Absence of MyD88 signaling reduces chronic allograft damage Kidney transplantation is the best treatment for end-stage kidney disease, however chronic allograft dysfunction remains the major barrier to long-term allograft survival. Toll-like receptors (TLRs) play an important role in innate immunity but also provide a link between innate and adaptive immunity. MyD88 is a key TLR signal adaptor. In this study, we aimed to determine whether MyD88 signaling is required for the development of chronic kidney allograft rejection using MyD88-/- mice in a fully MHC mismatched murine model of kidney allograft rejection. Kidney transplants were performed: BALB/c (H2d) to C57BL/6 (H2b) (WT, n=20), BALB/c.MyD88-/- to C57BL/6.MyD88-/- (MyD88-/-, n=9) as allografts and C57BL/6 to C57BL/6 (isografts, n=5). Mice underwent bilateral native nephrectomy, thus survival was dependent on graft function. Survival was observed to day 100 post-transplant and samples were harvested at day 100 for examination by histology, immunohistochemistry and quantitative RT-PCR. Data are expressed as mean ± SD and analysed by ANOVA. A p-value <0.05 was considered statistically significant. 12 out of 20 WT allografts were rejected with a mean graft survival of 49.5 days. In contrast, 7 out of 9 MyD88-/- allografts survived for >100 days (p<0.05). WT allografts developed kidney dysfunction with increased serum creatinine (51.1±28.0 vs. 14.4±6.0 & 13±3.9μmol/L, p<0.01) and proteinuria (0.93±0.18 vs. 0.51±0.24 & 0.43±0.07, p<0.05) as compared to MyD88-/- allografts and isografts. WT recipients developed histological evidence of chronic allograft damage which was less severe in MyD88-/- recipients, as measured by reduced interstitial fibrosis and tubular atrophy (2.0±1.0 vs. 0.23±0.1, p<0.001), glomerulosclerosis (48.5±24.4 vs. 12.3±5.5, p<0.01), αSMA expression (7.95±4.7 vs. 1.13±1.13, p<0.01), collagen accumulation (29.9±13.6 vs. 9.2±5.8, p<0.01), CD68+ cell infiltration (18.97±8.5 vs. 5.15±1.2, p<0.01) and CD11c+ infiltration (7.99±4.93 vs. 2.38±1.54, p<0.05). Compared to WT allografts, MyD88-/- allografts expressed less TH1 cytokine: IFN(p<0.01), pro-inflammatory cytokines: TNFα, IL-1β and IL-6 (p<0.05), chemokines: MCP1 and Mig (p<0.05) and fibrosis-related genes: TGFβ, TIMP1 and MMP2 (p<0.05). Absence of MyD88 signaling promoted kidney allograft acceptance, with reduced chronic allograft damage, in a fully MHC-mismatched murine model of kidney allograft rejection.