TLR4 Deficiency Attenuates Acute Kidney Allograft Rejection But Does Not Prolong Survival.

Abstract

Toll like receptors(TLRs) play an important role in innate immunity. TLR4 deficiency is protective in kidney ischaemia-reperfusion injury. TLR signalling provides a link between innate and adaptive immunity and we have reported that absence of MyD88(a TLR signal adaptor) induced donor-specific kidney allograft tolerance. Here we investigated the role of TLR4 signalling in kidney allograft rejection. Methods: Kidney transplants were performed in nephrectomised mice: BALB/c to B6(Wt-allografts), BALB/c.TLR4-/- to B6.TLR4-/- (TLR4-/- allografts) and B6 to B6 (isografts). Results: Survival to 100 days was observed in all isografts, 4 of 20 TLR4-/-allografts(MST=60days) and 12 of 31 WT-allografts(MST=40days). At day 14 post-transplant, WT allografts developed kidney dysfunction with increased serum creatinine(Scr) compared to isografts (p<0.001) while TLR4-/- allografts had better graft function than WT allografts(p<0.05). Both WT and TLR4-/- recipients developed histological evidence of acute rejection with similar degrees of tubulitis and infiltrates of CD4, CD8 and CD68 cells in allografts, while an increase in CD11c+ cells was evident in TLR4-/- compared to WT allografts(p<0.05). mRNA expression of IL6, TNFa, IFNγ, perforin and granzymeA&B was increased in WT and TLR4-/- allografts vs isografts(p<0.05-0.01). mRNA expression of iNOS was decreased but IL2 was increased in TLR4-/- compared to WT allografts(p<0.05). Consistent with increased accumulation of CD11c cells in TLR4-/- allografts, mRNA expression of IDO was increased in TLR4-/- allografts compared to WT allografts(p<0.01). Allo-specific IgG2a and IgG1 titres were not different between WT and TLR4-/- recipients. At day100 post-transplant, surviving WT and TLR4-/- allografts exhibited similar degrees of kidney dysfunction with increased Scr versus isografts. Conclusion: Acute kidney allograft rejection was modestly attenuated in TLR4 deficient mice, however long-term allograft survival and function were not affected in this fully MHC-mismatched allograft rejection model. Protection against acute rejection may involve increases of DC11c+ cells and IDO expression.