Experimental studies on immunosuppression: how do they predict for man?

Abstract

The ultimate goal of any animal model in immunotoxicity testing is that it be a sensitive predictor of xenobiotic-induced immune dysfunction in humans. Such models should be capable of identifying the target(s) within the immune system affected by the xenobiotic. In particular the tier testing models have been successfully used to identify and characterize a variety of different immunotoxicants in animals as it pertains to immunosuppression and reduced resistance to infectious diseases. These tier models in mice and rats have been validated in interlaboratory studies. Although these protocols were designed for studies of rats and mice, some have been applied succesfully for studying immunotoxicity in other animal species, including non-human primates. A great amount of data has been generated by the application of these models, which demonstrate that xenobiotics alter the immune system of animals. In man, the database on chemical-induced immunosuppression is limited, as the use of markers of immunotoxicity has received little attention in clinical and epidemiological studies. Such studies have not been performed frequently, and their interpretation often does not permit unequivocal conclusions to be drawn, due for instance to the presence of confounding factors and the uncontrolled nature of exposure. Also, testing possibilities in humans are limited and immune function changes by chemical exposure are often subtle. In humans, a number of agents have been shown to have immunosuppressive properties (including PCBs, PCDDs, PCDFs, oxidant gases, and ultraviolet radiation), but the strongest evidence stems from the clinical use of immunosuppressant drugs in transplant patients. These human data do in general terms confirm the data gained with experimental animals. Immunotoxicity assessment in rodents therefore adequately forms the basis for human risk assessment. Knowledge on the predictability of these animal models and immune assays can be further improved by comparison of the human and animal data obtained in the development of drugs.