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Biologic Therapies for Rheumatoid Arthritis
Published in Thomas F. Kresina, Monoclonal Antibodies, Cytokines, and Arthritis, 2020
Ian R. Mackay, Merrill J. Rowley, Claude C. A. Bernard
Studies in experimental autoimmune disease have validated immunotherapy with anti-Ia directed to blocking antigen presentation. For example, in experimental autoimmune encephalomyelitis (EAE) in the susceptible SJL mouse, the injection of a MAb to an Ia molecule before immunization with brain emulsion prevented EAE in 25 of 28 treated mice, and treatment with MAb after the appearance of lesions, or in mice with chronic relapsing EAE, reduced the frequency of relapses (7 of 18 versus 18 of 18 in controls) and the frequency of deaths (22). There are equivalent data for EAE in monkeys, although acute deaths are recorded in some monkeys given MAb (23). Various other experimentally induced autoimmune diseases have been attenuated by anti-Ia MAb, including myasthenia gravis induced by immunization with acetylcholine receptor (24). This therapy is also effective in spontaneously developing autoimmunity exemplified by thyroiditis or diabetes in the BB rat (25) or lupus in mice when MAb to the appropriate Ia molecule is used over months 4–8 of life (26). Moreover, since collagen may be an antigen relevant to rheumatoid arthritis, it is of interest that monoclonal and polyclonal antisera to Ia suppressed the occurrence of collagen-induced arthritis in mice after immunization with type II collagen (27).
Animal Models of Rheumatoid Arthritis
Published in Yuehuei H. An, Richard J. Friedman, Animal Models in Orthopaedic Research, 2020
Erica L. Moran, Earl R. Bogoch
Collagen induced arthritis is distinct from other models of arthritis in that it is induced by an endogenous antigen, and also because arthritis can be induced in naive animals by the injection of anticollagen antibodies. As has been observed and reported for RA, the cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF-α) appear to be involved in the pathogenesis of collagen induced arthritis (reviewed by Durie et al.23). For example, recent studies employing the IL-1 receptor antagonist (IL-1 ra), show that edema, cellular infiltration, and increased proteoglycan levels in synovial fluid during the induction phase of adjuvant arthritis are not inhibited, but IL-1 ra has an anti-fibrotic action, decreasing abnormal interstitial collagen deposits and promoting regeneration of normal fat spaces in the synovial lining.31,32 Collagen induced arthritis differs from RA in that subcutaneous nodules and pulmonary fibrosis are lacking, as are extraarticular manifestations, with the exception of lesions in the hyaline cartilage of the ear.
Anti-inflammatory activities of a new VEGF blocker, Conbercept
Published in Immunopharmacology and Immunotoxicology, 2021
Collagen-induced arthritis (CIA) in rats has been widely used for preclinical testing of numerous anti-arthritic agents. In our study, rat CIA models were established to evaluate the anti-inflammation activities of Conbercept. Joint swelling was observed mainly at two back feet of rats after Type II Collagen immunization. RA rats had decreased appetite, weight loss, and difficulty in walking. Etanercept is a TNFα inhibitor composed of the soluble extracellular domain of TNF receptors and the Fc region of a human immunoglobulin and is widely used to treat rheumatoid arthritis. We used Etanercept as a positive control. As shown in Figures 2 and 3, after Conbercept and Etanercept treatment, paw edema volume and ankle thickness were significantly reduced compared to the control treatment. The AI score significantly reduced in the Conbercept group and Etanercept group compared to the control group (Figure 4). For the control treatment group, paw edema volume, ankle thickness, and AI score had no significant change during the experiment. There was no significant difference in paw edema volume, ankle thickness, and AI score between the Conbercept group and Etanercept group. All results indicate that Conbercept significantly inhibits collagen-induced arthritis in rats.
Mavrilimumab: a unique insight and update on the current status in the treatment of rheumatoid arthritis
Published in Expert Opinion on Investigational Drugs, 2019
Chiara Crotti, Martina Biggioggero, Andrea Becciolini, Elena Agape, Ennio Giulio Favalli
In a preclinical study Greven and colleagues demonstrated, through immunohistochemistry analyses, an increased expression of GM-CSFRα by specific clusters of synovial macrophages (particularly CD68+ and CD163+) from RA and psoriatic arthritis compared with osteoarthritis patients and healthy controls [44]. The same authors demonstrated that at the onset of collagen induced-arthritis the administration of a monoclonal antibody against GM-CSFRα (CAM3003) inhibited disease progression by reducing synovial inflammation and joint destruction [44]. Again, CAM3003 treated mices models reported a reduction of the number of F4/80+ macrophages in the antigen-induced arthritis [45]. GM-CSFRα blockade reduces inflammatory macrophages/monocyte-derived dentritic cell differently to TNF or IL-6 blockade, modulating the inflammatory response in more than a way [45]. Finally, other in vitro studies suggested a role for GM-CSF pathway inhibition in TNFi resistant arthritis, as the result of combination strategy with other molecules (i.e. IL-17) [46].
Can oral bacteria affect the microbiome of the gut?
Published in Journal of Oral Microbiology, 2019
Ingar Olsen, Kazuhisa Yamazaki
In a mouse (DBA/1J) experimental rheumatoid arthritis (RA) model, P. gingivalis was orally administered, intended to mimic periodontitis patients swallowing the bacterium. The gut microbiome changed, followed by increased serum endotoxin and inflammatory markers, and the gut barrier function was impaired [9]. A clear relationship between the oral and gut microbiota and RA was demonstrated. Thereafter, DBA/1J mice were given orally P. gingivalis and Prevotella intermedia, which contrary to P. gingivalis has no peptidyl arginine deiminase causing citrullination. This was followed by induction of collagen-induced arthritis (CIA). A significant change in the gut microbiome occurred [9]. P. gingivalis but not P. intermedia significantly increased IL-17 levels in sera and culture supernatants, as well as the Th17 cell proportions among mesenteric lymphocytes and Peyer’s patches. Although P. gingivalis aggravated CIA in the DBA/1J mice, it did not further increase the level of anti-citrullinated protein antibody. The suspected role of P. gingivalis in RA could, therefore, be by affecting the gut immune system and by causing composition shifts in the gut microbiota rather than by citrullination of proteins.