Cytokine regulation in rodents with experimental arthritis

Abstract: The general aim of this project has been to try to elucidate the mechanisms behindinduction of arthritis by using in situ hybridization and immunohistochemicalmethods to analyse the dynamics of the cytokine network in vivo, in the peripheralIymphoid system and in the joints of rodents with collagen-induced arthritis (CIA)and oil-induced arthritis (OIA). We first examined the kinetics of cytokine gene expression in vivo, in the drainingIymphnodes of DA rats following immunization with rat type II collagen (RCII) emulsifiedin Freund's incomplete adjuvant oil (FIA) or with only FIA, which are regimens thatinduce CIA and OIA, respectively. We also investigated if inhibition of arthritisthrough inclusion of an irrelevant antigen, ovalbumin (OVA) in the emulsions wasassociated with an altered cytokine production. A rapid and pronounced expressionof TNFa mRNA was observed in RCII/FIA and FIA immunized rats but not in OVA/FIA immunizedanimals, which instead expressed IL-4 mRNA. We further compared the cytokine secretion pattern in the draining lympnodes ofarthritis susceptible DA rats and non-susceptible F344 and DA MHC congenic PVG. IAV 1 rats following RCIVFIA immunization. In contrast to DA rats which did not expressIL-4, immunization of RCII/FIA in F344 rats and PVG IAVI rats was characterized byinduction of IL-4 mRNA. Moreover, TNFa, IL-2 and IFNr mRNA expression was significantlyreduced compared to DA rats at all timepoints studied. We also investigated which cell population is involved in OIA by using adoptivetransfer. The results indicate that polyclonal CD4+ cells expressing a type I cytokinesecretion pattern could transfer OIA. As induction of TNFa synthesis in CIA appears to be a key feature in the inductionof the disease, the effect of Rolipram, a drug with documented downregulatory effecton TNFa, was evaluated in the CIA model. An ameliorative effect of Rolipram on thedevelopment of arthritis was recorded, an effect associated with a profound reductionin the expression of TNFa and IFNy. The presence of TGFß isoforms and TGFß receptor-expressing cells wasexamined in the synovial tissue of arthritic rats during the course of CIA, and anabundant expression of TGFßs and its receptors in arthritic joints was demonstrated. Finally, we analysed the dynamics and distribution of cytokine production in arthriticlimbs of mice with CIA. A dominant and universal presence of monokines in contrastto a paucity of T cell-derived cytokines throughout the disease process was recorded.Moreover, differences in cytokine patterns at various stages of disease were observedwith T cell-derived cytokines (IFNy) only being expressed during the initial phaseof disease and monokines being expressed during all phases of disease. Our results indicate that (I) a strong local expression of TNFa may be importantfor the induction of arthritis, (2) the elicitation of an immune reaction againstan irrelevant antigen, may inhibit arthritis development by contributing to a shiftin the initial arthritogenic cytokine response, (3) non-MHC gene(s) determine thedirection of the anti-RCII response towards a type I disease-promoting, or a type2 disease-limiting response, (4) a type I cytokine response may be important in theinduction of experimental arthritis. Key words: collagen-induced arthritis, oil-induced arthritis, IL-2, IL-4, TNFa,IFNy, TGFß ISBN 91-628-2862-2