Hyper IgM syndrome in humans
The first demonstration of the critical role of CD40(CD40-L) interactions in vivo came from the discovery that the hyper IgM syndrome, an X-linked immunodeficiency, is due to a genetic alteration of the CD40-L. This disease is characterized by a severe impairment of T cell dependent antibody responses with no B cell memory, no circulating IgG, IgA and IgE and no somatic hypermutation, as a consequence of the lack of germinal centers within secondary lymphoid organs. Enhanced susceptibility of patients to opportunistic infections, such as Pneumocystis carinii pneumonia and Cryptosporidium diarrhea, also indicates a role for CD40-CD40-L interactions in cell-mediated immune responses. Interruption of CD40 (CD40-L) interactions in vivo in mice impairs B cell memory as well as T cell priming. Initial experiments performed with antagonists to CD40(CD40-L) interactions, such as antibodies to CD40-L or CD40-Fc fusion proteins, demonstrated impairment of B cell memory. The generation of CD40 and CD40-L knockout (KO) mice confirmed and further extended these observations and revealed a phenotype comparable to that of the patients suffering from the hyper IgM syndrome. In particular, these mice display decreased IgM responses to thy-mus-dependent antigens, no antigen-specific IgGl, IgA and IgE and no germinal centers but normal T and B lymphocyte numbers. As expected, these mice respond normally to thymus-independent antigens with increased IgM and IgG3 levels. CD40-L KO mice display a considerable impairment of antigen-specific T cell priming and appear particularly susceptible to Leishmania infection. This is the result of a defective TH1 response which is related to an impaired production of IL-12 by antigen-presenting cells. As observed in patients, CD40 KO mice show decreased reactive granulopoiesis in response to infections. Studies with a CD40-Fc fusion protein have highlighted the important role of T cell signaling through CD40 ligand in the development of helper function. In particular, administration of soluble CD40 in vivo to CD40 KO mice initiates germinal center formation, and T cells primed in the absence of CD40 are unable to help normal B cells to class switch and to form germinal centers. In this context, ligating CD40 ligand of human activated T cells considerably enhances their production of IL-4.
Interruption of CD40-CD40-L interactions as a treatment of autoimmunity
Administration of antibodies to CD40-L has been shown to prevent the establishment of autoimmune symptoms in various murine models including: 1) collagen type II-induced arthritis, a model for human rheumatoid arthritis; 2) lupus nephritis in lupus-prone mice that represent models of systemic lupus erythematosus; 3) proteolipoprotein-induced experimental encephalomyelitis, a model of human multiple sclerosis. Importantly, in this last case, the antibody could induce a substantial reduction of the disease even when administered after onset. Consistently, activated helper T cells expressing CD40-L surface protein are detected in multiple sclerosis patient brain sections where CD40-bearing APCs can be found.
Interruption of CD40-CD40-L interactions as a way of inducing transplantation tolerance
Administration of CD40-L-specific antibodies prevents the development of graft-versus-host disease (GVHD) that occurs as a major complication of allogeneic bone marrow transplantation. This treatment affects both the acute GVHD, essentially mediated by cytotoxic T cells, and the chronic GVHD, mainly due to the polyclonal B cell activation and the production of self reactive antibodies. Antibodies against CD40-L markedly prolong the survival of cardiac allografts in both naive and sensitized hosts when administered at the time of transplantation. Finally, a combination of allogeneic B cells and CD40-L-specific antibody considerably decreases host reactivity of both CD4+ and CD8 ' T lymphocytes, thereby allowing efficient transplantation of allogeneic pancreatic (3 islet cells. The addition of CD40-L-specific antibody appears to considerably enhance the tolerogenic effect of B cells.
Thus, multiple pathologic states appear to be improved by interruption of CD40-CD40-L interactions. While this is presently accomplished by preventing the association of the receptor with its ligand, using antibodies or soluble receptor, small synthetic chemical agents preventing this interaction may eventually be identified. However, it is likely that pharmacologic agents may be found that will block the intracellular pathways turned on after ligation of either CD40 or CD40-L.
See also: B lymphocyte activation; Dendritic cells; Germinal center; Hyper-IgM syndrome; TNF receptors.
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