The Effects of Azathioprine and 6 mp on Immunity

Abstract

The thiopurines, azathioprine and 6 MP are potent inhibitors of both experimental and clinical immune responses. The primary pharmacological activities are mediated by competitive inhibition of enzymes concerned with de novo purine base synthesis; Immunosuppressive activities appear to result from cytotoxic activities directed against antigen-responsive lymphocytes; this inhibition is maximal when the treatment course coincides with the proliferative expansion phase of the response. By contrast, thiopurines are comparatively ineffective if used during an effector phase of an immune response. Furthermore, administration prior to antigenic challenge does not lead to immune inhibition; in fact, it may lead to augmentation of selected immune responses. Treatment with thiopurines does not result in acute lymphopenia; prolonged courses will cause a moderate decrease in circulating lymphocytes. The drug does not selectively deplete peripheral T or B cells but can acutely reduce K (killer) cells, which are effectors in ADCC responses. In addition, short-lived thymocytes and marrow lymphocytes are rapidly depleted by these anti-metabolites. Many in vitro functions of lymphocytes, from treated animals remain normal. Recent studies indicate that, in vitro, azathioprine is specifically able to bind murine T lymphocytes; this can be shown by their ability to inhibit their capacity to rosette with sheep erythrocytes. Azathioprine is also a potent inhibitor of mixed lymphocyte culture responses and can readily suppress the in vitro generation of cytotoxic T cells. These observations suggest that drugs exert preferential toxicities for murine T cells. B lymphocytes for mice appear to vary in their susceptibility for thiopurines. By contrast, the activity of human B cells can be readily suppressed with this drug whereas T helper function is comparatively resistant. In addition to immunosuppressive properties, thiopurines are capable of exerting anti-inflammatory activities, primarily by inhibiting the replication of hematopoietic precursors.