Systemic administration of agonist peptide blocks the progression of spontaneous CD8-mediated autoimmune diabetes in transgenic mice without bystander damage

Insulin-dependent diabetes is an autoimmune disease targeting pancreatic be ta-islet cells. Recent data suggest that autoreactive CD8(+) T cells are in volved in both the early events leading to insulitis and the late destructi ve phase resulting in diabetes. Although therapeutic injection of protein a nd synthetic peptides corresponding to CD4(+) T cell epitopes has been show n to prevent or block autoimmune disease in several models, down-regulation of an ongoing CD8(+) T cell-mediated autoimmune response using this approa ch has not yet been reported. Using CL4-TCR single transgenic mice, in whic h most CD8(+) T cells express a TCR specific for the influenza virus hemagg lutinin HA(512-520) peptide:K-d complex, we first show that i.v. injection of soluble HA(512-520) peptide induces transient activation followed by apo ptosis of Tc1-like CD8(+) T cells. We next tested a similar tolerance induc tion strategy in (CL4-TCR x Ins-HA)F-1 double transgenic mice that also exp ress HA in the beta-islet cells and, as a result, spontaneously develop a j uvenile onset and lethal diabetes. Soluble HA(512-520) peptide treatment, a t a time when pathogenic CD8(+) T cells have already infiltrated the pancre as, very significantly prolongs survival of the double transgenic pups, In addition, we found that Ag administration eliminates CD8(+) T cell infiltra tes from the pancreas without histological evidence of bystander damage. Ou r data indicate that agonist peptide can down-regulate an autoimmune reacti on mediated by CD8(+) T cells in vivo and block disease progression. Thus, in addition to autoreactive CD4(+) T cells, CD8(+) T cells may constitute t argets for Ag-specific therapy in autoimmune diseases.