Background: Toll-like receptors (TLRs) play essential role in the allograft rejection and tolerance induction. The signal transfer of TLRs, except TLR3, depends either entirely or partially on the MyD88. Here we use a self-created novel MyD88 inhibitor, TJ-M2010, in fully-mismatched cardiac and skin transplantation models in mice, and investigate if short-term treatment of TJ-M2010 could induce transplant tolerance, and the potential mechanism. Methods: BALB/c ⇒ C57 cardiac and skin transplantation mouse models were employed. TJ-M2010 was administrated (50mg/kg, i.p.) for 1 and 2 weeks separately after transplantation. In the skin transplant model, MR1 was additionally administrated. In vitro, immature BMDCs were stimulated by TLR9 agonist CpG, with or without the presence of TJ-M2010 for 12 hours. The expression of CD80, CD86 was analyzed by flow cytometry. NaÏve C57 T cells stained with CFSE were co-cultured with BALB/c DCs for 3 days with or without TJ-M2010, and CD3+/CFSE+ cells were analyzed by flow cytometry. Splenocytes were harvested from long-term survived recipients and CD4+CD25+FoxP3+ cells were analyzed by flow cytometry. Results: TJ-M2010 inhibited the upregulation of CD80, CD86 on DCs upon the stimulation of CpG and it inhibited T cell proliferation in MLR. TJ-M2010 significantly prolonged the allografts survival in both cardiac and skin transplantation models when compared with the control groups (MST=70.6 days vs MST=7.4 days ; MST= 69.2 days vs MST=8.4 days, P<0.05). The proportion of regulatory T cells in TJ-M2010 groups also has a remarkable increase. Conclusion: MyD88 inhibitor TJ-M2010 exhibits excellent anti-rejection and tolerance induction effects in allograft models in mice. The inhibitory effects on DC maturation and the subsequent T cell proliferation, and the ability to increase Tregs proportion of TJ-M2010, may be the mechanisms involved. This study provides a new target for anti-rejection treatment or tolerance induction.
To cite this abstract in AMA style:Zhou P, Li C, Huang X, Zhang L, Yang T, Feng S, Li M. Novel MyD88 Inhibitor Induced Robust Tolerance in Both Cardiac and Skin Transplantation in Mice, A [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/novel-myd88-inhibitor-induced-robust-tolerance-in-both-cardiac-and-skin-transplantation-in-mice-a/. Accessed January 27, 2021.
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