Journal
TRANSPLANTATION
Volume 93, Issue 10, Pages 997-1005Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/TP.0b013e31824e75d7
Keywords
Costimulatory blockade; Memory T cells; Integrins; LFA-1; Heterologous immunity
Categories
Funding
- US National Institutes of Health [R01 AI073707, R56 AI081789]
- Roche Organ Transplant Research Foundation
- Roche Laboratories from the American Society of Transplant Surgeons
- NIH [T32AI070081-05]
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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 naive 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.
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