Transient Combination Therapy Targeting the Immune Synapse Abrogates T Cell Responses and Prolongs Allograft Survival in Mice

Abstract

T cells play a major role in allograft rejection, which occurs after T cell activation by the engagement of several functional molecules to form an immune synapse with alloantigen presenting cells. In this study, the immune synapse was targeted using mAbs directed to the TCR beta-chain (TCRβ) and lymphocyte function-associated antigen−1 (LFA1) to induce long-term allograft survival. Evaluation of antigen-specific T cell responses was performed by adoptively transferring CFSE labeled transgenic OT-II cells into wild-type mice and providing OVA peptide by intravenous injection. Graft survival studies were performed in mice by transplanting BALB/c ear skins onto the flanks of C57BL/6 recipients. The anti-TCRβ plus anti-LFA1 mAb combination (but not either mAb alone) abrogated antigen-specific T cell responses invitro and invivo. Transient combination therapy with these agents resulted in significantly prolonged skin allograft survival in mice (51±10 days; p<0.01) when compared to treatment with either anti-TCRβ mAb (24±5 days) or anti-LFA1 mAb (19±3 days) alone or no treatment (10±1 days). When lymphoid tissues from these mice were analyzed at different times post-transplant, only those receiving the combination of anti-TCRβ and anti-LFA1 mAbs demonstrated long-lasting reductions in total T cell numbers, cellular and humoral anti-donor responses, and expression of CD3 on the surface of T cells. These results demonstrate that transient anti-TCRβ and anti-LFA1 mAb combination therapy abrogates antigen-reactive T cell responses with long-lasting effects that significantly prolong allograft survival.

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

“…[65][66][67][68] In light of the intriguing recent finding that during selection in thymopoiesis asymmetric death is the key determinant of the CD4/CD8 ratio, it seems reasonable to assume intrinsically disparate cascades of transcriptional regulators and programming segregating the CD4 versus the CD8 lineage in their susceptibilies to activation, anergy and death. 69 In summary, here we demonstrate the efficient and selective depletion of activated αβT cells both in vitro and in vivo with the novel, humanized mAb GZ-αβTCR-targeting human αβTCR.…”

PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCRβ mAb therapy

“…Previous work has demonstrated the effectiveness of anti-TCRβ therapy, both alone and in combination with other treatments, in abrogating alloimmune T cell responses in order to prolong allograft survival in mice [24,25]. Unlike the effects in C57BL/6 allograft models, in which anti-TCRβ caused a broad depletion of CD4 + and CD8 + T cells [25], treatment with anti-TCRβ in NOD mice led to only limited Fig.…”

“…A number of anti-TCR mAbs have also been tested for prolonging allograft survival, including clones T10B9 [22] and BMA031 [23] in humans and H57-597 in mice [24].…”