Tryptophan metabolite analog, N-(3,4-dimethoxycinnamonyl) anthranilic acid, ameliorates acute graft-versus-host disease through regulating T cell proliferation and polarization

摘要

Local catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. N-(3,4-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is an active synthetic anthranilic acid derivative which was proved to be effective to treat type1helper T lymphocyte (Th1) mediated autoimmune diseases such as multiple sclerosis. In this report, we investigated the effects of 3,4-DAA on the acute graft versus host disease (aGVHD) following allogeneic bone marrow transplantation (allo-BMT) and its potential mechanism of action. We established a murine aGVHD model, 3,4-DAA was injected intraperitoneally at 200 mg/kg/day per mouse immediately after allo-BMT or at the onset of aGVHD for 14 consecutive days; the signs of aGVHD and the survival were recorded periodically. We revealed that administration of 3,4-DAA after allo-BMT significantly reduced the severity and the histological score of aGVHD; the survival for mice receiving 3,4-DAA prophylaxis and treatment was prolonged in comparison to the vehicle control mice. The plasma levels of IFN-γ, TNF-α, IL-12 and IL-2 in 3,4-DAA treatment group were found to be decreased, while the IDO activity, CD4+/CD25+ Treg cells, and the IL-10, IL-5 and IL-4 levels elevated in these mice. In consistent with the in vivo results, 3,4-DAA also inhibited IFN-γ and IL-2 production of spleen T lymphocytes in vitro. Our findings suggest that 3,4-DAA can diminish the murine experimental aGVHD through regulating T cell proliferation and polarization; this property makes it a potential alternative agent for prevention and treatment of GVHD in the clinic.