title: Manipulation of costimulatory pathways in autoimmune diseases.
abstract: Abstract There has recently been an increased understanding of the role of costimulatory pathways in the activation of the immune system and the maintenance of self-tolerance. It has been suggested that the absence of costimulatory molecules on normal tissue cells could serve to induce self-tolerance, and that inappropriate expression of costimulatory molecules on antigen-presenting cells (APCs) could activate self-reactive T cells, resulting in autoimmunity. Among several costimulatory molecules characterized, the interaction of CD28/CTLA4 on T cells with B7 (CD80 and CD86) on APC appears to be of primary importance. In fact, inhibition of the CD28-B7 interaction ameliorates several autoimmune diseases in experimental animal models. However, differential roles for CD80 and CD86 have been reported in certain conditions, and CTLA4 has been shown to play a negative role in T cell activation, suggesting that the actual regulatory mechanisms of this pathway in autoimmunity is much more complex. While the CD28-B7 interaction constitutes a predominant pathway of T cell costimulation, some intact T cell responses in CD28-deficient mice have suggested the presence of alternative pathways. T cell-dependent immunity is also critically regulated not only by other immunoglobulin superfamilies such as B7RP-1/ICOS, but also by tumor necrosis factor (TNF) and TNF-receptor superfamilies, which control immune responses in both a positive and a negative fashion. Therefore, further investigation of the physiological function of these costimulatory pathways in vivo may help in developing rational therapeutic approaches for autoimmune diseases.
authors.affiliation: Department of Joint Disease and Rheumatism, Nippon Medical School , 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603 , Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nakajima