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arthritic indices by macroscopic inspection of joints, it is recommended that the scoring, which is to some extent subjective, be done by someone who does not know if the animal is an experimental or a control animal.

Troubleshooting

Success rates of AA induction in Lewis rats should be 90% to 100%. If the incidence of AA is lower, one of the following should be changed: the batch of mycobacteria used, the source (commercial supplier) of the animals, or the individual performing the immunizations.

Alternative procedures that may reduce resistance to disease induction include thymec-tomy, splenectomy, low-dose total-body irradiation (200 rad), and administration of low doses of cyclophosphamide or hydrocortisone 2 to 3 days prior to AA induction (Kayashima et al., 1976). Prior immunization of the animals involving inoculation with incomplete Fre-und's adjuvant (IFA) or mineral oil may lead to reduced disease susceptibility (Cozine et al., 1972). Moreover, prior administration of certain adjuvants, such as dimethyldioctadecyl ammonium bromide (DDA, Eastman Kodak; Snippe and Kraaieveld, 1989), may enhance AA severity. No solid mechanistic explanations are available for these effects at present.

Anticipated Results

Successful immunization will lead to the development of macroscopically visible inflammation of ankles, wrists, and/or interpha-langeal joints starting within 10 to 17 days post immunization. Disease development is accompanied by an immediate inhibition of the normal weight increase seen for rats of the preferred age group. Furthermore, ulcer formation will be visible at the site of immunization.

Disease severity will increase over a period of 2 weeks and then diminish. Malformation of joint anatomy (which usually starts around day 20 after M. tuberculosis immunization) will remain permanent in most (severe) cases after remission of disease. It will be difficult to reestablish disease by a second immunization once animals have experienced AA.

Histopathological examination of joints in the early phase will reveal vascular dilation, mixed neutrophil and mononuclear infiltrates, hyperplasia of synovial lining cells, and focal granulation of tissue. There will be some mixed inflammatory exudate in the synovial cavity. At this stage, articular cartilage will be intact. In severe disease, infiltrates will be more intense and (sub)synovial tissue will be edematous with areas of focal necrosis. Hyperplastic synovium may extend into the joint cavity. Reactive granulation tissue may extend into periarticular soft tissues and subchondral bone, with destruction of cartilage and invasion of marrow space. In late disease, pannus (membrane of granulation tissue, which is chronic and progressive and produces joint erosion) will extend over the surface of articular cartilage, resulting in fibrous ankylosis. Bone remodeling and periostal new bone formation will be evident (Terrier et al., 1985).

Radiographical examination will reveal soft tissue swelling, osteoporosis, widening or narrowing of joint cavity, periostal bone formation, bone erosions, and heterotopic ossification (Terrier et al., 1985).

Time Considerations

Preparation of the suspension of bacteria in oil will take ~10 min and can be done in advance. Immunization of 5 to 10 rats will require 25 to 50 min.

Arthritis will develop starting 10 to 17 days after primary immunization. Active disease will last for 10 to 25 days and may persist. In total, AA induction and clinical scoring over the period of disease development and subsequent remission will take ~6 weeks. Optimal clinical scoring by determination of arthritic indices and body weight will require daily examination (which takes 1 hr a day) of the animals over the active disease period (days 10 to 40 after induction). After the disease period is finished, rats can be used as sources of spleen cells or lymph-node cells for lymphocyte proliferation assays.

Literature Cited

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Battisto, J.R., Smith, R.N., Beckman, K., Sternlicht, M., and Welles, W.L. 1982. Susceptibility to adjuvant arthritis in DA and F344 rats. Arthritis Rheum. 25:1194-1199.

Bersani-Amado, C.A., Duarte, A.J., Tanji, M.M., Cianga, M., and Jancar, S. 1990. Comparative study of adjuvant-induced arthritis in susceptible and resistant strains of rats. III. Analysis of lymphocyte subpopulations. J. Rheumatol. 17:153158.

Best, R., Christian, R., and Lewis, D.A. 1984. Effect of particle size of dried mycobacteria on adjuvant-induced arthritis in the rat. Agents Actions 14:265-268.

Billingham, M.E.J., Carney, S., Butler, R., and Colston, J. 1990. A mycobacterial 65-kDa heat shock protein induces antigen-specific suppression of adjuvant arthritis, but is not itself arthri-togenic. J. Exp. Med. 171:339-344.

