Blockade of the Interleukin-7 Receptor Inhibits Collagen-Induced Arthritis and Is Associated With Reduction of T Cell Activity and Proinflammatory Mediators

Objective. To study the effects of interleukin-7 receptor alpha-chain (IL-7R alpha) blockade on collagen-induced arthritis (CIA) and to investigate the effects on T cell numbers, T cell activity, and levels of proinflammatory mediators. Methods. We studied the effect of anti-IL-7R alpha antibody treatment on inflammation and joint destruction in CIA in mice. Numbers of thymocytes, splenocytes, T cell subsets, B cells, macrophages, and dendritic cells were assessed. Cytokines indicative of Th1, Th2, and Th17 activity and several proinflammatory mediators were assessed by multianalyte profiling in paw lysates. In addition, T cell-associated cytokines were measured in supernatants of lymph node cell cultures. Results. Anti-IL-7R alpha treatment significantly reduced clinical arthritis severity in association with reduced radiographic joint damage. Both thymic and splenic cellularity were reduced after treatment with anti-IL-7R alpha. IL-7R alpha blockade specifically reduced the total number of cells as well as numbers of naive, memory, CD4+, and CD8+ T cells from the spleen and significantly reduced T cell-associated cytokines (interferon-gamma, IL-5, and IL-17). IL-7R alpha blockade also decreased local levels of proinflammatory cytokines and factors associated with tissue destruction, including tumor necrosis factor alpha, IL-1 beta, IL-6, matrix metallo-proteinase 9, and RANKL. IL-7R alpha blockade did not significantly affect B cells, macrophages, and dendritic cells. B cell activity, indicated by serum anticollagen IgG antibodies, was not significantly altered. Conclusion. Blockade of IL-7R alpha potently inhibited joint inflammation and destruction in association with specific reductions of T cell numbers, T cell-associated cytokines, and numerous mediators that induce inflammation and tissue destruction. This study demonstrates an important role of IL-7R-driven immunity in experimental arthritis and indicates the therapeutic potential of IL-7R alpha blockade in human arthritic conditions.