Short-term Pharmacological Inhibition of MyD88 Homodimerization by a Novel Inhibitor Promotes Robust Allograft Tolerance in Mouse Cardiac and Skin Transplantation

Abstract

In Brief Background Most strategies for antirejection and tolerance induction in clinical transplantation have focused on modifying adaptive immunity, it is unclear whether pharmacological suppressing the innate immune system can promote transplant tolerance. Methods We inhibited innate immunity by using our self-generated inhibitor of myeloid differentiation factor 88 (MyD88), TJ-M2010-5, and investigated its therapeutic effects and mechanisms in cardiac and skin transplant models. Results TJ-M2010-5 directly and indirectly interacted with the Toll/IL-1R domain of MyD88, inhibiting MyD88 homodimerization. In vitro, TJ-M2010-5 inhibited maturation of dendritic cells, which suppressed nuclear translocation of NF-κB and T cell activation. In vivo, short-term (10 days) monotherapy of TJ-M2010-5 resulted in long time survival of 50% of the cardiac allografts, and longer-term (14 days) combination treatment of TJ-M2010-5 with CD154 mAb resulted in survival of 29% of skin allografts, which outperformed far more than CsA did and stimulated the proliferation of CD4+CD25+FoxP3+ Regulatory T cells in recipient mice. Conclusions Pharmacological inhibition of MyD88 signaling by this novel inhibitor TJ-M2010-5 shows a powerful anti-rejection effect, which may have therapeutic potential in clinical transplantation. The inhibition of both innate and adaptive immunity may be necessary for tolerance induction in nonsolid organs. Li et al report that a novel 2-aminothiazole-derived MyD88 inhibitor, modeled on the MyD88 Toll/Interleukin-1 receptor (TIR) homology domain, inhibited MyD88 homodimerization and maturation of dendritic cells in vitro, and promoted long-term survival of cardiac and skin allografts in mice.