Tyrosine kinase inhibition in experimental kidney transplantation

Chronic allograft injury is a multifactorial process mediated by both immunological and non-immunological factors, leading to organ dysfunction and humoral and cellular rejection. Currently, no specific treatment is available for chronic allograft injury. Pathological growth factor expression is observed before the development of end-stage renal disease (ESRD), and several growth factors (e.g., PDGF, TGF-β, EGF, and VEGF) are induced during the rejection process. This increased growth factor expression is induced by multiple pathways that are unaffected or partly induced by modern immunosuppressive medication. Individual growth factors induce their own expression and, via interactions, the expression of other growth factors. This cascade may lead to prolonged growth factor expression and subsequent chronic allograft injury. Many growth factors exert their effects through specific receptor tyrosine kinases (RTKs). RTKs can be inhibited by novel tyrosine kinase inhibitors (TKIs), which are orally administered and clinically used to treat several malignancies. In our experiments, we tested the efficacy of four different drugs with RTK-inhibition activity on chronic rejection in a rat transplantation model. First, we investigated FK778, an analogue of the active metabolite of leflunomide, which inhibits T- and B-cell proliferation and functions by interfering in de novo pyrimidine biosynthesis. FK778 also inhibits PDGF-RTK both in vitro and in vivo. In our experiments, FK778 decreased acute rejection in a dose-dependent manner and had additive effects with both cyclosporine and tacrolimus, decreasing both acute and chronic rejection. FK778 also decreased post-transplant PDGF and TGF-β expression. In our second study, we investigated short-term imatinib treatment in a chronic rejection model. According to our results, short-term (i.e., 30-day) treatment with PDGF-inhibiting TKI imatinib is sufficient to decrease subsequent chronic rejection changes at day 90. This short-term imatinib treatment also decreased post-transplant PDGF and TGF-β expression and restored allograft function. In the third study, we used erlotinib, a specific EGF-inhibiting TKI. We showed that, when combined with cyclosporine, erlotinib prevents chronic rejection changes and maintains better graft renal function. Erlotinib also decreased post-transplant EGF expression. In our fourth study we tested a potent, PDGF- and VEGF-inhibiting TKI, sunitinib, in combination with cyclosporine. Our data showed that sunitinib decreased early arterial expression of VEGF and PDGF as well as chronic expression of both PDGF and VEGF. Sunitinib decreased chronic rejection and maintained better graft function after transplantation. Taken together, our results show that growth factor inhibition via the inhibition of tyrosine kinases is a potent pathway to prevent chronic rejection and maintain graft function in the transplanted kidney. Our finding that even short-term imatinib treatment is sufficient to prevent chronic rejection indicates that life-long treatment may not be mandatory and early post-transplant events are crucial in mediating chronic rejection changes. TKIs imatinib, erlotinib, and sunitinib are well tolerated when combined with cyclosporine and prevent chronic rejection in an experimental kidney transplantation model. In addition, these drugs maintain better graft function after transplantation. Therefore, they could have beneficial effects in clinical transplantation.