title: Tryptophan metabolite analog, N-(3,4-dimethoxycinnamonyl) anthranilic acid, ameliorates acute graft-versus-host disease through regulating T cell proliferation and polarization.
abstract: 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 200mg/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.
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Jinhuan
authors.initials: J
authors.lastname: Xu
authors.forename: Jia
authors.initials: J
authors.lastname: Wei
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Xianmin
authors.initials: X
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Guan
authors.forename: Jin
authors.initials: J
authors.lastname: Yin
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiao
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007420:Intestine, Large / Q000187:drug effects / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D007737:Kynurenine / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012867:Skin / Q000187:drug effects / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014364:Tryptophan / Q000097:blood; D062367:ortho-Aminobenzoates / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; C587351:N-(3',4'-dimethoxycinnamonyl)anthranilic acid; D062367:ortho-Aminobenzoates; D007737:Kynurenine; D014364:Tryptophan
keywords: Acute graft-versus-host disease; Cytokine; Indoleamine 2,3-dioxygenases; N-(3,4-dimethoxycinnamonyl) anthranilic acid; T cell