LFA-1 Antagonism Inhibits Early Infiltration of Endogenous Memory CD8 T Cells into Cardiac Allografts and Donor-Reactive T Cell Priming

Abstract

Alloreactive memory T cells are present in virtually all transplant recipients due to prior sensitization or heterologous immunity and mediate injury undermining graft outcome. In mouse models, endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts and produce IFN-γ in response to donor class I MHC within 24 hours post-transplant. The current studies analyzed the efficacy of anti-LFA-1 mAb to inhibit early CD8 T cell cardiac allograft infiltration and activation. Anti-LFA-1 mAb given to C57BL/6 6 (H-2b) recipients of A/J (H-2a) heart grafts on days −1 and 0 completely inhibited CD8 T cell allograft infiltration, markedly decreased neutrophil infiltration, and significantly reduced intra-graft expression levels of IFN-γ-induced genes. Donor-specific T cells producing IFN-γ were at low/undetectable numbers in spleens of anti-LFA-1 mAb treated recipients until day 21. These effects combined to promote substantial prolongation (from day 8 to 27) in allograft survival. Delaying anti-LFA-1 mAb treatment until days 3 and 4 post-transplant did not inhibit early memory CD8 T cell infiltration and proliferation within the allograft. These data indicate that peri-transplant anti-LFA-1 mAb inhibits early donor-reactive memory CD8 T cell allograft infiltration and inflammation suggesting an effective strategy to attenuate the negative effects of heterologous immunity in transplant recipients.

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

“…This notion is supported by a recent report assessing the ability of LFA-1 to inhibit T-cell trafficking into allografts. 40 However, work in nonhuman primates revealed that treatment with anti-LFA-1 and rapamycin resulted in long-term graft-survival of islet allografts even after discontinuation of all immunosuppression. 34 This discrepancy may be explained by the stringency of the model system used in these studies.…”

Cognate antigen directs CD8+ T cell migration to vascularized transplants

“…According to this paradigm, chemokines displayed on the inflamed endothelium engage Gα i -coupled chemokine receptors on rolling T cells and trigger their firm adhesion and transmigration via integrin-dependent mechanisms (7). Although blocking integrins has been shown to reduce T cell infiltration and delay graft rejection (8,9), targeting individual or multiple chemokine receptors has had modest or no effects (10)(11)(12). This prompted us to reexamine the role of Gα i -coupled chemokine receptors in the migration of effector and memory T cells to vascularized organ transplants.…”

Transplantation Tolerance: Memories That Haunt Us

“…Alternatively, designing new therapeutics to inhibit donor-reactive memory T cell responses would allow transplantation even between donor and recipient pairs with unfavorable memory T cell precursor frequencies. Recent studies in both mouse and nonhuman primate models have suggested that targeting adhesion molecules such as CD2 or LFA-1 can inhibit gra rejection mediated by donor-reactive memory T cells (22)(23)(24). Although agents speci cally targeting these molecules are currently FDA approved for the treatment of plaque psoriasis (25,26), the e cacy of these therapeutics in inhibiting memory T cell-mediated gra rejection in humans remains to be tested in more extensive phase II and III clinical trials (27,28).…”