Targeted depletion of lymphotoxin-a–expressing TH1 and TH17 cells inhibits autoimmune disease
Targeted depletion of lymphotoxin-a-expressing TH1 and TH17 cells inhibits autoimmune disease
Chiang, E. Y. et al. Nature Medicine 15:766-773 (2009)
Speaker: Wan-Shan Chou (周琬軒) Time: 13:10~14:00, Dec. 30, 2009
Commentator: Dr. Ai-Li Shiau (蕭璦莉 博士) Place: Room 601
Abstract:
T helper cell type 1 (TH1) and TH17 are characterized by unique cytokine production, such as IFN-g and IL-17, respectively. Increasing evidence shows that proinflammatory TH1 and TH17 are associated with autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis1,2. The authors identified a surface protein lymphotoxin-a (LT-a) stably expressed on TH1 and TH17 but not TH2 cells, and with low level expression on non-T lymphocytes. This phenomenon could be used as the mAb target for depleting pathogenic TH cells. At first, the authors confirmed the specific expression of LT-a on TH1 and TH17 subsets on both human cells and mouse model. Anti-LT-a mAb showed the specific binding, and did not disturb germinal center formation in vivo. After a mutation in the Fc region of anti-LT-a mAb, the antibody lost the depletion ability. In TH1 and TH17 dependence acute inflammatory model, the numbers of IFN-g- and IL-17- producing cells were decreased and there was no delayed-type hypersensitive response in anti-LT-a mAb-treated mice. In experimental autoimmune encephalomyelitis model, anti-LT-a mAb treated-mice showed lower clinical scores than the control group, and had decreased infiltrated cell numbers in secondary lymphoid organ. These results support that anti-LT-a mAb could deplete activated LT-a-expressing pathogenic TH cells in vivo and inhibit T-cell-mediated inflammation. In collagen-induced arthritis model, mice were induced to develop the arthritic syndrome at hind paws, such as disfiguration at joints and lost of bone volume. The authors found that anti-LT-a mAb could reverse this arthritic syndrome. Taken together, the authors suggest that depleting LT-a-expressing pathogenic TH cells with LT-a-specific mAb may be beneficial in the treatment of autoimmune disease.
Reference:
1. Weiner, H.L. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J. Neurol. 255 Suppl 1, 3–11 (2008).
2. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and TH17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).