Role of T lymphocytes in the development of rheumatoid arthritis. Implications for treatment.

T cells play a role in the initiation and perpetuation of tissue inflammation that can lead to tissue destruction. With the discovery of a number of T helper subsets and their potential plasticity during disease it became clear that the T cell behaviour in autoimmune diseases is much more complex than the first Th1/Th2 concept. From experimental autoimmune arthritis models it became clear that the IL-23/IL-17 immune pathway is critical in the development of autoimmune arthritis and IL-17A has been recognized to be a key cytokine involved in initiation and perpetuation of chronic destructive arthritis. Functional studies using T cells and stromal cells from patients with RA revealed improvement of anti-TNF effects when combined with agents neutralizing IL-17A or agents suppressing Th17 cytokines production. Clinic trials will be needed to test whether these data from experimental settings can be translated to human arthritis. Different approaches are available or under investigation to target: (1) pathogenic T cell activity by inhibiting RORc or STAT3 or the costimulator pathway by CTLA4-Ig; (2) Th17 cytokine production by anti-IL-17A, anti-IL-22, or combination of anti-IL-17A/anti-TNF approaches; (3) Th17 polarization by neutralizing IL-23 using an anti-IL-23 specific antibody, IL-12/IL-23 by an anti-p40 antibody, or the IL-6 signaling pathway; (4) Th17 migration by interfering the CCR6-CCL20 interaction. The challenge is to bring the best to the clinic to further improve current therapy for patients with RA and to reach stable remission or even prevent the development of this disabling disease.