Clinical issue
Kidney transplantation is the treatment of choice for end-stage renal disease, but carries a risk of transplant rejection and death. The rates of late graft loss and subsequent patient mortality are poor, with rejection of up to 50% of donor allografts. The major problem limiting long-term allograft survival is chronic allograft dysfunction (CAD), characterized by scarring of the transplant, with progressive loss of renal function. There is currently no treatment for CAD and its pathophysiology remains poorly defined. Although the contribution of the adaptive immune system to transplant rejection has been known for many years, increasing attention is now focusing on the innate immune system, the body’s first line of defence against invading microorganisms, in which an inflammatory response is mounted following activation of pattern recognition receptors (PRRs). In addition to their role in infection, PRRs sense damaged or non-self tissue, and hence may react against grafts. Here, using a mouse renal transplant model, a specific subset of PRRs, the Toll-like receptors (TLRs), is shown to be involved in CAD.
Results
By monitoring the upregulation of renal TLR-binding molecules, the authors show that the innate immune system is activated in both acute and chronic situations in kidney grafts. To determine whether loss of the TLR pathway might result in better graft outcome, mice lacking both TLR2 and TLR4, or either of the key TLR adaptor proteins MyD88 and TRIF, were given kidneys from wild-type animals. In all cases, chronic graft damage developed to a significantly lower extent, and scarring and atrophy of the transplant kidney were largely prevented. The beneficial effect of inhibition of the TLR pathway was mediated by both the adapter proteins MyD88 and TRIF.
Implications and future directions
These findings show that the innate immune system, and specifically the TLR signaling pathway, is involved in CAD. Since conventional immunosuppression, which inhibits adaptive immunity (B- and T-cell activity), does not prevent CAD, the innate immune system represents an important new target for pharmacological intervention. Currently, TLR antagonists are being evaluated as inhibitors of acute inflammation in clinical trials. It would be of great interest to initiate further trials to determine whether blockade of TLRs could be used to prevent CAD in transplant patients.
