Distinct in vitro binding properties of the anti-CD20 small modular immunopharmaceutical 2LM20-4 result in profound and sustained in vivo potency in cynomolgus monkeys

Objectives. To characterize the in vitro binding and effector function properties of CD20-directed small modular immunopharmaceutical (SMIP) 2LM20-4, and to compare its in vivo B-cell depletion activity with the mutated 2LM20-4 P331S [no in vitro complement-dependent cytotoxicity (CDC)] and rituximab in cynomolgus monkeys

Increased expression of interleukin-22 by synovial Th17 cells during late stages of murine experimental arthritis is controlled by interleukin-1 and enhances bone degradation

Item does not contain fulltextOBJECTIVE: Interleukin-22 (IL-22) is a mediator in antimicrobial responses and inflammatory autoimmune diseases. Although IL-22 and its receptor, IL-22R, have been identified in the synovium of rheumatoid arthritis patients, the source of IL-22 and its contribution to disease pathogenicity remain to be established. This study was undertaken to investigate the regulation of IL-22 by Th17 cells in vitro and to evaluate the potential for IL-22 depletion in an experimental arthritis model using mice deficient in the IL-1 receptor antagonist (IL-1Ra-/-). METHODS: Naive murine T cells were cultured under conditions leading to polarization of the cells into subsets of Th1, Th2, induced Treg, and Th17. Cytokines were measured in the culture supernatants, and the cells were analyzed by fluorescence-activated cell sorting. Tissue samples from the inflamed ankle synovium of IL-1Ra-/- mice were isolated, and messenger RNA levels of marker genes were quantified. IL-1Ra-/- mice were treated with neutralizing anti-IL-22 antibodies. Synovial cells were isolated from the inflamed tissue and sorted into fractions for analysis of cytokine production. RESULTS: In vitro tests showed that Th17 cells produced high levels of IL-22 after stimulation with IL-1 or IL-23. Interestingly, a synergistic increase in the production of IL-22 was observed after combining IL-1 and IL-23. In vivo, IL-1Ra-/- mice displayed a progressive erosive arthritis, characterized by up-regulation of IL-17 in mildly and severely inflamed tissue, whereas the levels of IL-22 and IL-22R were increased only in severely inflamed synovia. Anti-IL-22 treatment of IL-1Ra-/- mice significantly reduced the inflammation and bone erosion. Analysis of isolated single cells from the inflamed synovia revealed that IL-22 was mainly produced by IL-17-expressing T cells. CONCLUSION: These findings suggest that IL-22 plays an important role in IL-1-driven chronic joint destruction

IL-21R-deficiency increases the initial TLR2 response but protects against joint pathology by reducing Th1/17 cells during SCW-arthritis

Contains fulltext : 138199.pdf (publisher's version ) (Closed access)Objective: The cytokine IL-21 can have both proinflammatory and immunosuppressive effects. Purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis in relation to Th17-cells. Method: In IL-21R-deficient mice and wild-types, antigen-induced arthritis (AIA) and chronic Streptococcal Cell Wall (SCW) arthritis were induced. Knee joints, synovial tissue and serum were analyzed for arthritis pathology and inflammatory markers. Results: Our studies show that during AIA and chronic SCW-arthritis, IL-21R-deficiency protects against severe inflammation and joint destruction. This is accompanied by suppressed serum IgG1 levels and antigen-specific T cells responses. IL-17 was reduced during AIA, and synovial lymphocytes isolated during SCW-arthritis for flowcytometry demonstrated that mainly IL-17+ IFNgamma+ T cells were reduced in IL-21R-deficient mice. However, during the acute phases of SCW arthritis significantly higher joint swelling scores were observed, in line with enhanced TNF and IL-6 expression. Interestingly, IL-21R-/- mice were significantly less capable in upregulating SOCS 1/3 mRNA. IL-21 stimulation also affected the TLR2/NOD2 response to SCW fragments in vitro, indicating that impaired SOCS regulation in the absence of IL-21 signaling might contribute to the increased local activation during SCW arthritis. Conclusion: In contrast to the proinflammatory role of IL-21 in adaptive immunity, driving IL-17/IFN double-positive cells and joint pathology during chronic experimental arthritis, IL-21 also has an important immunosuppressive role, presumably by inhibiting TLR signaling via SOCS1/3. If this dual role of IL-21 in various immune processes is present in human disease, it could make IL-21 a difficult therapeutic target in RA. (c) 2013 American College of Rheumatology