Collagen - Induced Arthritis (CIA) Rhesus Monkey Model And Drug Therapy

The study is divided into two main parts: The first part aims to inducearthritis with bovine type II collagen in rhesus monkeys. The second part aimsto use the commercial drugs like CELEBREX and rhTNFR:Fc (etanercept,Recombinant human tumor necrosis factor-α receptor II: IgG Fc fusion proteinfor injection) to confirm the utilit y of this model.Part one Bovine type II collagen induced arthritis(CIA) in rhesusmonkeys.Objective: To investigate the pathogenesis of collagen induced arthritis inrhesus monkeys. Methods:6monkeys were injected with mixture made bybovine type II collagen(CII) and Freund’s complete adjuvant(FCA). Results:The pathogenesis of collagen induced arthritis in rhesus monkeys mainlyshowed as: on D12-D15after immunization, all monkeys showed symptoms ofinflammation with formation of ulcerative skin lesi ons, loss of appetite, morethan14%of body weight loss or slow growth, abnormal of biped behavior(clinical scores were1-2points). on Day15-Day25, animals were divided intotwo disease status: acute phase RA and chronic phase RA, the former showedserum and cytokines changes with the corresponding X-ray changes andmacroscopic soft tissue swelling, the latter showed a slightly serologicalchanges and not sensitive cytokines changes with X-ray changes not obvious.Conclusion: CIA in rhesus monkeys was similar to human RA in radiographicimages and serological indexes, and mimicked human RA clinicalmanifestation, which will be a good model for further new compounds testing.Part two Confirmatory tests of CELEBREX and etanercept on CIA rhesusmonkeys. Objective: To evaluate clinical observation of CELEBREX and etanercepton CIA rhesus monkeys.Methods: The3animals of part one (1/3was acute phase RA,2/3waschronic phase RA) were administrated with CELEBREX on the fourth week afterimmunization(9mg kg-1，once a day，po.). Another5animals were givenetanercept on D26after collagen immunization（1mg kg-1，twice a week，sc.）,6animals in the control group was monitored dynamically afterimmunization,including detection of biochemical indicators, usingsemi-quantitative scoring system to monitor the animal’s weight and behaviorstatus; Before the administration and the end of administration detected: X-rayexamination of bone and joint lesions, serum cytokines TNF-α, IFN-γ changes,the bovine anti-type II collagen IgG changes.Results: Three active RA monkeys were administrated with Celebrex (9mgkg-1) for30days, slow control of inflammation, after continuousadministration of D16-D30can significantly improve the clinical diseaseactivity index, inhibited CRP, WBC, NEUT increase, while alleviating ALB,HGB reduction; X-ray indicated local soft tissue swelling of the affected jointsrelieved (3/3), but the regulation of bone protection, especially the continueddevelopment of bone destruction on feet (3/3).Etanercept (1mg kg-1) is estimated delivering for one month. OnD1-D26after immunization,5/5animals were acute active RA (clinicalscore,3-4points), CRP, WBC, NEUT, MONO levels increased significantly orvery significantly (P≤0.05or P≤0.01), HGB and ALB levels droppedsignificantly; after2weeks of administration (the fourth injection), an obviousanimal weight rebounded, the biochemical parameters gradually recovered; onD20after administration (the fifth injection), WBC, MONO, NEUT of4/5animals appeared to rebound, then given Celebrex (9mg kg-1, once a day for13days), after three days of administration, body weight tended to decrease, the final effect after administration showed that the increasing trend of animal bodyweight (clinical score reduced to1-2points), and MONO decreased, but theWBC, NEUT continued to maintain a high level. Compared with the X-ray ofbefore administration, soft tissue swelling of the limbs were significantlyimproved(5/5), bone damage did not prog ress.Control group belonged to chronic active immunization of animals(systemic clinical score,2points); the disease course progressed slowly, mainlyshowed as slow growth or decrease of body weight (3/5), clinical score was2-3points, blood biochemical indicators increased slowly(CRP、 WBC、 NEUT、MONO) or reduced to（HGB、 ALB） a lesser extent. X-ray films showed softtissue swelling of limbs of4/5animals progressed, development of articularsurface damage on2/5animals, mainly on the2-5th digits proximal phalangealjoints (PIP) of feet, compared with the pre-immune animals.Compared with animals On D26,cytokines in acute active RA monkeysshowed serum IFN-γ, TNF-α levels elevated (≥2-3times); compared withnormal animals, animals with chronic active RA showed serum IFN-γ, TNF-αlevels was normal or elevated slightly. Compared with normal animals, on D26after immunization, each group of anti-bovine type II collagen IgG levelssignificantly increased (P≤0.05), with the immune prolonged administrationof D33, IgG levels of control group showed a rising trend; etanercept withCELEBREX group showed decreasing.Conclusion: Celebrex can control inflammation on collagen-inducedarthritis in rhesus monkeys, but showed no protective effect on the damage ofarticular surface of the bone, in this study RA symptoms improved after onemonth of continuous admintration. Etanercept mainly play roles on thesymptoms of moderate or severe arthritis, and control the further damage ofarticular surface, short efficacy ti me, in this study animal’s symptoms improvedafter two week.