Manipulation of costimulatory pathways in autoimmune diseases.

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.