INTERVENTION OF CD4(+) CELL SUBSET SHIFTS AND AUTOIMMUNITY IN THE BXSB MOUSE BY MURINE CTLA4IG

In the BXSB autoimmune disease-prone mouse strain, male mice develop s evere lupus-like symptoms and die early in life (4-6 mo), whereas fema les do not. We have previously demonstrated that profound phenotypic a nd functional changes occur with age in CD4(+) cells from BXSB males. CD4(+) cells from males (4 mo old) were predominantly CD44(high), CD45 RB(low), and MEL-14(low) (activated/memory phenotypes), while the reci procal phenotypes characteristic of naive cells were prevalent in age- matched females and young adult males (2 mo old). CD4(+) cells from ol der males proliferated less and produced less IL-2 and IFN-gamma than cells from either females or young males in response to immobilized an ti-CD3 mAb. We tested the effect of CTLA4Ig treatment on the progressi on of disease in BXSB males. CD4(+) cells from CTLA4Ig-treated mice at 4 mo of age were predominately CD44(low), CD45RB(high) and MEL-14(hig h) phenotypes that were identical with those observed in CD4(+) cells from young (3-mo-old) females. In contrast, control male mice treated with IgG2a accumulated the CD4(+) memory phenotype. CD4(+) cells from 4-mo-old male CTLA4Ig-treated mice proliferated and produced IL-2 at l evels similar to those of cells from females in response to immobilize d anti-CD3 mAb. Furthermore, in contrast to IgG2a-treated mice, female and CTLA4Ig-treated male mice at 4 mo of age produced no anti-chromat in Abs. Three of four male mice injected with CTLA4Ig until 6 mo of ag e appeared healthy at 8 mo of age, whereas all five of IgG2a-treated c ontrol males died by 6 mo of age. These 8-mo-old CTLA4Ig-treated males showed variable resistance to autoimmunity as well as function and ph enotype marker expression, and a less striking glomerulonephritis than 4-mo-old untreated males. The results of this study demonstrate that the rampant T cell activation and T cell dysfunction that occur in mal e BXSB mice by 4 mo of age are abrogated by blocking the CTLA4-depende nt costimulatory signal(s). They also show that treatment with CTLA4Ig can suppress the pathogenesis of disease and increase longevity.