Effect of Psychological Stress on the Induction of Arthritis in Rats

The effect of rat cytomegalovirus (RCMV) infection on type I1 collagen-induced arthritis was studied in DA rats. Rats were infected with RCMV 5 days before, simultaneously with, or 5 days after immunization with calf type 11 collagen. Control rats were either given type II collagen alone or were injected with normal rat salivary gland (NRSG) simultaneously with collagen immunization. Severity of arthritis in each limb was graded on a scale of 1 4 (maximum score 16). In 5 experiments, peak arthritis scores in the RCMV groups were twice those of the control groups which received NRSG or collagen only (8-9 versus 4-6). Radiographs of involved joints showed greater destruction of cartilage and articular bone in the RCMV rats than in the NRSG control group. Repeated attempts to culture RCMV from joint tissues were unsuccessful. Our results indicate that RCMV infection enhances the arthritic process in this experimental model of an autoimmune arthritis.Among the many hypotheses which have been proposed to explain the pathogenesis of rheumatoid arthritis, we have been interested in the possibility that viral infection may exacerbate an underlying, diseaserelated autoimmune process in genetically predisposed individuals (1,2). To test this hypothesis, we have From the Veterans Administration Medical Center and the Department of Medicine, University of Utah College of Medicine, Salt Lake City.Supported by The Veterans Administration and by NIH grant no. AM-30763.Charles B. Smith, MD; Marie M. Griffiths, PhD; Lian S. Wei, MS.Address reprint requests to Charles B. Smith, MD, Medical Service, Veterans Administration Medical Center, 500 Foothill Drive, Salt Lake City, UT 84148.Submitted for publication January 6, 1986; accepted in revised form May 30, 1986. studied the effect of experimental rat cytomegalovirus (RCMV) infection on the course of type I1 collageninduced arthritis in laboratory rats. Cytomegalovirus was chosen for study because of its ubiquitousness and its ability to alter the immune system in human subjects and laboratory animals (3). Type I1 collagen-induced arthritis was selected because it has many similarities to human rheumatoid arthritis and to the seronegative polyarthritides (43). This animal model of autoimmune arthritis is also desirable to study because the target of the autoimmune process (type I1 collagen) is well-defined biochemically and immunochemically (6,7), because it is possible to measure the contributions of humoral and T cell-mediated aspects of the immune system (5,8-lo), and because susceptibility to the autoimmune process is genetically determined in rats ($1 1,12). Our studies indicated that RCMV infection of DA laboratory rats is associated with increased severity of type I1 collagen-induced arthritis. MATERIALS AND METHODSAnimals. DA (RTlaV1) strain rats were obtained from our breeding colonies at the VA Hospital, Salt Lake City. Periodic testing for antibodies to common rat pathogens (Microbiological Associates, Bethesda, MD) indicated that the colony has been free of the foll...

Section: Discussionmentioning

confidence: 99%

Rat cytomegalovirus infection enhances type II collagen arthritis in rats

Smith

Griffiths

Wei

1986

“…The severity of arthritis was graded visually, according to an adaptation of a method previously described for use with rats (27). The arthritic changes in each limb were scored 0-3 (0 = no changes and 3 = severe arthritic changes).…”

Section: Methodsmentioning

confidence: 99%

Enhanced production of interleukin‐6 in mice with type II collagen–induced arthritis

Takai

Seki

Senoh

et al. 1989

We established an interleukin‐6 (IL‐6)–dependent cell line from murine plasmacytoma MOPC‐104E cells. This cell line (designated PIL‐6) was found to respond to murine and to human IL‐6, but not to any other cytokines. We used this cell line to investigate the involvement of IL‐6 production in type II collagen–induced arthritis in DBA/1 mice. Only marginal IL‐6 activity was detected in sera from DBA/1 mice inoculated with Freund's complete adjuvant (FCA) alone, with an unrelated protein (bovine serum albumin) plus FCA, or with type II collagen plus Freund's incomplete adjuvant. However, enhanced IL‐6 activity was observed in DBA/1 mice that had been injected with type II collagen plus FCA to induce arthritis. The elevated level of serum IL‐6 activity was associated with high levels of IL‐6 produced when lymph node cells from arthritic mice were stimulated in vitro with type II collagen. We also found that the L3T4+ T cell subset is responsible for the enhanced production of IL‐6 in arthritic mice. The results are discussed in the context of potential roles of IL‐6 in the induction and/or expression of chronic, progressive arthritis.

