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 α-chain (IL-7Rα) 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-7Rα 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-7Rα 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-7Rα. IL-7Rα 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-γ, IL-5, and IL-17). IL-7Rα blockade also decreased local levels of proinflammatory cytokines and factors associated with tissue destruction, including tumor necrosis factor α, IL-1ß, IL-6, matrix metalloproteinase 9, and RANKL. IL-7Rα 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-7Rα 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-7Rα blockade in human arthritic conditions.

RIP4 regulates epidermal differentiation and cutaneous inflammation.

The receptor-interacting protein (RIP) family kinase RIP4 interacts with protein kinase C (PKC) isoforms and is implicated in PKC-dependent signaling pathways. RIP4(-/-) mice die at birth with epidermal differentiation defects, causing fusions of all external orifices and loss of the esophageal lumen. To further understand RIP4 function in the skin, we generated transgenic mice with epidermal-specific expression of RIP4 using the human keratin-14 promoter (K14-RIP4). The K14-RIP4 transgene rescued the epidermal phenotype of RIP4(-/-) mice, showing that RIP4 acts autonomously in the epidermis to regulate differentiation. Although RIP4(-/-) mice share many phenotypic similarities with inhibitor kappaB kinase (IKK)alpha(-/-) mice and stratifin repeated epilation (Sfn(Er/Er)) mice, the K14-RIP4 transgene failed to promote epidermal differentiation in these mutant backgrounds. Unexpectedly, topical treatment of K14-RIP4 mice with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced dramatic, neutrophilic inflammation, an effect that was independent of tumor necrosis factor type 1 receptor (TNFR1/p55) function. Despite their enhanced sensitivity to TPA, K14-RIP4 mice did not have an altered frequency of tumor formation in TPA-promoted skin cancer initiated with 7,12-dimethylbenz[a]anthracene (DMBA). These data suggest that RIP4 functions in the epidermis through PKC-specific signaling pathways to regulate differentiation and inflammation.

Elevated expression of interleukin-7 receptor in inflamed joints mediates interleukin-7-induced immune activation in rheumatoid arthritis.

OBJECTIVE: To evaluate the expression and functional ability of the high-affinity interleukin-7 receptor (IL-7Ralpha) in patients with rheumatoid arthritis (RA). METHODS: Expression of IL-7Ralpha 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). IL-7Ralpha expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL-7Ralpha(bright) and IL-7Ralpha(dim/-) T cells was measured. In addition, we examined IL-7R blockade with soluble human IL-7Ralpha (hIL-7Ralpha) in the prevention of immune activation of peripheral blood mononuclear cells. RESULTS: We found significantly higher IL-7Ralpha expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL-7Ralpha expression correlated significantly with the levels of CD3 and IL-7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL-7Ralpha. A substantial percentage of B cells and macrophages from RA synovial fluid and synovial tissue also expressed IL-7Ralpha, although less prominently than T cells. We found that peripheral blood IL-7Ralpha(bright) T cells that did not express FoxP3 were highly proliferative as compared with IL-7Ralpha(dim/-) T cells that did express high levels of FoxP3. Soluble hIL-7Ralpha inhibited IL-7-induced proliferation and interferon-gamma production by mononuclear cells from RA patients. CONCLUSION: Our data suggest that enhanced expression of IL-7Ralpha and IL-7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL-7R-mediated immune activation by soluble hIL-7Ralpha further indicates an important role of IL-7Ralpha in inflammatory responses in RA, suggesting IL-7Ralpha as a therapeutic target for immunotherapy in RA.

Deciphering CD30 ligand biology and its role in humoral immunity.

Ligands and receptors in the tumour necrosis factor (TNF) and tumour necrosis factor receptor (TNFR) superfamilies have been the subject of extensive investigation over the past 10-15 years. For certain TNFR family members, such as Fas and CD40, some of the consequences of receptor ligation were predicted before the identification and cloning of their corresponding ligands through in vitro functional studies using agonistic receptor-specific antibodies. For other members of the TNFR family, including CD30, cross-linking the receptor with specific antibodies failed to yield many clues about the functional significance of the relevant ligand-receptor interactions. In many instances, the subsequent availability of TNF family ligands in the form of recombinant protein facilitated the determination of biological consequences of interactions with their relevant receptor in both in vitro and in vivo settings. In the case of CD30 ligand (CD30L; CD153), definition of its biological role remained frustratingly elusive. Early functional studies using CD30L+ cells or agonistic CD30-specific antibodies logically focused attention on cell types that had been shown to express CD30, namely certain lymphoid malignancies and subsets of activated T cells. However, it was not immediately clear how the reported activities from these in vitro studies relate to the biological activity of CD30L in the more complex whole animal setting. Recently, results from in vivo models involving CD30 or CD30L gene disruption, CD30L overexpression, or pharmacological blockade of CD30/CD30L interactions have begun to provide clues about the role played by CD30L in immunological processes. In this review we consider the reported biology of CD30L and focus on results from several recent studies that point to an important role for CD30/CD30L interactions in humoral immune responses.