P-189 Pegylated Arginase-1 Mediates Suppression of Mouse and Human CD4 T Cellsстатья из журнала
Аннотация: Accumulating evidence shows that myeloid-derived suppressor cells (MDSC) expand in chronic inflammatory settings, including inflammatory bowel diseases (IBD), and have potent suppressive effects on the T cells. MDSC are pathologically activated heterogeneous population of myeloid cells consisting of neutrophils, monocytes, and their precursors. Expansion of MDSC is thought to represent a homeostatic mechanism aimed at dampening chronic inflammation and attenuating collateral tissue damage. One of the mechanisms of T cell suppression used by MDSC is arginase-1-mediated depletion of nonessential amino acid L-arginine. Because T cells with enhanced reactivity towards bacterial antigens in the gut play an important contributing role in IBD, we decided to test the effectiveness of pegylated arginase-1 (Peg-Arg1) in mediating the suppression of mouse and human CD4 T cells. Naive CD4 T cells were isolated from spleens of wild-type (WT) mice. Some of these cells were polarized in vitro into Th1 and Th17 subsets according to the standard protocols. Mononuclear cells were isolated from mice with chronic colitis, which was induced by the adoptive transfer of CD45RBhigh T cells into the immunodeficient mice. Human CD4 T cells were isolated from peripheral blood of healthy volunteers. All cells were cultured in vitro in the presence of Peg-Arg1 or control Peg-BSA. We found that addition of Peg-Arg1 dramatically suppressed proliferation and production of IL-2, IFN-g, and IL-17 from mouse naïve CD4 T cells, Th1, and Th17 cells, respectively. We also found that suppression was due to the induction of apoptosis, which was rescued by addition of excess L-arg. Naïve T cells were more sensitive to Peg-Arg1-induced apoptosis than in vitro polarized T-cells. Moreover, Peg-Arg1 treatment of colon LP mononuclear cells isolated from colitic mice was effective at suppressing their proliferation and IFN-g production. Finally, treatment of human anti-CD3/CD28-activated CD4 T cells with Peg-Arg1 was accompanied by dose-dependent suppression of their proliferation and cytokine production. However, Peg-Arg1 treatment did not trigger human T cell apoptosis but arrested their proliferation in the G0-G1 phase of the cell cycle. Taken together, we demonstrated that Peg-Arg1-mediated depletion of L-arginine is very effective at suppressing mouse or human CD4 T cells through either induction of apoptosis or triggering cell cycle arrest and dysfunction, respectfully. Our data suggest that catabolism of amino acid mediated by Peg-Arg or related enzymes could be an effective approach for the treatment of IBD in the future. Supported in part by the Career Development Award #2923 to DVO.
Год издания: 2013
Издательство: Oxford University Press
Источник: Inflammatory Bowel Diseases
Ключевые слова: Immune cells in cancer, Immune Response and Inflammation, Reproductive System and Pregnancy
Открытый доступ: closed
Том: 19
Страницы: S101–S101