Rodent Preclinical Models for Developing Novel Antiarthritic Molecules: Comparative Biology and Preferred Methods for Evaluating Efficacy

Figure 1

The ability to model immune-mediated disease is affected by many factors, including the animal strain (top triangle), the choice of model (middle triangle), and the nature of the antiarthritic molecules being tested (bottom triangle). For rat strains, susceptibility to arthritis is highest in DA and lowest in F344 animals. For rat model systems, the adjuvant-induced arthritis (AIA) variants are more aggressive than are the collagen-induced arthritis (CIA) and streptococcal cell wall (SCW) versions; furthermore, the extent of AIA lesions depends on the inciting agent (lipoidal amine (LA) versus heat-killed Mycobacterium (Myc)), while the severity of the CIA lesions is more extensive if the source of incomplete Freund's adjuvant (IFA) is Sigma Chemical Co. (St. Louis, MO) rather than Difco Laboratories (Detroit, MI). With regard to treating rats with CIA, the greatest improvement in joint disease is achieved using the cytokine-inhibiting biologics interleukin-1 (IL-1) receptor antagonist (IL-1ra) and soluble tumor necrosis factor (TNF) receptor (sTNFR) and intermediate using small molecule blockers of p38 kinase (which regulates IL-1 and TNF). Depending on the treatment window, cyclosporin A (CsA) will inhibit, delay, or even exacerbate arthritis in Lewis rat CIA (compare also to Figure 8).