The general aim of this project is to determine the chemical interactions and energetics such as membrane potential and pH and ion gradients which are involved in the insertion of proteins into cellular membranes and/or the translocation of proteins across cellular membranes. The events are studied from the initial receptor binding to the final physiologic response or pathological response in the case of toxins such as ricin, colicins, diphtheria and tetanus toxins. Utilizing basic data from such studies immunotoxins (toxins linked to monoclonal antibodies) are constructed to serve as a new class of pharmacologic reagents to eliminate unwanted cell types such as cancer cells or T-4 lymphocytes in AIDS infections, or to manipulate specific cells such as T cell subsets to correct imbalances which exist in autoimmune diseases which can effect the CNS such as multiple sclerosis and lupus and cause psychosis. In addition immunotoxins continue to prove useful in deminishing the incidence of graft- versus-host-disease following bone marrow transplantation and thus will also have utility in enzyme replacement therapy and organ transplantation.