Section: Methodsmentioning

confidence: 99%

“…After digestion of the tissue, the radioactivity present in each biopsy is counted, and the radiometric ear index is then expressed as the ratio of the counts per minute (cprn) in the antigen-challenged ear versus the control ear. Radiometric ear indices 21.6 have been previously calculated to represent significant DTH reactions to chick type I1 collagen in this assay (25).…”

Section: Methodsmentioning

confidence: 99%

“…The sum of scores of all 4 paws is designated by the arthritic index (20,22). Histologic evaluations were not performed in these experiments because of the correlation between macroscopic and microscopic judgements of the severity of arthritis found in previous studies (25,27).Radiographic evaluation. After killing the rats by ether anesthesia, we disarticulated all hindpaws above the knee; then the hindpaws were coded, mounted with adhesive tape on cardboard, and frozen at -20°C until radiographs on plain x-ray film were performed.…”

mentioning

confidence: 99%

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Immunosuppression by fractionated total lymphoid irradiation in collagen arthritis

McCune

Buckley

Belli

et al. 1982

Self Cite

Treatments with fractionated total lymphoid irradiation (TLI) and cyclophosphamide were evaluated for rats injected with type I1 collagen. Preadministration of TLI and repeated injections of cyclophosphamide suppressed the severity of arthritis and lowered antibody titers to collagen significantly. TLI initiated at the onset of collagen arthritis decreased humoral and cellular responses to collagen but did not affect the severity of arthritis. These data demonstrate that both TLI and cyclophospharnide are immunosuppressive in an experimentally inducible autoimmune disease.The immunosuppression produced in mice by fractionated total lymphoid irradiation (TLI) can pro-A preliminary account of this work was presented at the annual meeting of the American Rheumatism Association at Boston, MA, June 5 , 1981, and was published in abstract form in Arthritis and Rheumatism, 242359, 1981. From long allogeneic skin (1,2) and bone marrow (2-5) engraftment , expedite the development of tolerance to foreign protein antigens (6), decrease the antibody response to a foreign antigen (7), and ameliorate autoimmune disease in the NZB/NZW (8,9) and MRL/1 (10) strains. In rats, TLI has been shown to facilitate the induction of allograft tolerance (1 1,12), to decrease, preferentially, lymphocyte concentrations in the blood, and to partially suppress adjuvant arthritis (13). In view of the prospect of using this technique [which is a recognized therapy for Hodgkin's disease (14,15)] as an alternative to cytotoxic drug therapy (16,17) in the treatment of patients with severe rheumatoid arthritis (18,19), we investigated whether TLI could modify in rats the clinical, radiographic, and immunologic manifestations of an inflammatory polyarthritis induced by immunization with type I1 collagen (20,21). We also compared the efficacy of TLI with that of cyclophosphamide in this model. MATERIALS AND METHODSRats. We used female Sprague-Dawley rats (Charles River Breeding Laboratories, Wilmington, MA) that weighed 100-130 gm.Collagen and immunization. Rats were immunized during ether anesthesia by intradermal injection of the dorsal skin with approximately 0.4 mg of previously prepared (22) native pepsin-modified chick type I1 collagen dissolved in 0.1M acetic acid and emulsified in incomplete Freund's adjuvant (20). In one experiment, immunized rats were boosted with approximately 0.4 mg of dissolved collagen that was injected intraperitoneally (20).Irradiation. Rats were irradiated with a 250-kV Westinghouse x-ray machine operated at 15 mamp at a rate of 40 rads per minute and a source-axis distance of 60 cm. The beam was corrected with 0.5-mm copper and 1 .O-mm alumi- (13), except for these modifications: the anatomic confines of the thymus and spleen were identified by autopsies, and the ports over these organs were slightly enlarged to ensure total inclusion of these tissues. Because of the lateral scatter that occurs when irradiation is delivered in this energy spectrum (23,24), vertical lead shields, 2 mm in thickness, were positioned...