Objective. To study the effects of interleukin-7 receptor ␣-chain (IL-7R␣) blockade on collageninduced 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␣ 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␣ 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␣. IL-7R␣ 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-␥, IL-5, and IL-17). IL-7R␣ blockade also decreased local levels of proinflammatory cytokines and factors associated with tissue destruction, including tumor necrosis factor ␣, IL-1␤, IL-6, matrix metalloproteinase 9, and RANKL. IL-7R␣ 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␣ potently inhibited joint inflammation and destruction in association with specific reductions of T cell numbers, T cellassociated 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␣ blockade in human arthritic conditions.

Chronic pain is a major clinical problem that is difficult to treat and requires novel therapies. Although most pain therapies primarily target neurons, neuroinflammatory processes characterized by spinal cord and dorsal root ganglion production of proinflammatory cytokines play an important role in persistent pain states and represent potential therapeutic targets. Anti-inflammatory cytokines are attractive candidates to regulate aberrant neuroinflammatory processes, but the therapeutic potential of these cytokines as stand-alone drugs is limited. Their optimal function requires concerted actions with other regulatory cytokines, and their relatively small size causes rapid clearance. To overcome these limitations, we developed a fusion protein of the anti-inflammatory cytokines interleukin 4 (IL4) and IL10. The IL4-10 fusion protein is a 70 kDa glycosylated dimeric protein that retains the functional activity of both cytokine moieties. Intrathecal administration of IL4-10 dose-dependently inhibited persistent inflammatory pain in mice: three IL4-10 injections induced full resolution of inflammatory pain in two different mouse models of persistent inflammatory pain. Both cytokine moieties were required for optimal effects. The IL4-10 fusion protein was more effective than the individual cytokines or IL4 plus IL10 combination therapy and also inhibited allodynia in a mouse model of neuropathic pain. Mechanistically, IL4-10 inhibited the activity of glial cells and reduced spinal cord and dorsal root ganglion cytokine levels without affecting paw inflammation. In conclusion, we developed a novel fusion protein with improved efficacy to treat pain, compared with wild-type anti-inflammatory cytokines. The IL4-10 fusion protein has potential as a treatment for persistent inflammatory pain.

Objective Innate lymphoid cells (ILCs) are a recently discovered group of cells that are essential to epithelial homeostasis and are implicated in psoriasis pathogenesis, yet they have never been reported in psoriatic arthritis (PsA). Methods ILC classes and subsets were characterized in the peripheral blood (PB) of healthy controls, patients with psoriasis, and patients with PsA and in the synovial fluid (SF) of patients with PsA and patients with rheumatoid arthritis (RA). Cell surface marker expression and intracellular cytokine production following stimulation were analyzed using flow cytometry. Results ILCs were identified in the SF and were 4‐fold more abundant in PsA SF than in PsA PB. Fewer CCR6+ ILCs were found in PsA PB than in healthy control PB, while PsA SF was enriched for CCR6+ ILCs compared to PsA PB and RA SF. Natural cytotoxicity receptor NKp44+ group 3 ILCs were rare in PB and RA SF, but abundant in PsA SF. Increased numbers of interleukin‐17A (IL‐17A)–producing ILCs were present in PsA SF compared to RA SF. CCR6, NKp44, and melanoma cell adhesion molecule (MCAM) were expressed on the cell surface of SF ILCs that produced IL‐17A. The number of circulating NKp44+, CCR6+, and MCAM+ ILCs in blood was inversely correlated with PsA disease activity. Conclusion Our findings indicate that PsA SF is enriched for group 3 ILCs that express CCR6 and NKp44, which distinguishes the synovial compartment from RA. The increased IL‐17A production by SF ILCs indicates a novel role for ILCs in PsA.

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Objective. To evaluate the expression and functional ability of the high-affinity interleukin-7 receptor (IL-7R␣) in patients with rheumatoid arthritis (RA).Methods. Expression of IL-7R␣ and IL-7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA).