Model Systems for IN Vivo Immunotoxicity Screening

Pruett, Stephen

Abstract

Host resistance to infection or cancer is presently the most biologically relevant measure of immune function. The most widely used method for monitoring host resistance in immunotoxicity studies is the susceptibility (survival) test. In this procedure, the effect of test agents on the ability of animals to survive a challenge with infectious agents or tumor cells is determined. This method requires large numbers of animals, subjects them to pain and suffering, and, as generally performed, does not distinguish between agents which affect the adaptive phase of immune responses and those which affect the effector phase. Also, genetically determined innate resistance and strictly non-adaptive immunity are often not examined. The purpose of the proposed work is to develop model systems which will allow evaluation of the effects of drugs and chemicals on host resistance but will require fewer animals than susceptibility studies, will avoid pain and suffering on the part of the test animals, will distinguish between the adaptive and effector phases of immunity, and will examine genetically determined innate resistance and non-adaptive immunity. This will be accomplished by measuring bacterial elimination (or growth) in host blood or tissues following a challenge dose of bacteria. Since bacterial elimination does not always correlate at all time points with ultimate host survival rates, these studies will examine blood or tissue bacterial concentrations at various times and compare them with ultimate survival rates. Known immunotoxins will be tested to determine a time after challenge at which bacterial elimination will correlate with the ultimate host survival rate in both immunotoxin-treated animals and untreated controls. Four mouse disease models are proposed which will allow examination of all the aspects of immunity already mentioned and for which bacterial elimination patterns and host survival rates have been reported in the literature.