Hypersensitivity animal models

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. 

Helm, R.M., Hypersensitivity reactions non-rodent animal models, in Investigative Immunotoxicology. Tryphonas, H., Fournier, M., Blakley, J.E.G., Smits, J.E.G., and Brousseau, Eds., Taylor Francis - A CRC Press Book, Boca Ratton, Florida, 2005, Chapter 18. 

Griffiths-Johnson, D.A. and Karol, M.H., Validation of a non-invasive technique to assess development of airway hyperreactivity in an animal model of immunologic pulmonary hypersensitivity, Toxicology, 65, 283, 1991. 

Types II and III Hypersensitivity. No simple animal models are currently available to assess Type II (antibody-mediated cytotoxicity) hypersensitivity reactions. IgE antibodies and immune complexes in the sera of exposed animals can be assayed using ELISA or RIA techniques that require the use of specific antibodies to the drug. 

Contact Hypersensitivity and Animal Model of Tolerance to Haptens... 

NTl86 Justus, D. E., and D. A. Adams. Evaluation of tobacco hypersensitivity responses in the mouse. A potential animal model for critical study of tobacco allergy. Int Arch Allergy Appl Immunol 1976 51(6) 687-695. 

Oxcarbazepine is less potent than carbamazepine, both in animal models of epilepsy and in epileptic patients clinical doses of oxcarbazepine may need to be 50% higher than those of carbamazepine to obtain equivalent seizure control. Some studies report fewer hypersensitivity reactions to oxcarbazepine, and cross-reactivity with carbamazepine does not always occur. Furthermore, the drug appears to induce hepatic enzymes to a lesser extent than carbamazepine, minimizing drug interactions. Although hyponatremia may occur more commonly with oxcarbazepine than with carbamazepine, most adverse effects that occur with oxcarbazepine are similar in character to reactions reported with carbamazepine. 

The aim of homogenization is to reduce fat droplet size, which changes the structure of milk and may affect health-related properties (Michalski and Januel 2006). Research on an animal model has suggested that homogenization seems to favor hypersensitivity. Hypersensitive mice orally fed homogenized milk experienced an anaphylactic shock (Polusen and Hau 1987), increased milk-specific IgE production (Nielsen et al. 1989), increased intestinal segment mass, and demonstrated... 

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. 

At present recognized animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, animal testing may be used, e.g. a modification of the guinea pig maximization test for determination of relative allergenicity ofproteins. However, these tests still needfurther validation. 

It is obvious that the development of new animal models, for example transgenic and knock-out mice, should create new possibilities for predicting the sensitizing potential of new antimicrobials. The sad fact that hypersensitivity reactions are among the most commonly occnrring adverse effects when antibiotics are nsed nnder-Unes the nrgent need for research efforts in academia and indnstry (227). 

Choquet-Kastylevsky G, Descotes J. Value of animal models for predicting hypersensitivity reactions to medicinal products. Toxicology 1998 129(l) 27-35. 

Uetrecht J Role of animal models In the study of drug-induced hypersensitivity reactions. Aaps J 2005 7 E914-21. 

Relatively non-specific T cell immunosuppression has been successful in animal models. Treatment of hypersensitivity pneumonitis in mice with cyclosporin A led to improvement of the disease as seen by an abrogation of the increase in lung index, lack of IL-1 and TNFa release in BAL (Denis etal., 1992). However, this drug has not proven to be useful in clinical lung fibrosis in humans. 

Dermal. There are very few reported cases of skin reaction responses in the multinational industry survey,7 and animal models in other surveys do not provide reliable predictive utility for these effects.91114 However, when they occur, dermal hypersensitivity-type reactions are a significant contributor to termination of drugs in various stages of development (Clinical Phases 2 and 3 in particular).719... 

Autoimmunity is much more complex than hypersensitivity. Animal models exist for many autoimmune conditions, and autoimmunity has been clearly demonstrated in humans, although it is a relatively infrequent occurrence. Therefore, the existence of autoimmune disease and the expected consequences cannot be denied. However, the ability of drugs and chemicals to exacerbate or trigger autoimmune disease in either animal models or humans is poorly understood. In fact, of all the possible consequences of immunotoxicity, autoimmunity is unquestionably the least understood. Primarily... 

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