Manipulating the repair response by vascular progenitor cells; a strategy for preventing and treating chronic rejection

Organ transplantation is the best treatment for severe kidney, heart and liver disease. But transplanted organs don?t last very long, relative to the natural lifespan of healthy individuals. Instead, many suffer an insidious decline in function due to ?chronic rejection?, for which there is currently no treatment. Surprisingly, although individual organs are lasting longer than they used to, the incidence of chronic rejection has altered little over the last decade, despite a marked improvement in acute rejection rates. So this is a significant problem. This project will provide the basis for a completely novel approach to treatment. There is evidence that one of the major manifestations of chronic rejection, a thickening of arteries called ?transplant arteriosclerosis?, is caused by smooth muscle cells derived from the circulation of the recipient. Our work indicates that these cells are fully capable of repairing damaged blood vessels, but they are prevented from doing so in this setting because of the ongoing inflammation generated by the rejection response. We have identified a critical protein, belonging to the clotting family, that dictates whether these cells repair or exacerbate the arteriosclerosis, but others have identified other inflammatory factors that influence arterisoclerosis, so we need to fully investigate how these interact. All of the work proposed is in mice, because the mechanisms of arteriosclerosis are similar to those in humans and, importantly, using genetically modified strains will simplify the interpretation of results. We are already studying human repair cells in patients with kidney failure, and this proposal will complement these clinical studies. Our goal is to be able to manipulate the conditions under which repair cells operate, independently of targeting the immune system so that, despite an ongoing rejection response, they repair damaged tissue; in effect, turning the transplanted tissue into self. We believe this will be possible using current technologies, if we can identify the correct signals to target. This is a very novel approach, but one that is likely to deliver interesting and promising results. The knowledge gained will significantly enhance our ability to prevent premature organ failure after transplantation, which will have a significant, immediate and lasting impact on the lives of many thousands of patients. But importantly, the results are likely to be of significance for understanding how to promote regenerative repair in other chronic inflammatory diseases.

Organ transplantation is a therapeutic success, but allografts fail prematurely, rarely sustaining recipients for their natural lifespan. A major problem is chronic rejection (CR) manifesting in many organs as transplant arteriosclerosis (TA), in which (as in other types of vascular injury) intimal hyperplasia (IH) leads to progressive ischaemia and fibrosis. There is currently no effective treatment for TA or CR. The basic hypothesis for this proposal is that each of us has vascular progenitor (VP) cells capable of repairing damaged blood vessels, but in TA they are inhibited from doing so by inflammatory factors generated by the immune response. The hypothesis arises directly from our current MRC-funded work, in which we have shown that IH can be completely inhibited by preventing the generation or actions of thrombin on the surface of bone marrow-derived VP. These manipulations lead to regeneration of vessel wall architecture, even in the face of an ongoing alloimmune response. We have concluded that thrombin is a critical factor determining how VP respond to repair cues. We postulate that other factors known to impact on TA, such as the ?danger signal? high mobility group box-1 protein, interferon gamma and nitric oxide, do so by influencing the responsiveness of VP to thrombin, thereby affecting the recruitment, phenotype or function of these cells, independently of effects on the alloimmune response. The goal is to define how these factors enhance or inhibit regenerative repair by VP. The specific aims are to; 1) Define the influence of IFN gamma, NO and HMGB-1 on the phenotype, mobilization and recruitment of VP subpopulations after vascular injury; 2) Link the influence of these factors to thrombin generation or responsiveness; 3) Demonstrate that the neointimal disease in TA is due to phenotypic or functional changes in VP independently of the alloimmune injury. These studies will define, for the first time, the relationships between immune effector and vascular repair mechanisms and establish the foundation for a novel therapeutic strategy to prevent or treat CR, based on manipulating the responsiveness of VP. The results of this study will be used directly to influence the design of therapeutic trials in the dialysis and renal transplant populations at the Hammersmith, in whom clinical research into the biology of circulating VP has already begun.