Animal Models of Host Resistance

Immunotoxicology Strategies for Pharmaceutical Safety Assessment, edited by Danuta X Herzyk 

TABLE 5.1-1 Commonly Used Host Resistance Assays 

B16F10 Syngeneic tumor cell assay Mouse 

MODELS OF HOST RESISTANCE TO INFECTIONS Influenza Host Resistance Assay 

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Several opiate receptors have been identified on cells of the nervous systems of animals and humans, with mu (p), kappa (k), and gamma (y) subtypes being predominant. These classical opiate receptors are G- protein coupled 7-transmembrane molecules.27 Opiates predominantly affect immune responses directly by ligation of p, k, and y opiate receptors, as well as non-classical opiate-like receptors, on immune cells and indirectly by binding to receptors on CNS cells. Studies conducted in vitro with opiate-treated immune cells demonstrated receptor-mediated reduced phagocytosis, chemotaxis and cytokine and chemokine production. These effects are linked to modulation of host resistance to bacterial, protozoan, viral and fungal infections using animal models, cell lines and primary cells. 

Further evidence to support the notion of a role for immunotoxic environmental contaminants in the 1988 outbreak came from two studies of laboratory rats carried out in tandem with the seal studies. PVG rats were fed the same two batches of herring used in the seal study, with a similar pattern of effects observed in the seals [63,64], However, there were additional indications of immunotoxicity that could not be evaluated in seals for ethical or technical reasons, including increased virus titers in a rat cytomegalovirus (RCMV) host resistance model, and reduced thymus cellularity in the rats fed Baltic Sea herring. A positive control group of rats in one of the studies was exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin, thereafter exhibiting an amplified pattern of the effects that had been observed in the Baltic group. The collective results from the captive seal studies and the laboratory animal studies were seen to implicate an AhR-mediated immunotoxicity, in which dioxin-like PCBs played a dominant role [64, 65],... 

It is generally accepted that two types of immune response are involved in the host defence against salmonellosis - cellular and humoral (41). In attempts to control salmonellosis by active immunization of humans, or of animals in experimental model systems, living vaccines have been superior to killed vaccines consequently, cellular immunity has been considered to be of greater importance for the host resistance (42, 43). 

Tier 2 also include host resistance models, tests in which an animal is exposed to a xenobiotic and then challenged with an infectious agent or tumor cells. This is considered the ultimate test for an adverse effect on the immune system. However, it should be noted that the amount of immune suppression that can be tolerated is greatly dependent on the dose and virulence of the challenging agent, as well as the genetics of the host. Manipulation of these variables can affect greatly results obtained in host resistance tests. 

Abstract Marijuana and other exogenous cannabinoids alter immune function and decrease host resistance to microbial infections in experimental animal models and in vitro. Two modes of action by whichA -tetrahydrocannabinol (THC) and other cannabinoids affect immune responses have been proposed. First, cannabinoids may signal through the cannabinoid receptors CBi and CB2. Second, at sites... 

Experimental animal models, using guinea pigs and mice, have been used for nearly a century to document effects of various toxic and infectious agents on host resistance. These in vivo models have offered unique advantages for assessment of... 

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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