Combined costimulatory and leukocyte functional antigen-1 blockade prevents transplant rejection mediated by heterologous immune memory alloresponses

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.