Abstract:

BACKGROUND: In a DA (RT1a) to LEW (RT1l) rat model, inhibition of B7-CD28 co-stimulatory signal blockade by adenovirus-mediated cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (AdCTLA-4Ig) induces long-term acceptance of cardiac allografts. However, allograft tolerance is incomplete and rejection eventually occurs. In particular, donor-type skin grafting to recipients with functional cardiac allografts causes accelerated heart rejection. 
OBJECTIVE: To evaluate the combined effects of inducible co-stimulator (ICOS) therapy and AdCTLA-4Ig treatment on preventing accelerated cardiac rejection caused by donor-strain skin grafting and validate that ICOS therapy can block accelerated cardiac rejection, no matter with or without AdCTLA-4Ig treatment.
METHODS: DA hearts were transplanted into the abdominal cavity of LEW recipients. The recipients intravenously received a single dose of 109 plaque-forming units of AdCTLA-4Ig immediately after transplantation. Recipients with grafts surviving > 50 days were given a full-thickness donor-type skin graft to the lateral thoracic wall. These recipients received intravenous injection of anti-ICOS antibody (1 mg/kg) or control IgG from the 50th day, once every other day, for 2 weeks. Complete graft rejection was defined as cessation of beating and was histologically confirmed by mononuclear cell infiltration and cardiac myocyte necrosis using hematoxylin and eosin staining of graft sections.
RESULTS AND CONCLUSION: Cardiac sections of AdCTLA-4Ig-treated recipients surviving > 100 days showed typical ICOS-positive mononuclear cell infiltration and vasculopathy. AdCTLA-4Ig treatment combined with anti-ICOS therapy induced stable tolerance to chronic rejection. Anti-ICOS therapy significantly reduced ICOS-positive inflammatory cell infiltration, and prevented accelerated cardiac graft rejection following secondary skin grafting. These findings identify a critical role of ICOS in chronic and accelerated cardiac allograft rejection and suggest a novel approach to prevent chronic rejection of vascularized organ allografts.