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Cure Arthritis Naturally

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aFrom Cremer et al. (1994a).

b+, 1-25% incidence; ++, 26-50% incidence; +++ 51-75% incidence; ++++, 76-100% incidence. c+, 1-4; ++, 5-8; +++, 6-12; ++++, 13-16. A score of 1 is the lowest and 16 the highest. ^Female/male scores separated by slash where applicable. e Antibody specific for bovine CII.

aFrom Cremer et al. (1994a).

b+, 1-25% incidence; ++, 26-50% incidence; +++ 51-75% incidence; ++++, 76-100% incidence. c+, 1-4; ++, 5-8; +++, 6-12; ++++, 13-16. A score of 1 is the lowest and 16 the highest. ^Female/male scores separated by slash where applicable. e Antibody specific for bovine CII.

strains have also been shown to be susceptible to CIA, with the exception of the SWR strain, which has a complement deficiency (Watson and Townes, 1985). Two of the CIA-susceptible H-2q strains in Table 15.5.4 (B10.0QBr and BUB) have large genomic deletions of T cell-receptor variable genes. Male mice are frequently preferred for CIA studies, as the incidence of arthritis is somewhat higher in male than in female mice. Although mice 8 weeks of age are generally preferred for CIA experiments, DBA/1 mice remain highly susceptible to arthritis at least through the age of 6 months.

Both B and T cell responses can be measured in mice following immunization with CII. As with most antigen systems, the T cell responses with CII peak around day 10 to 12, but can be detected for several weeks following immunization. Serum antibody production peaks as the incidence and severity of arthritis peaks, and, within a given strain, the levels of antibody correlate well with the presence or absence of arthritis. Among different susceptible and non-susceptible strains, antibody levels can vary widely. Some nonsusceptible strains produce significant amounts of CII-specific antibody, yet fail to develop arthritis (Wooley et al., 1981).

CIA rat model

CIA as an experimental model of autoimmune arthritis was first described by Trentham et al. (1977) using an inbred rat strain. The following are the major characteristics of CIA in the rat.

(1) There is a larger number of highly inbred strains of rat that are susceptible to CIA (Table 15.5.5) than there are susceptible mouse strains. Many of these strains differ in their class II RT1 genes, thus providing a variety of genetics for studying the autoimmune response.

(2) Rats not only develop arthritis after immunization with CII, but also after immunization with type XI collagen, mycobacteria, and streptococcal cell walls. This feature provides useful controls and comparisons with the autoimmune arthritis induced by CII.

(3) Arthritis can be induced easily in rats with incomplete Freund's adjuvant (IFA), obviating the use of potent immunoadjuvants such as mycobacteria and pertussis which produce immune response to antigens other than CII.

(4) After immunization, high-responder rats develop arthritis more quickly (in 9 to 16 days) than mice (in 24 to 42 days), thereby shortening the length of the experiments and the amount of time the animals must be maintained.

(5) The rat's larger size makes many procedures easier (or possible) to perform—e.g., thoracic-duct canulation, implantation of longstanding venous access devices, recovery of cells from arthritic joints, and accurate, reproducible measurement of paw volume by Hg manometry (see Support Protocol 5).

The three most important variables in the induction of CIA in rats are: (1) strain selection, (2) animal health, and (3) the effectiveness of the CII used for immunization. Conveniently, a number of susceptible strains are available from commercial vendors that maintain required health standards. CIA has been repro-ducibly elicited in eight strains of inbred rats differing at RT1 (Table 15.5.5) and in two strains of commercially available outbred rats. The information summarized in Table 15.5.5 should be interpreted with the understanding that the strains shown were obtained from different sources, housed under different conditions for various lengths of time, immunized with different doses and preparations of CII, and in some instances given a single injection but in others boosted one to five weeks later. Although it is unlikely that these variables would affect the susceptibility of high-re-sponder strains, they might have a significant impact on moderate- to low-responder strains. Notably, two inbred strains of rats, F344 and MAXX (RT1lv1 and RT1n, respectively), have proven highly resistant to CIA following immunization with different species sources of CII, thus they are not included in Table 15.5.5.

Like many animal models, bacterial and viral infections can adversely affect the incidence and severity of CIA. Hence, only specific pathogen-free rats (see unit 1.1) should be used to obtain reproducible results. The best documented infectious agent impairing CIA in the rat is Mycoplasma pneumoniae. High-responder LEW rats appearing deceptively healthy are quite resistant to CIA when infected with M. pneumoniae (Taurog et al., 1984). Likewise, active infection can impair lymphocyte proliferation in long and short-term in vitro studies. Regular monitoring of sentinel animal health and serology is mandatory when frequent or long-term studies of CIA are undertaken.

CIA first appears as early as 8 days after immunization in high-responder BB and WF rats and 12 to 16 days after immunization in outbred Wistar rats. Onset, however, can occur as late as 30 to 60 days after immunization in

Animal Models for Autoimmune and

Inflammatory Disease

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