Prevention of chronic GVHD by 4-1BB stimulation

4-1BB, a member of the TNF receptor superfamily, is an important costimulator primarily expressed on activated T cells. Previous studies have established that treatment with agonistic anti-4-BB mAb is highly effective in reversing the progression of spontaneous systemic lupus erythematosus (SLE) in mouse models. Its therapeutic effect is mediated by a profound suppression of autoantibody production, presumably as a result of deleting autoreactive B cells. In this report we show that a single injection of anti-4-1BB mAb (3H3) completely blocks chronic graft-versus-host disease (cGVHD) in the parent-into-F₁ model. In particular, donor CD4⁺ T cells are rapidly eliminated from host spleens by activation-induced cell death (AICD) after 4-1BB triggering. Since donor CD4⁺ T cells are required for the development of cGVHD, and H3-mediated inhibition of autoantibody production (a hallmarker of cGVHD) occurs without donor CD8⁺ T cells, 3H3 blocks cGVHD by preventing alloreactive CD4⁺ T cells from activating host B cells. 3H3 treatments also result in massive deletion of B cells through IFN-γ but not IgG₁ autoantibody production, indicating that 3H3-mediated inhibition of autoantibody production is due to deletion of autoreactive CD4⁺ T cells. Importantly, 3H3 can reverse the progression of advanced cGVHD disease. Our findings indicate that agonistic anti-4-1BB mAb is a potential immunotherapeutic agent for both preventing and treating cGVHD.