Cozine, W.S., Stanfield, A.B., Staephens, C.A.L., and Mazur, M.T. 1972. Adjuvant disease—The paradox of prevention and induction with complete Freund's adjuvant. Proc. Soc. Exp. Biol. 141:911-914.

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Holoshitz, J., Naparstek, Y., Ben-Nun, A., and Cohen, I.R. 1983. Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science 219:56-58.

Kayashima, K., Koga, T., and Onoue, K. 1976. Role of T lymphocytes in adjuvant arthritis. Evidence for the regulatory function of thymus-derived cells in the induction of the disease. J. Immunol. 117:1878-1883.

Kleinau, S., Erlandsson, H., Holmdahl, R., and Klareskog, L. 1991. Adjuvant oils induce arthritis in the DA rat. I. Characterization of the disease and evidence for an immunological involvement. J. Autoimmun. 4:871-880.

Koga, T., Kato, K., Kotani, S., Tanaka, A., and Pearson, C.M. 1976. Effect of degradation of the arabinomannan portion of a water-soluble component of M. tuberculosis Wax D on polyarthritis induction in the rat. Int. Arch. Allergy Appl. Immunol. 51:395-400.

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Kohashi, O., Kuwata, J., Umehara, K., Uemura, F., Takahasi, T., and Ozawa, A. 1979. Susceptibility to adjuvant arthritis among germ-free, specific pathogen-free, and conventional rats. Infect. Immun. 26:791-794.

Larsson, P., Holmdahl, R., Dencker, L., and Klares-kog, L. 1985. In vivo treatment with w3/13 (anti-pan-T) but not with OX8 (anti-suppressor/cyto-toxic T) monoclonal antibodies impedes the development of adjuvant arthritis in rats. Immunology 56:383-391.

Parrott, D.P. and Lewis, D.A. 1977. Protease and antiprotease levels in blood of arthritic rats. Ann. Rheum. Dis. 36:166-169.

Pearson, C.M. 1956. Development of arthritis, periarthritis and periostitis in rats given adjuvant. Proc. Soc. Exp. Biol. Med. 112:95-101.

Pearson, C.M., Waksman, B.H., and Sharp, J.T. 1961. Studies of arthritis and other lesions induced in rats by injection of mycobacterial adjuvant. J. Exp. Med. 113:485-510.

Rosenthale, M.E. 1970. A comparative study of the Lewis and Sprague Dawly rat in adjuvant arthritis. Arch. Int. Pharmacodyn. 188:14-22.

Snippe, H. and Kraaieveld, C.H. 1989. The immu-noadjuvant dimethyldioctadecyl-ammonium bromide. In Immunological Adjuvants and Vaccines (G. Gregoriades, A.C. Allison, and G. Poste, eds.) pp. 47-50. Plenum Press, New York.

Stanescu, R., Lider, O., van Eden, W., Holoshitz, J., and Cohen, I.R. 1987. Histopathology of arthritis induced in rats by active immunization to myco-bacterial antigens or by systemic transfer of T lymphocyte line. Arthritis Rheum. 30:779-792.

Swingle, K.F., Jaques, L.W., and Kram, D.C. 1969. Differences in the severity of adjuvant arthritis in four strains of rats. Proc. Soc. Exp. Biol. Med. 132:608-612.

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Taurog, J.D., Kerwar, S.S., McReynolds, R.A., San-berg, G.P., Leary, S.L., and Mahowald, M.L. 1985. Synergy between adjuvant arthritis and collagen-induced arthritis in rats. J. Exp. Med. 162:962-978.

Terrier, F., Hricak, H.L., Revel, D., Alpers, C.E., Reinold, C.E., Levine, J., and Genant, H.K. 1985. Magnetic resonance imaging and spec-troscopy of the periarticular inflammatory soft-tissue changes in experimental arthritis of the rat. Invest. Radiol. 20:813-823.

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van Eden, W., Thole, J.E.R., Van der Zee, R., Noordzij, A., Van Embden, J.D.A., Hensen, E.J., and Cohen, I.R. 1988. Cloning of the mycobac-terial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 331:171-173.

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Animal Models for Autoimmune and

Inflammatory Disease

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