Short-term MyD88 inhibition ameliorates cardiac graft rejection and promotes donor-specific hyporesponsiveness of skin grafts in mice

Abstract

SUMMARYRecognition of evolutionarily conserved ligands by Toll-like receptors (TLRs) triggers signaling cascades in innate immune cells to amplify adaptive immune responses. Nearly all TLRs require MyD88 to transduce downstream signaling. MyD88 deficiency has been shown to promote the allograft acceptance in mice. However, direct evidence for therapeutic potential of MyD88 inhibitors remains lacking. Herein, we used a MyD88 inhibitor, namely ST2825, to explore its therapeutic potential and mechanisms in fully allogeneic skin and heart transplant models. Phenotypic maturation of dendritic cells stimulated by TLR ligands was alleviated by ST2825 in parallel with reduced T-cell proliferation in vitro. A short-course treatment with ST2825 significantly prolonged cardiac graft survival (mean survival time = 18.5 AE 0.92 days vs. 7.25 AE 0.46 days). ST2825-treated group had significantly reduced proinflammatory cytokines in allografts compared with control group. ST2825 combined with anti-CD154 induced long-term skin allograft acceptance in about one-third of recipients (>100 days). 'Skin-tolerant' recipients showed attenuated donor-specific IFN-c responses, intact IL-4 responses, and compromised alloantibody responses. We conclude that MyD88 inhibitor ST2825 attenuates acute cardiac rejection and promotes donor-specific hyporesponsiveness in stringent skin transplant models. The direct evidence suggests that pharmacological inhibition of MyD88 hold promising potential for transplant rejection. Transplant International 2016; 29: 941-952

Inhibition of intimal hyperplasia in murine aortic allografts by administration of a small-molecule TLR4 inhibitor TAK-242

“…Our current findings indicate that TAK-242 monotherapy could disrupt TLR4 signaling to ameliorate intimal hyperplasia at week 2, but the effect was not sufficient to prevent graft atherosclerosis. Previous studies reported that deficient of MyD88 or short-term MyD88 inhibition promoted the survival of grafts 30 , 31 . Downstream of TLR4, two adaptors, MyD88 and TRIF, mediate the signaling.…”

Thalidomide Alleviates Apoptosis, Oxidative Damage and Inflammation Induced by Pemphigus Vulgaris IgG in HaCat Cells and Neonatal Mice Through MyD88

“…TLRs are well-characterized receptors that recognize conserved components from both own and other organisms and initiate signaling pathways of the innate immune system, thus, enhancing adaptive immune responses. 32 Nearly all TLRs require MyD88 for downstream signal transduction. MyD88 functions as a central mediator of the inflammatory response and can initiate signal transduction from multiple receptors.…”

Untangling Local Pro-Inflammatory, Reparative, and Regulatory Damage-Associated Molecular-Patterns (DAMPs) Pathways to Improve Transplant Outcomes

“…Pre-clinical studies using MyD88 or TLR deficient mice have identified both as effective targets to limit IRI, inflammation, and improve transplant outcomes ( 36 ). These early rodent studies utilizing TLR and MyD88 deficient mice have led to the development of numerous biologics targeting TLRs and MyD88, which have shown promise in promoting tolerance or limiting rejection ( 37 – 42 ). For example, newer agents like Eritoran, which is a synthetic analog of the lipid A portion of lipopolysaccharide (LPS) that can antagonize LPS binding ( 43 , 44 ), or the 2-aminothiazole-derived MyD88 inhibitor TJ-M2010-5, are potent inhibitors of DC activation and promoted long-term heart and skin graft survival in rodents ( 37 ).…”