"Unwanted immune responses to self-tissues and transplants have a major impact on human health and wealth. Their management has required long-term immunosuppressive drugs which penalise the whole immune system. The big challenge has been to understand how the individual is naturally tolerant to self, and to exploit this knowledge for treatments better targeted to the relevant antigens. Since 1980 the applicant’s laboratory have, in rodent models, defined mechanisms of acquired tolerance, and used monoclonal antibodies to transiently block lymphocyte function, or deplete lymphocytes with the goal of establishing tolerance therapeutically. This led to the discovery of ”infectious tolerance” where tolerance was shown to require regulatory CD4+FoxP3+ T cells. Although efficacious in rodent models, equivalent blockading antibodies for man, although available, have not been commercialised by the pharmaceutical industry. To deplete lymphocytes in man, our laboratory has also developed the anti-CD52 monoclonal antibody, CAMPATH-1H. This was the first humanised therapeutic antibody (Alemtuzumab/Lemtrada) and is being actively pursued for multiple sclerosis and stem cell and organ transplantation. Although lymphocyte depletion has clearly proven to be clinically useful, it has not, when used alone, permitted tolerance to transplanted organs or allowed for durable immune reprogramming in autoimmune disease. This proposal seeks to understand how to build on the benefits of lymphocyte depletion with CAMPATH-1H, and promote tolerance by exploiting tolerance–promoting mechanisms learned from our studies of co-receptor/co-stimulation blockade. The novel approach taken by this project is to investigate and manipulate the reconstitution phase of lymphocyte recovery through Physician Aided Reconstitution of the Immune System (PARIS), by aiming to contain those T-cells that mediate damage whilst empowering competing regulatory T-cells."