Long-Term Inhibition of Murine Lupus by Brief Simultaneous Blockade of the B7/CD28 and CD40/gp39 Costimulation Pathways

Murine lupus in NZB/NZW F₁ (B/W) mice can be retarded by sustained administration of CTLA4lg and by brief treatment early in life with mAb that block CD40/gp39 interactions. We sought to determine whether brief therapy with CTLA4lg could provide sustained benefit in B/W mice and whether a synergistic effect could be derived by blockade of both the B7/CD28 and the CD40/gp39 pathways. We found that a short course of CTLA4lg at the onset of disease produced only short-term benefit. However, when CTLA4lg was combined with anti-gp39, there was long-lasting inhibition of autoantibody production and renal disease. Ten months after the 2-wk course of therapy, 70% of these mice were alive, compared with only 18% and 0% of those that received only anti-gp39 or CTLA4lg, respectively. These findings demonstrate that brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways can produce benefit that lasts long after treatment has been discontinued.