Combined Costimulatory and Leukocyte Functional Antigen-1 Blockade Prevents Transplant Rejection Mediated by Heterologous Immune Memory Alloresponses

• Type of Material: Article
• Authors: Mandy Ford, Emory University; Mingqing Song, Emory University; William Kitchens Jr, Emory University; WH Kitchens, Emory University; D Haridas, Emory University; ME Wagener, Emory University
• Language: English
• Date: 2012-05-27
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Lippincott Williams & Wilkins, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1097/TP.0b013e31824e75d7
• Title of Journal or Parent Work: Transplantation
• ISSN: 0041-1337
• Volume: 93
• Issue: 10
• Start Page: 997
• End Page: 1005
• Grant/Funding Information: This work was supported by grants from the US National Institutes of Health (R01 AI073707 and R56 AI081789 to M.L.F.) and the Roche Organ Transplant Research Foundation. W.H.K. is supported by a Roche Laboratories Scientist scholarship from the American Society of Transplant Surgeons and an NIH training grant (T32AI070081-05).
• Keywords: CARDIAC ALLOGRAFT SURVIVAL; TERM GRAFT-SURVIVAL; LFA-1; Science & Technology; Life Sciences & Biomedicine; PHASE-III; Integrins; MONOCLONAL-ANTIBODIES; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; Costimulatory blockade; BONE-MARROW; INTERCELLULAR ADHESION MOLECULE-1; Surgery; Transplantation; IFN-GAMMA; MICE; Heterologous immunity; Memory T cells; T-CELL PROLIFERATION; Immunology
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background: Recent evidence suggests that alloreactive memory T cells are generated by the process of heterologous immunity, whereby memory T cells arising in response to pathogen infection crossreact with donor antigens. Because of their diminished requirements for costimulation during recall, these pathogen-elicited allocrossreactive memory T cells are of particular clinical importance, especially given the emergence of costimulatory blockade as a transplant immunosuppression strategy. Methods: We used an established model of heterologous immunity involving sequential infection of a naïve C57BL/6 recipient with lymphocytic choriomeningitis virus and vaccinia virus, followed by combined skin and bone marrow transplant from a BALB/c donor. Results: We demonstrate that coupling the integrin antagonist anti-leukocyte functional antigen (LFA)-1 with costimulatory blockade could surmount the barrier posed by heterologous immunity in a fully allogeneic murine transplant system. The combined costimulatory and integrin blockade regimen suppressed proliferation of alloreactive memory T cells and attenuated their cytokine effector responses. This combined blockade regimen also promoted the retention of FoxP3 + Tregs in draining lymph nodes. Finally, we show that in an in vitro mixed lymphocyte reaction system using human T cells, the combination of belatacept and anti-LFA-1 was able to suppress cytokine production by alloreactive memory T cells that was resistant to belatacept alone. Conclusions: As an antagonist against human LFA-1 exists and has been used clinically to treat psoriasis, these findings have significant translational potential for future clinical transplant trials. Copyright © 2012 Lippincott Williams & Wilkins.