From nonspecific to specific immunosuppression: facts and speculation.

Following the pioneering work of Schwartz et al. [35] who showed that the formation of antibody by bovine serum albumin can be suppressed in rabbits with 6-mercaptupurine (6 MP), a number of investigators have used immunosuppressive drugs. About 20 years ago, Spiegelberg and Miescher [37] treated experimentally induced immune thyroiditis in guinea pigs with methotrexate and 6 MP, and suggested that other autoimmune diseases, including systemic lupus (SLE) might benefit from treatment with immunosuppressive drugs. At about the same time we attempted to dissociate the various immune phenomena by the administration of 6 MP in experimental animals and found that delayed hypersensitivity was more susceptible than humoral antibody formation to 6 MP [-7]. Likewise, IgG antibody was more likely to be suppressed than IgM [9]. It later became apparent that immunosuppression can also be achieved with antigens. The concept of partial or split tolerance in which one type of immune response, such as delayed hypersensitivity, can be suppressed without suppressing humoral antibody to the same antigen was found independently by three different groups of workers [3, 10, 18]. The quest to control the immune response in a specific way is in part a consequence of work in basic immunology, i. e., on the mechanism of immunologic tolerance to simple antigenic determinants. Ideally, if one can induce immunologic tolerance to any antigens, it would alleviate the need for nonspecific drug therapy. In this regard, the observation that haptens can be either immunogenic or tolerogenic depending upon the carrier molecule was particularly useful [-4, 5, 23]. This discovery helped not only the understanding of the cellular mechanism of tolerance [1], but also the therapeutic application of tolerance induction to the treatment of autoimmune disease [11].