Mice bearing the single autosomal recessive gene designated lpr develop an autoimmune disease which serves as an excellent model for human systemic lupus erythematosus. A major immunological abnormality in these mice is the proliferation of an unusual T cell that has the phenotypic characteristics of a helper cell but produces a skewed pattern of lymphokines compared to normal mice. We propose studies to analyze 1) the activation of, and 2) the lymphokine production by autoantigen specific T cell clones. The spontaneous production of mitogen and antigen activated lymphokines (interleukin-2, Gamma interferon, B cell differentiation factor, and macrophage Ia recruiting factor) will be studied in clones derived from lpr mice and normal congenic partners. We will study the ability of autoreactive T cell clones from lpr mice to induce natural killer cells from isolated T cell subpopulations or large granular lymphocytes during a syngeneic mixed lymphocyte reaction. The induced NK cells will be analyzed for target specificity and their ability to regulate autoantibody production. These studies should provide valuable new insights into the abnormal immunoregulatory mechanisms present in autoimmunity. Defining imbalances in lymphokine production and subsequent activation (or failure to activate) normal regulatory cells could suggest therapeutic strategies for the use of T cell derived biologicals in the treatment of autoimmune disease.
