Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease.

Abstract

Chronic and acute graft-versus-host disease (cGVHD and aGVHD) result from donor cells responding to host disparate MHC alleles. In cGVHD (H-2d --H-2bd)), heightened polyclonal immunoglobulin production is due to the interaction of donor allospecffic helper T cells (Th) and the host B cells. In vivo administration of antibody to the ligand for CD40, gp39, blocked cGVHD-induced serum anti-DNA autoantibodies, IgE production, spontaneous immunoglobulin production in vitro, and associated splenomegaly. Antibody production remained inhibited for extended periods of time after termination of anti-gp39 administration. Antiallogeneic CTL responses induced in aGVHD were also prevented by the in vivo administration of anti-gp39 as was the associated splenomegaly. These data suggest that CD40-gp39 interactions are critical in GVHD and that CD40-gp39 may be a valuable ligand-receptor pair for targeting immunotherapeutic agents to control GVHD. (J. Clin. Invest. 1994.

The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells

“…Parallel studies characterizing cell-mediated immune responses in CD154-deficient and anti-CD154-treated mice against adenovirus also demonstrated impaired helper cytokine production [32] and cytotoxic T cell activity [32,33] after infection. Anti-CD154 administration has been shown to block cytotoxic T cell (CTL) generation against alloantigen as well [34].…”

“…Given this assumption, how might one explain why blockade of CD40/CD154 interactions impairs CD8 ϩ CTL priming in some systems [32][33][34]? Many studies have illustrated the dependence of a variety of CD8 ϩ CTL responses on CD4 ϩ T cell help [78][79][80][81], and this relationship can be interpreted in two ways.…”

Suppressor of Cytokine Signaling 1 Inhibits Cytokine Induction of CD40 Expression in Macrophages

“…Recently, increased numbers of CD40-positive microglia were detected in HIV-1-infected brain tissue (16). Because CD40 is functionally critical and nonredundant for the activation of immune responses, blocking the interaction between CD40-CD154 with anti-CD154 or CD40-Ig has been shown to be significantly beneficial in animal models of autoimmune diseases such as experimental autoimmune encephalomyelitis (17)(18)(19)(20), graft-vs-host disease (21,22), and atherosclerosis (23). These findings collectively illustrate the importance of CD40-CD154 interactions for homeostasis of immune responses.…”

Biologic agents for treating rheumatoid arthritis. Concepts and progress

“…Anti-gp39 probably exerts its immunosuppressive effects by directly blocking gp39-CD40 interac-tions (106). Antibodies to gp-39 have been shown to prevent collagen-induced arthritis (107) and to suppress graft-versus-host disease and rejection of allogenic beta islet cells (108). In mice, tolerance can be induced by interference with the gp-39 signal, thereby preventing up-regulation of cell surface B7.…”