T cell directed therapies and biologics

Abstract

One result of the growing evidence that T cells are responsible for the initiation and perpetuation of chronic arthritis is that therapies aimed at downregulating the effects of lymphocytes may prove to be beneficial for arthritis patients. Thoracic duct drainage, lymphapheresis, total lymphoid irradiation and cyclosporin treatment, whose principal action is assumed to be confined to lymphocytes, have been reported to be effective in patients with rheumatoid arthritis (RA) [1-5]. The association of some of these therapies with serious side-effects and their failure to induce permanent remission warranted the development of new therapies that would more specifically downregulate disease-relevant T cells. Based on promising results in experimental autoimmune disease models [6], and pilot studies in human subjects [7], clinical trials using biological agents targeted at T cell surface antigens were initiated. These included both monoclonal antibodies (mAb) and recombinant fusion proteins. Another approach involved targeting the trimolecular complex of antigen, human leucocyte antigen (HLA) molecule, and T cell receptor (TCR) to selectively influence the response to a specific autoantigen without compromising normal immune function. Cohen et al. demonstrated in experimental autoimmune disease models that disease-inducing T cell clones could be employed to induce immunity following attenuation of the T cells before inoculation. This procedure, designated T cell vaccination (TCV), was assumed to be based on the interference of a network of T cells that recognize cell surface structures expressed by certain other T cells [8,9].