Targeting the complement system in transplantation

Complement consists of a normal set of circulating proteins whose role in fighting infection is long established, but which is also now known to impede the acceptance of healthy foreign tissue such as a kidney transplant. Complement seems to work together with more sophisticated elements of the immune response called T lymphocytes, and we now believe that collaboration between complement and T cells is essential for graft rejection. It follows that blocking the alliance between complement and lymphocytes may hold a key to a new method of treatment, which could lead to more effective prevention of graft rejection and allow lower use of toxic drugs that are directed against T lymphocytes. However in order to plan effectively, we need better understanding of the cells that produce and secrete complement and how complement enhances the performance of these cells to stimulate T lymphocytes. From a shortlist of two cell types transferred with the donor kidney, we propose to examine the relative importance of these cells types in triggering graft rejection. We also have strategies for reducing the secretion of complement by these cell types, and wish to see if we can build this into a treatment strategy suitable for clinical therapy. More effective ways to prevent rejection crises would be expected to cut graft losses in the short and long term, and thus lead to a significant health and economic benefit associated with transplant success.

Our laboratory has been instrumental in defining the role of complement in renal transplant rejection, in particular the role of local production of C3 on the inflammatory and immune responses influencing short and long term transplant survival. Key publications in Nature Medicine and the NEJM describe our findings. In order to correctly target therapeutic regulators that form part of our translational programme, we need to precisely identify the cell types whose properties depend on this local production. Parenchymal tissue cells and migratory antigen presenting cells (APC) of donor origin are prime candidates, as both are known, from our work on isolated cells, to secrete C3 and stimulate the immune system in a complement dependent manner. However we need to establish the primacy of these cell types on a more physiological basis and determine whether cell-targeted inhibition of the complement system is relevant to the goal of inducing immune hyporesponsiveness for human therapy. To accomplish this we will work to the following set of objectives. (1) We will generate mouse chimeras which produce C3 in either parenchymal or passenger APCs. Transplantation of organs from these mice will tell us the extent to which the recipient antidonor T cell response is dependent on parenchymal or passenger cell synthesis of C3. (2) Functional studies on APCs from the chimeric mice will determine if their potency for T cell stimulation is dependent on endogenous or exogenous synthesis of C3. (3) We will build a therapeutic strategy for inactivating complement at the surface of parenchymal cells and/or APCs using a membrane targeted complement regulator in a mouse model. (4) We shall extend our findings to a human system based on either peripheral blood and myeloid APC, or renal parenchymal cells, and human T cells. Our aim will be to show if gene silencing, protein inactivation or receptor blockade of C3 reduces the human T cell response and favours the generation of inhibitory T cells. Further exploitation of human therapy would then require targeting the relevant cell type, with appropriate timing at the correct location.