Harnessing mechanisms of immunological tolerance for therapeutic purposes.
Unwanted immune responses 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, our laboratory has defined mechanisms of acquired tolerance in rodent models, and used monoclonal antibodies to transiently deplete lymphocytes or block their function, with the goal of establishing tolerance therapeutically. This led to the discovery of ”infectious tolerance”, where transplantation tolerance through blockade of the co-receptor/co-stimulatory molecules CD4, CD8 and CD40L was shown to require regulatory CD4+FoxP3+ T cells. Although efficacious in rodent models, “tolerising” non-lytic antibodies to CD4, CD8 and CD40L have not been developed by the pharmaceutical industry.
Our laboratory has also developed CAMPATH-1H, the first humanised therapeutic antibody (Alemtuzumab/Lemtrada) that acts by ablating T cells in patients with multiple sclerosis and for transplantation. Although lymphocyte depletion has clearly proven to be clinically useful, it has not, when used alone, permitted tolerance to transplanted organs or reliable immune reprogramming in autoimmune disease. We seek to understand how to build on the benefits of CAMPATH-1H and promote tolerance by exploiting tolerance –promoting mechanisms learned from our studies of co-receptor/co-stimulation blockade.
We are investigating how to 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 pro-tolerance and immune regulatory elements.
American Journal of Transplantation 14: 1678-89.
The Journal of Clinical Investigation 124: 1439-45.
Journal of Immunology 189: 3947-56.
The Journal of Experimental Medicine 208: 2043-53.