A graft-versus-host (GVH) reaction from injecting parental T cells into normal F1 recipient mice can result in a disease resembling human systemic lupus erythematosus. The central goal of this research project is to understand the cellular mechanisms that allow for lupus-like autoantibody production and renal disease in GVH disease. Experiments are designed to test the hypothesis that IgG antinuclear antibody production and disease in the GVH model is dependent on an interaction of specific B cells with their respective nuclear antigens, and the stimulation of these B cells by donor CD4+ T cells that are specific for allogeneic class II MHC antigens. Studies are proposed to analyze the fine specificity of GVH-induced anti- H2B antibodies using an ELISA and synthetic peptides corresponding to the N-terminal region of H2B. Specificities determined by binding and by competition assays will also be compared with those induced by immunization of normal animals. The potential interaction of B cells with antigen will also be investigated by examining anti-H2B secreting B cell hybridomas (derived from individual GVH mice) for Ig chain gene usage. Studies will focus on their clonal relationship as well as determine if B cell maturation is characterized by somatic mutation of Ig variable regions. T cell specificities in GVH will be examined by enriching donor CD4+ T cells for the expression of particular V beta- encoded receptors (i.e. Vbeta 17a+) that have been shown to mediate reactivity to self (and allogeneic) I-E antigens. The GVH potential of this population will be tested in F1 recipients that differ in their I-E expression. In other experiments, recipients will be examined for the expansion of Vbeta 17a+ T cells during the GVH reaction. In addition, experiments will analyze the specificity and T cell receptor gene expression of T cell hybridomas derived from GVH T cells. Oligoclonaltiy of T cell receptor gene expression will be determined by comparison to hybridomas derived from T cells stimulated in the allogeneic MLR and from T cells nonspecifically activated by mitogen. In a final group of experiments, the in vivo GVH reaction produced by injecting alloreactive T cell clones will be examined. The mechanisms of autoantibody production in GVH disease may be closely related to those operative in spontaneous lupus, and it is interesting to speculate that autoantibody production in spontaneous disease is also the result of bystander B cell activation but with T cells reactive to self class II antigens.
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