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

Abstract

Despite encouraging results using lymphocyte function antigen-1 (LFA-1) blockade to inhibit BM and solid organ transplantation rejection in nonhuman primates and humans, the precise mechanisms underlying its therapeutic potential are still poorly understood. Using a fully allogeneic murine transplantation model, we assessed the relative distribution of total lymphocyte subsets in untreated versus anti-LFA-1-treated animals. Our results demonstrated a striking loss of naive T cells from peripheral lymph nodes, a concomitant gain in blood after LFA-1 blockade, and a shift in phenotype of the cells remaining in the node to a CD62L lo CD44 hi profile. We determined that this change was due to a specific enrichment of activated, graft-specific effectors in the peripheral lymph nodes of anti-LFA-1-treated mice compared with untreated controls, and not to a direct effect

LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3β Signaling–Dependent Notch Pathway

“…A number of previous in vitro, in vivo, and preclinical studies in patients with immune-mediated diseases clearly indicate LFA-1 involvement in modulating T cell functions, including activation and proliferation (34,35). LFA-1 blocking using humanized anti-LFA-1 Ab efalizumab (Raptiva), developed for the treatment of the autoimmune skin disease psoriasis, was found to induce a unique state of T cell hyporesponsiveness in terms of activation and proliferation (36).…”

IL-7 receptor blockade following T cell depletion promotes long-term allograft survival

“…Nevertheless, mouse skin allograft is a predictive preclinical model frequently used in the early phase of development of new immunosuppressive drugs in transplantation (42)(43)(44). The skin graft survival obtained in our study is remarkable because, without bone marrow transplantation, not many treatment protocols could result in similar graft outcomes, especially when fully allogeneic BALB/c and C57BL/6 mice are used for donors and recipients (43,44).…”

“…The skin graft survival obtained in our study is remarkable because, without bone marrow transplantation, not many treatment protocols could result in similar graft outcomes, especially when fully allogeneic BALB/c and C57BL/6 mice are used for donors and recipients (43,44). Therefore, our results suggest that IL-7R blockade may present as a promising therapeutic candidate in organ transplantation.…”

Leukocyte Function-associated Antigen-1/Intercellular Adhesion Molecule-1 Interaction Induces a Novel Genetic Signature Resulting in T-cells Refractory to Transforming Growth Factor-β Signaling

“…In particular, it remains to be established whether LFA-1/ICAM-1-mediated signaling in T-cells has a functional involvement in these processes. Recent data from trials of monoclonal antibodies directed against LFA-1 in humans, as well as data from animal models, suggest that such therapies are associated not only with inhibition of migration but also with broad perturbations in T-cell functions, including activation, proliferation, and differentiation (18,19).…”