Modulation of adaptive immune responses in mice upon exposure to peroxisome proliferators

Abstract: At present, there is an increasing awareness that exposure of mammals to drugs or other foreign chemicals can result in modulation of immunological responses via direct or indirect mechanisms. Changes in the immune system can obviously have profound physiological and pathological consequences. One important family of xenobiotics, the peroxisome proliferators (PPs), including numerous industrial chemicals (e.g., phthalates and perfluoro fatty acids), agrochemicals (e.g., phenoxyacetic acids) and important clinical drugs (e.g., hypolipidemic agents, such as fibrate derivatives, and acetylsalicylic acid) have not yet been examined in this respect.Accordingly, examination of possible effects of PPs on the immune system of mice was undertaken in the present study. For the first time, we have demonstrated that PPs do indeed modulate the immune system of mice in a number of ways. (1) Severe thymic and splenic atrophy occur upon treatment of mice with potent PPs. (2) These changes reflect dramatic decreases in the numbers of thymocytes and splenocytes as a consequence of inhibition of thymocyte proliferation. (3) These effects are dose- and time-dependent and are rapidly reversed upon withdrawal of PP from the diet. (4) PP treatment also results in dramatic suppression of the ability of splenocytes to produce specific antibodies in response to T-cell dependent antigens, as well as reducing the proliferation of both T- and B-cells in response to specific activators.Further investigation established that an indirect mechanism is involved in these changes. In addition, the atrophy of the thymus and spleen occurred later than hepatic peroxisomal proliferation and required a higher dose, suggesting that these two responses are not coordinated. Finally, by employing transgenic mice, we demonstrated that these immunomodulating effects of PPs are, to a large extent, mediated by the peroxisome proliferator-activated receptor-a (PPARa).