[Manipulation of costimulatory pathways in autoimmune disease]

The past year has seen significant advances in our understanding of the role of costimulatory pathways in antigen-specific T cell activation and maintenance of self-tolerance. It has been suggested that the absence of costimulators on normal tissue cells could serve to induce self-tolerance and that inappropriate expression of costimulators on antigen-presenting cells (APC) could activate self-reactive T cells, resulting in autoimmunity. CD28 on T cells and CD80 and CD86 on APC are key molecules in the maintenance and breakdown of anergy. CTLA-4Ig fusion protein, that binds to both CD80 and CD86 with high affinity and thereby prevents interaction of CD80/CD86 with CD28/CTLA-4, prevents or ameliorates several autoimmune disease in experimental animal models, supporting an importance of this pathway in the development of autoimmune diseases. However, the studies using specific monoclonal antibodies against CD80 and CD86 have shown different outcomes in individual autoimmune models. This suggests that the actual regulatory mechanisms of this pathway in autoimmunity is much more complex, because of the existence of two receptors (CD28 and CTLA-4) and two ligands (CD80 and CD86) and the opposite function of CD28 and CTLA-4 in T cell activation. Further investigation on physiological function of this pathway in vivo may help for developing rational therapeutic approaches manipulating this pathway.