Toxicity, immuno

United States Environmental Protection Agency, Biochemicals Test Guidelines, Immuno-toxicity, OPPTS 880.3550, Washington, D.C., 1996. 

ICICIS Group Investigators, Report of validation study of assessment of direct immuno-toxicity in the rat, Toxicology, 125, 183, 1998. 

Kuper, C.F. et al., Histopathologic approaches to detect changes indicative of immuno-toxicity, Toxicol. Pathol., 28, 454, 2000. 

Luster, M.I., Dean, J.H., and Germolec, D.R., Consensus workshop on methods to evaluate developmental immuno toxicity, Environ. Health Perspect., Ill, 579, 2003. 

There are a number of examples in which histopathology and the functional immuno-toxicity tests recommended by regulatory guidance documents would not detect known... 

Lawrence, B.P. and Kerkvliet, N.I., T helper clones and in vitro assessment of immuno-toxicity, in TLymphocyte Subpopulations in Immunotoxicology, Kimber, I. and Selgrade, M.J., eds. John Wiley Sons, New York, 1998, p. 143. 

The immunotoxicology of metals in fishes has been reviewed elsewhere [74-76, 45], Overall, the immune systems of fishes are highly sensitive to metals, although the effects are not always suppression of immune functions. Burnett [76] demonstrated that low levels of metals increased intracellular calcium, increased protein phosphorylation, and stimulated lymphocyte proliferation in fish. Since most metals are toxic to both the nervous system and the immune system, a neuroendocrine-immune link to immuno-toxicity from metal exposure is likely. 

Most marine mammals are exposed to relatively high concentrations of those contaminants considered to be persistent (do not breakdown readily in the environment), bioaccumulative (are not readily metabolized and excreted by biota in aquatic food webs), and (immuno)toxic. Candidates in this category include various congeners of... 

Among the most sensitive endpoints (on a body burden basis) are endometriosis, developmental neurobehavioural (cognitive) effects, hearing loss, developmental reproductive effects (sperm counts, female urinogenital malformations) and immuno-toxic effects, both adult and developmental. The most sensitive biochemical effects are CYP1A1/2 induction, hepatic retionid depletion, EGF-receptor down-regulation and oxidative stress. 

Use of in vivo Tests. In vivo tests are more relevant indicators than are in vitro tests of immunotoxicity since the dynamic interactions between the various immuno-components, as well as the pertinent pharmacokinetic (absorption, distribution, plasma concentrations) and metabolic factors, are taken into consideration. However, it is important to select the appropriate animal model and to design the protocol such that it will accurately reflect drug (or relevant metabolite) exposure to humans. For example, one should consider species variability when selecting the animal model, since biological diversity may further obscure the ability to accurately predict human toxicity. 

U.S. Congress, Office of Technical Assessment. (1991). Identifying and Controlling Immuno-toxic Substances—Background Paper. U.S. Government Printing Office, Washington, D.C., pp. 1-93. 

The results of the chronic administration study indicate that LC-AmB does not induce any new toxicity and that its side effects are the same as those produced by the conventional formulation (Fungizone) and a commercial lipid formulation (Abelcet) but that they appear at higher doses. This difference is probably due to both the stability of the formulation, preventing rapid release of AmB as aggregates or transfer to lipoproteins, and its size difference with Abelcet, which could lead to less rapid uptake by phagocytic cells. These encouraging results with respect to toxicity prompted us to test the efficacy of the formulation. For this, we chose to look at in vitro and in vivo models of Leishmaniasis, as well as the immuno-modulating properties of AmB. 

Studies in pre-clinical models with human tumours are often carried out in (immuno)defi-cient mice. However, particularly in the case of monoclonal antibody-directed therapy, it is important to recognize that these models, while useful, frequently over-predict activity and under-predict toxicity because the target antigen is tumour-specific in the animal but only tumour-associated in man. 

In appendix B of the CPMP Note for Guidance on Repeated Dose Toxicity (adopted October 2000), there is a request for an initial immuno-toxicity screen (primarily for measuring immunosuppression). This consists of an assessment of haematology (i.e. differential cell counting). 

While it is generally true that recombinant proteins containing amino-acid sequences identical to those of humans are less immunogenic than mouse-based recombinant proteins, human-based recombinant proteins can, because of their size, elicit immune responses on repeated administration. The impact of immuno-genicity on pharmacologic and toxic effects is only now beginning to be adequately appreciated. 

As is implied by its name, the first TNF-a-dependent mechanism described was the induction of tumor necrosis in vivo through its role in tumor vasculature. However the mechanisms of the in vitro toxicity of TNF-a to tumor cells imply apoptosis rather than necrosis [97], Tumor necrosis in SCID (severe combined immuno-deficiency) mice treated with LPS does not lead to the rejection of tumors [98], Furthermore, necrosis and tumor regression must be dissociated since anti-IFN-y antibodies inhibit LPS-induced regression of Meth A sarcoma in mice, but not the necrotic hemorrhage attributed to TNF-a. It is now accepted that the antitumoral effect of TNF-a is indirect and dependent on acquired immune response. Matsumoto et al. [99] reported that, while TNF-a itself has no effect on hepatoma KDH-8 tumor cells in vitro, the antitumoral effect of the lipid A ONO-4007 against KDH-8 tumors in vivo is inhibited by anti-TNF-a antibodies in WKAH rat, showing an indirect effect of TNF-a. 

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