Outcomes in transplantation have been limited by suboptimal long-term graft survival and toxicities associated with current immunosuppressive approaches. T cell costimulation blockade has shown promise as an alternative strategy to avoid the side effects of conventional immunosuppressive therapies, but targeting CD28-mediated costimulation alone has proven insufficient to prevent graft rejection in primates. Donor-specific memory T (TM) cells have been implicated in costimulation blockade–resistant transplant rejection, due to their enhanced effector function and decreased reliance on costimulatory signaling. Thus, we have tested a potential strategy to overcome TM cell–driven rejection by targeting molecules preferentially expressed on these cells, such as the adhesion molecule lymphocyte function–associated antigen 1 (LFA-1). Here, we show that short-term treatment (i.e., induction therapy) with the LFA-1–specific antibody TS-1/22 in combination with either basiliximab (an IL-2Rα–specific mAb) and sirolimus (a mammalian target of rapamycin inhibitor) or belatacept (a high-affinity variant of the CD28 costimulation–blocker CTLA4Ig) prolonged islet allograft survival in nonhuman primates relative to control treatments. Moreover, TS-1/22 masked LFA-1 on TM cells in vivo and inhibited the generation of alloproliferative and cytokine-producing effector T cells that expressed high levels of LFA-1 in vitro. These results support the use of LFA-1–specific induction therapy to neutralize costimulation blockade–resistant populations of T cells and further evaluation of LFA-1–specific therapeutics for use in transplantation.
Idelberto R. Badell, Maria C. Russell, Peter W. Thompson, Alexandra P. Turner, Tim A. Weaver, Jennifer M. Robertson, Jose G. Avila, Jose A. Cano, Brandi E. Johnson, Mingqing Song, Frank V. Leopardi, Sarah Swygert, Elizabeth A. Strobert, Mandy L. Ford, Allan D. Kirk, Christian P. Larsen
Combined LFA-1/CD28 blockade extends islet allograft survival.