Animal models autoimmunity

Many regulators of the cell cycle are also involved in regulation of apoptosis. There is growing evidence that some of these genes are also dysregulated in autoimmune animal models as well as in patients with autoimmune disease (for examples, see Table 3). In particular, the cell cycle blockade at the Go/G -phase could be a major factor in the apoptosis resistance and accumulation of activated/memory T... 

Rose, N.R. Bhatia, S. (1995). Autoimmunity animal models of human autoimmune disease In Methods in Immunotoxicology, 2, (Burleson, G.R., Dean, J.H., Munson, A.E. eds.), pp. 427-445, Wiley-Liss, New York. 

In addition to antibodies targeting the CD3 subunit of the TCR complex, antibodies against the a and (3 subunits of the TCR have been tested as therapeutic agents. A benefit for the treatment experimental autoimmune encephalomyelitis or collagen induced arthritis could be shown in animal models [8]. 

Some aspects of multiple sclerosis are reflected in the animal model experimental autoimmune encephalomyelitis, which is induced by immunization of susceptible animals with appropriate encephalogenic proteins or peptides. In these animals, if cultured adult stem cell neurospheres are injected into the bloodstream, injected cells can find their way to damaged portions of the nervous system and improve function in mice. How the injected cells augmented the recovery process is unclear. One possibility is that cells recruited to the lesions differentiated into oligodendrocytes and generated new myelin sheaths, but this seems unlikely in the face of ongoing cellular destruction. 

Experimental allergic encephalomyelitis is an animal model of autoimmune demyelination 640... 

Some xenobiotics may have divergent mechanisms of autoimmune responses. For example, hydralazine demonstrates adduct reactivity as well as inhibition of DNA methylation [68,73], while procainamide inhibits DNA methylation, forms immunogenic NPA, and disrupts clonal selection in the thymus [68, 72, 74], It is this complicated pattern of effects that makes assessment of autoimmune potential in the laboratory for new xenobiotics almost impossible. Animal models can sometimes be recreated to resemble human disease [74], and thus may be useful for therapy considerations, but are difficult to utilize for screening chemicals for hazard potential due to the diverse nature of autoimmunity mechanisms and physiological presentation. While evidence supports many different mechanisms for xenobiotic-induced autoimmune reactions, none have conclusively demonstrated the critical events necessary to lead to the development of autoimmune disease. Therefore, it is difficult to predict or identify xenobiotics that might possess the potential to elicit autoimmune disorders. 

Much of the methods development and validation efforts in the past have been focused on evaluation of immunosuppression and contact or dermal sensitization. Currently available animal models and assays are not valid to assess the potential for systemic hypersensitivity and, at this time, reliable models to assess autoimmunity are not available. 

Animal models have established that infections can induce autoimmune disease. For example, coxsackievirus B3 infection of susceptible strains of mice results in inflammation in the heart that resembles the myocarditis and dilated cardiomyopathy that occurs in humans.28 44 The same disease can be induced by injecting mice with cardiac myosin mixed with adjuvant, thereby reproducing the disease in the absence of virus infection, indicating that an active viral infection is not necessary for the development of autoimmune disease.9 29 44 Likewise, a number of autoimmune diseases can be... 

The mechanism most commonly invoked to explain the association of infection with autoimmune disease is molecular mimicry that is, the concept that antigens (or more properly, epitopes) of the microorganism closely resemble self-antigens.50 The induction of an immune response to the microbial antigen thus results in cross-reactivity with selfantigens and the induction of autoimmunity. Although epitope specific cross-reactivity has been shown in some animal models,48,51 53 molecular mimicry is clearly demonstrated to be the causative mechanism in few, if any, human diseases.3 54,55... 

An important animal model of lupus is the lpr mouse. It was discovered that the abnormality leading to autoimmunity in this model is a defect in the gene coding for Fas protein and this leads to impaired apoptosis [103], This, in turn, leads to lymphade-nopathy and prevents elimination of autoimmune T cells, thus interfering with tolerance. Minocycline inhibits apoptosis, and it has been postulated that this contributes to the mechanism of minocycline-induced lupus [104],... 

In the case of spontaneous autoimmune diseases mice are the most frequently used animal model. With the advent of transgenic and genetically modified (knockout, KO) mice, the number of genetically predisposed autoimmune models has substantially increased. Other species that have been useful include rats, monkeys, cats, dogs, rabbits, and chickens for some specific forms of autoimmune diseases [4, 5]. 

Genetically predisposed animals or induced animal models may also be used to study and predict chemical-induced autoimmunity. In induced models, a susceptible animal strain is immunized with a mixture of an adjuvant and an autoantigen isolated from the target organ. Examples are adjuvant arthritis (AA), experimental allergic encephalomyelitis (EAE) and experimental uveitis in the Lewis strain rat. Examples of spontaneous models... 

Talal, N. (1998). Autoimmune mechanisms in patients and animal models. Toxicol. Path. 15 272-275. 

An autoimmune response is rarely detected during preclinical drug development because of the lack of good predictive animal models for the human immune system. Owing to their low incidence and idiosyncratic nature, autoimmune diseases quite often appear as a serious issue only after product launch [2,22]. 

Some studies have demonstrated that chemicals can increase autoimmune disease in autoimmune-prone mice (e.g, NZB mice) [70, 81, 82]. Together, these and other examples demonstrate that indeed chemical-induced autoimmunity can be induced in ariimals. However, these examples also show that a chemical may require very specific circumstances to induce autoimmune phenomena. In other words, it may be an illusion that one single animal model will be found or developed that will cover all different chemical-related autoimmune diseases. 

Finally, it is tempting to speculate that in SC and postinfectious forms of TS the functional activity of the MSP neurons of the matrix is differentially impaired as a result of the autoimmune response. Indeed, preliminary data suggest that either bilateral striatal infusion into rats of antineuronal antibodies from TS patients or the immunization of mice with rat striatal homogenates may produce animal models of TS complete with stereotypical movements and audible vocalizations (Hallett et al., 2000 Hoffman and Lipkin, 2000). One plausible hypothesis is that the antineural antibodies found in a subset of TS patients may modulate synaptic transmission and alter the balance between the striosomal and matrisomal compartments of the striatum (Leckman and Riddle, 2000). 

---