Toll-Like Receptor 4 Deficiency Improves Short-term Renal Function but not Long-term Graft Survival in a Fully MHC-Mismatched Murine Model of Renal Allograft Transplantation

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Abstract

Background

We have previously demonstrated that absence of myeloid differentiation primary response gene 88 (MyD88) induced donor-specific kidney allograft tolerance. The upstream pathways of MyD88 that mediate this process, however, remain unclear. Toll-like receptor 4 (TLR4) is an innate immune receptor that is dependent upon MyD88 for activity of its dominant signaling pathway. Here, we investigated the role of TLR4 in kidney allograft rejection using a fully major histocompatibility complex–mismatched, life-sustaining, murine model of renal allograft rejection.

Methods

Donor (BALB/c) and recipient (C57BL/6) mice either both deficient or sufficient for TLR4 underwent heterotopic renal allograft transplantation, with an additional group of mice receiving renal isografts as controls. Survival was assessed up to 100 days posttransplantation. Animals were also sacrificed 14 days posttransplantation for assessment of the acute allograft rejection response.

Results

Both wild-type (WT) and TLR4−/− allografts showed inferior survival compared to isografts, with no difference in survival between the allograft groups. Serum creatinine was lower in TLR4−/− allografts at day 14 posttransplantation compared with WT allografts, but this was not sustained by day 100. At day 14 posttransplant, increased CD11c+ dendritic cell accumulation, expression of IL-2 and indoleamine 2,3-dioxygenase were evident in TLR4−/− compared with WT allografts, whereas expression of inducible nitric oxide synthase was decreased.

Conclusions

Acute kidney allograft rejection was modestly attenuated in TLR4−/− mice; however, long-term allograft survival and function were not affected in our model. Protection against acute rejection may involve increased accumulation of CD11c+ cells and indoleamine 2,3-dioxygenase expression.

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