Animal models immunogenicity

Orr N, Robin G, Cohen D, Arnon R, Lowell GH Immunogenicity and efficacy of oral or intranasal Shigella flexneri 2a and Shigella sonnei proteosome-lipopolysaccharide vaccines in animal models. Infect Immun 1993 61 2390-2395. 

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. 

Immunogenicity is a substantial complication for preclinical safety assessment studies. Antibodies can invalidate the animal model species. Antibody production alone, however, should not necessarily prohibit the conduct of these studies. The effect on pharmacokinetics and pharmcodynamics needs to be measured and evaluated. The potential consequences of the antibodies on endogenous molecules also needs to be evaluated. Secondary effects, such as antibody deposition, should be measured. The lack of ability to predict absolute human immunogenicity does not preclude the use of animals to assess the relative potential for an immune response. 

A variety of assays have been designed and validated to measure specific antibodies in the sera of treated animals. In addition efforts have been paid to minimizing the immunogenicity of therapeutic proteins. As these issues are addressed comprehensively in another chapter of this volume, the focus here will be on predicting problems that may ensue from the presence of such antibodies, namely hypersensitivity reactions. Presumably because allergic reactions have long been considered to be nonreproducible in animal models, limited efforts have been paid to designing predictive animal models until recently. Unexpectedly, the consequence is that no adequately standardized and validated model is available at the present time. 

Immunogenicity assays for investigating the frequency and consequences of antibody development against a protein therapeutic agent are typically based on an immunoassay technique (mostly ELIS As of various types). However, other assay formats are available such as radioimmunoprecipitation assay, surface plasmon resonance, and electrochemiluminescence [3]. Assays for measuring antibody response should be established in the early preclinical stage of development to estimate the value of the applied animal models (see Chapters 16 and 20). 

Many proteins, polypeptides, oligonucleotides, and other large molecules are immunogenic in the animal models used in pharmacology and toxicology evalu-... 

The discipline has progressed considerably since then, although some of the limitations (immunogenicity and targeting) still exist. The advent of recombinant DNA technology, cloning, and wide-scale enzyme purification have basically solved the first problem. Our laboratory and several others [21-28] have demonstrated clearly that enzymes can be modified so as to dramatically improve on their resistance to biodegradation or stability at 37°C or in the face of a host of different plasma proteases. The problem of animal models has also been partly... 

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