MICA: Targeting C5aR in chronic inflammation, renal fibrosis and late graft dysfunction

Early inflammation after organ transplantation caused by disturbance of blood flow can cause tissue damage and increase the risk of graft dysfunction. Complement is a set of inflammatory proteins that are easily activated during organ transplantation and we have shown it may have a causal role in this type of injury. Our aim is to identify whether the tissue receptor that detects the activated complement fragment known as C5a can be blocked to protect kidneys during transplantation. If this can be achieved with a new agent that we are testing in mice, this could lengthen the life of the transplant and make more kidneys available by organ donation.

The proposed research will explore the therapeutic potential for targeting C5aR in chronic inflammation, renal fibrosis and late graft dysfunction. We will employ a novel, orally bioavailable small inhibitor of C5aR (CCX168), a compound that is currently studying in Phase II clinic trial in subjects with ANCA-associated renal vasculitis, and the transgenic mice (huC5aRtg) in which mouse C5aR has been replaced by human C5aR under fully native transcriptional control.
Using this novel system, we will determine whether targeting C5aR attenuates renal chronic inflammation and fibrosis in a native kidney IR injury model and syngeneic kidney transplant model; and whether targeting C5aR improves long term graft function in an allogeneic kidney transplant model. We will test different protocols of CCX168 administration aiming to target C5aR at both the acute and the tissue repair phases (day -1 to 20), the acute phase only (day -1 to 3) and at the tissue repair phase only (day 3 to 20). The outcome will have clinical implications for prevention and intervention as well as improve our understanding of how C5aR signalling contributes to renal fibrosis. Performing kidney transplantation between donor and recipient mice specifically carrying the target receptor will enable us to dissect the impact of C5aR signalling on donor and recipient cells and its influence on renal fibrosis and late graft function. In addition to in vivo studies, we intend to explore cellular and molecular mechanisms involved in C5aR mediated renal fibrosis by using several cell culture systems (i.e. renal fibroblasts, renal tubular epithelial cells and myeloid derived cells).

Benefits to the scientific community:

Improved scientific methods and training skills, and understanding of scientific issues, which can deliver broader knowledge and solutions in transplantation, through:

i. Using a novel, orally stable small inhibitor of C5aR together with its specific human target in an animal model, to understand the biological significance in man and explore the therapeutic use in the prevention of chronic renal transplant injury.
ii. Using new approaches combining the use of human specific C5aRa/human C5aR transgenic mice with organ transplantation will allow us to specifically target C5aR expressed on the cells within the graft and in the circulation, and distinguish its influence on renal fibrosis. The finding may have implications for the development of a local delivery strategy for C5aRa to reduce renal fibrosis.
iii. Understanding of how renal fibrosis is regulated by C5aR signals and ways in which this can be manipulated for therapeutic purposes using new protein and small molecule therapy.
iv. The research team will continue to invest in developing highly skilled researchers in areas that the MRC has highlighted as Strategic Skill Priorities (advanced in vivo sciences). This will include the training in renal microsurgery afforded through this research project.
v. The expertise drawn together to conduct the research (on complement receptor function, immunology, organ transplantation, pharmacological innovation) will have an impact on sustainability to perform research that can be rapidly translated to the clinic for transplantation.

Evidence of progress should be visible within 3 years

Benefit to patients:
Improved quality of life, graft and patient survival rates, fewer interventions including less use of drug and dialysis treatment:

i. Treatment that has potential to reduce inflammation and stimulate tissue repair is likely to hasten recovery and increase the lifespan of the transplant.
ii. Having to take fewer drugs with unpleasant or dangerous side effects as a result of protecting the graft against inflammation and immunity.
iii. Shorter wait for a kidney transplant through more donor organs being available with the application of complement receptor manipulation to limit organ IR damage

Evidence should be visible within 10 years
Benefits to the NHS:

Cost/resource/efficiency benefits gained through costs of treatment (drug and dialysis costs) and patient and graft outcomes:

i. Lower dialysis costs by enabling more transplants to be carried out with the use of complement-based therapy and by fewer patients having to return to dialysis after transplantation
ii. Lower cost of dialysis in the early post transplant period due to more rapid recovery of treated patients
iii. Lower maintenance drug costs by keeping patients on fewer drugs where graft acceptance is improved by complement-based approaches
iv. Increased patient and graft survival rates with wider application of these treatment technologies, within 10 years

Benefits to the Economy:

Healthcare savings since maintenance on a transplant is more cost-effective than dialysis. Compared with dialysis, kidney transplantation is more cost effective over a five-year period (£45K, versus £125K for haemodialysis).

Benefits to Wider Society:

Engagement/participation, leading to:

i. Public confidence in organ donation, building on our ability to engage the public and influence policy on matters that include research in transplantation
ii. Influence willingness to participate in organ donation schemes by appreciating the scientific commitment through research
iii. Building confidence in the strategic investment of public funds in transplant research