The research in this proposal is based on two observations 1) that infusions of alpha ASGM1 serum can prevent all clinical manifestations of otherwise lethal GVH disease across minor- histocompatibility barriers in mice, and 2) that alpha ASGM1 serum can be used to immunoprecipitate a cell surface protein from activated T cells, in addition to its previously recognized ability to bind a glycoplipid. The primary objective is to identify the mechanism of alpha ASGM1 serum prophylaxis of GVH disease, both at the cellular and molecular level, in order to be able to develop antibodies with the appropriate specificity for controlling a variety of analogous immune-mediated processes in humans.
The specific aims are: 1) to characterize, phenotypically and functionally, the cells reactive with anti ASGM1 serum; 2) to study the effects of alpha ASGM1 infusions on established GVH disease and on skin graft rejection; 3) to identify the antibody specificity(s) contained in alpha ASGM1 suerum responsible for its potent in vivo immunomodulatory effects; and, once the molecule responsible for the functional activity of anti ASGM1 has been identified, 4) to generate mouse mononclonal antibodies against that molecule in order to demonstrate feasibility and efficacy in mice, before producing human monoclonal antibodies for use in man. These investigations will define the usefulness and the limitations of employing antibodies with asialo GM1 specificity to prevent graft-vs-host disease, treat graft-vs-host disease, treat selected autoimmune disorders, and prevent skin graft rejection. In addition the prosposed experiments may have implications for other areas of medicine in which cells reactive with alpha ASGM1 serum are of central importance: natural immunity (NK cells), cancer immunotherapy (lympholine activated killer cells, cytotoxic T cells, activative macrophages) leukemia research (acute lymphoblastic leukemia) and immune regulation (developing thymocytes, natural suppressor cells).
