Blockade of CD28/CTLA4-B7 pathway prevented autoantibody-related diseases but not lung disease in MRL/lpr mice

We studied the role of CD28/CTLA4 costimulatory T-cell activation pathway o n the pathogenesis of MRL/Ipr mice. Administration of CTLA4IgG from day 0 s ignificantly inhibited autoantibody production such as anti-double-stranded DNA antibody and rheumatoid factor. In addition, end-organ diseases in kid ney, salivary gland, and liver were significantly improved. Improvement of pathologic findings coincided with a significant improvement in survival. A t 350 days of age, 90% of mice treated with CTLA4IgG from day 0 were still alive, compared with none of mice treated with hIgG. As expected, activatio n of conventional T cells was significantly inhibited after CTLA4IgG treatm ent. However, lung disease that was characterized by perivascular accumulat ion and interstitial infiltration of lymphocytes and macrophages was not in hibited. Even after CTLA4IgG treatment from day 0, pathologic findings of l ung disease were not improved. Additionally, the expression of activation m arkers such as B7-1, B7-2, CD71, ICAM1, and LFA1 on Mac1(+) fraction in bot h spleen and lung and the concentration of TNF alpha in bronchoalveolar lav age fluid were not significantly suppressed. These results demonstrated tha t lung disease was independent of the CD28/CTLA4-B7 pathway. Thus, this stu dy emphasizes the differential dependence of the CD28/CTLA4-B7 pathway in d evelopment of diseases in MRL/Ipr mice.