Antigen-specific therapy of murine lupus nephritis using nucleosomal peptides: Tolerance spreading impairs pathogenic function of autoimmune T and B cells

In the (SWR x NZB)F-1 mouse model of lupus, we previously localized the cri tical autoepitopes for nephritogenic autoantibody-inducing Th cells in the core histones of nucleosomes at aa positions 10-33 of H2B and 16-39 and 71- 94 of H4, A brief therapy with the peptides administered i.v. to 3-mo-old p renephritic (SWR x NZB)F-1 mice that were already producing pathogenic auto antibodies markedly delayed the onset of severe lupus nephritis, Strikingly , chronic therapy with the peptides injected into 18-mo-old (SWR x NZB)F-1 mice with established glomerulonephritis prolonged survival and even halted the progression of renal disease. Remarkably, tolerization with any one of the nucleosomal peptides impaired autoimmune T cell help, inhibiting the p roduction of multiple pathogenic autoantibodies. However, cytokine producti on or proliferative responses to the peptides were not grossly changed by t he therapy. Moreover, suppressor T cells were not detected in the treated m ice, Most interestingly, the best therapeutic effect was obtained with nucl eosomal peptide H4(16-39), which had a tolerogenic effect not only on autoi mmune Th cells, but autoimmune B cells as well, because this peptide contai ned both T and B cell autoepitopes, These studies show that the pathogenic T and B cells of lupus, despite intrinsic defects in activation thresholds, are still susceptible to autoantigen-specific tolerogens.