The human immune response is governed by ordered interactions between functionally and phenotypically distinct lymphoid cells (T cells and their subsets, B cells) and monocytes in the context of Ia-like molecules encoded by the HLA complex of genes. Thus, the products of these HLA class II genes (DP, DQ and DR) control the proliferative response of T cells in mixed lymphocyte reactions, antigen presentation to T cells by macrophages and collaboration between T and B cells. In addition to influencing allograft survival, alleles of specific class II genes (DQ and DR) have been associated with susceptibility to a number of diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and multiple sclerosis. Phase I of this proposal successfully demonstrated the feasibility and effectiveness of our technology. A human monoclonal IgM antibody to HLA-DQwl was produced. We propose, in Phase II, to produce a panel of human monoclonal anti-DQ and anti-DR alloantibodies. In addition, the genes for these antibodies will then be manipulated by a variety of DNA cloning techniques to increase the affinity and to switch the isotypes. The generation of these antibodies should have an immediate practical impact in facilitating clinical HLA typing performed for determining transplantation compatibility. Further, their availability will allow a greater understanding of their specificity and functional effects on immune functions of normal and diseased individuals. Ultimately, these antibodies may be useful in the diagnosis and treatment of autoimmune disorders. This work will provide a reliable supply of anti-HLA monoclonal antibodies for use both in tissue typing and in the diagnosis and treatment of autoimmune disorders. This will be important in matching donors and recipients for bone marrow and renal transplants, in identifying people at risk for the development of autoimmune diseases and in the immunological treatment of autoimmune diseases.
