrolimus's, wanes on progressively developed effector responses, and may explain the observed clinical effects of belatacept. The authors characterize CMV- and allo-specific memory T cells and show that belatacept has decreasing inhibitory effect on increasingly matured memory cells, and minimal effect on the most highly differentiated CMV- and allo-specific cells.