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: Jinhuan Xu, Jia Wei, Min Huang, Xianmin Zhu, Jun Guan, Jin Yin, Yi Xiao, Yicheng Zhang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 17 Issue 3 Pg. 601-7 (Nov 2013) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 23993943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Cytokines
• N-(3',4'-dimethoxycinnamonyl)anthranilic acid
• ortho-Aminobenzoates
• Kynurenine
• Tryptophan

Topics

• Animals
• Bone Marrow Transplantation
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cell Proliferation (drug effects)
• Cytokines (blood)
• Female
• Graft vs Host Disease (drug therapy, immunology, pathology)
• Intestine, Large (drug effects, pathology)
• Intestine, Small (drug effects, pathology)
• Kynurenine (blood)
• Liver (drug effects, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Skin (drug effects, pathology)
• T-Lymphocytes, Regulatory (drug effects, immunology)
• Tryptophan (blood)
• ortho-Aminobenzoates (pharmacology, therapeutic use)