CTLA4Ig combined with anti-LFA-1 prolongs cardiac allograft survival indefinitely

LFA-1 blockade induces effector and regulatory T-cell enrichment in lymph nodes and synergizes with CTLA-4Ig to inhibit effector function

“…As discussed in the Introduction, blockade of the LFA-1 pathway has been shown to synergize with blockade of the CD28 pathway in experimental models of BM and solid organ transplantation 30,32 (supplemental Figure 1, available on the Blood Web site; see the Supplemental Materials link at the top of the online article). To determine the mechanisms by which LFA-1 blockade might impair alloreactive immune responses in vivo, we analyzed the LN and blood cellular composition before and after inhibition of LFA-1/ ICAM interactions during transplantation ( Figure 1A).…”

“…Previous studies in experimental models of both BM and solid organ transplantation have demonstrated variable results using anti-LFA-1 mAbs, both alone and in combination with other reagents. [25][26][27][28][29][30][31] Anti-LFA-1 synergized with CTLA-4 Ig in increasing survival and reducing the severity of GVHD after murine BM transplantation. 32 Anti-LFA-1 also resulted in significant prolongation in graft survival in a fully allogeneic model of cardiac transplantation in nonhuman primates.…”

LFA-1–specific therapy prolongs allograft survival in rhesus macaques

“…In mice, the mechanisms of costimulation blockade resistance have been shown to involve discreet populations of non-memory CD8 + T cells (28,29), with graft survival requiring CD8 + T cell deletion in some instances (30). In fact, the use of antibodies against LFA-1 to complement costimulatory regimens has proven effective in these systems (29,31,32), validating the use of LFA-1-specific agents to address unengaged targets like resistant CD8 + T cells.…”

Donor CD4 T Cells Trigger Costimulation Blockade-Resistant Donor Bone Marrow Rejection Through Bystander Activation Requiring IL-6

“…Both mammalian target of rapamycin inhibition with rapamycin (32,33) and LFA blockade with anti-LFA-1 have been shown to act synergistically with costimulation blockade (34). Notably, we recently found that rapamycin or anti-LFA-1 can control rejection in BMT recipients enriched with donorreactive Tmem (23).…”