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.
Highlights
Despite advances made over the past few decades in immunosuppressive protocols for transplantation, acute rejection remains a challenge for transplant recipients
We demonstrate the efficacy of this combination therapy in prolonging skin allograft survival and investigate its effects on T cell numbers, cellular and humoral anti-donor responses, and expression of cell surface CD3 that contribute to its efficacy
Identification of an induction therapy that abrogates antigen specific T cell responses In order to identify a potent induction therapy that could selectively inhibit T cell responses, we developed a unique invivo approach using adoptively transferred Carboxyfluorescein diacetate succinimidyl ester (CFSE) labeled OT-II transgenic (Tg) T cells to evaluate the effects of different immune interventions on the antigen-reactive T cells as well as on the nonreactive CD4+ T cells in the WT C57BL/6 recipients (Figure 1A)
Summary
Despite advances made over the past few decades in immunosuppressive protocols for transplantation, acute rejection remains a challenge for transplant recipients. T cells play a major role in acute rejection serving as effectors of cellular rejection and helping B-cells produce antibodies responsible for humoral rejection For this reason, many induction therapies and immunosuppressive regimens have targeted components of the T cell activation process [3]. Surface molecules on T cells like the TCR, CD28, and lymphocyte function-associated antigen (LFA1) engage molecules such as peptide-MHC, CD80/86, and intercellular adhesion molecule (ICAM1), respectively, on APCs forming the surface connection between the two cell types [4] These surface molecules are associated with intracellular molecules such as adaptor proteins, kinases, and cytoskeletal components to propagate the surface signals into the full T cell activation cascade [5]. We demonstrate the efficacy of this combination therapy in prolonging skin allograft survival and investigate its effects on T cell numbers, cellular and humoral anti-donor responses, and expression of cell surface CD3 (a critical TCR signaling component) that contribute to its efficacy
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