It is far too early to assess the ultimate role of the antimetabolites in the therapy of autoimmune diseases in general. In a few specific instances, such as the thiopurines in autoimmune hemolytic anemia and the antifolic acids in psoriasis, these uses are approaching the state of recognized therapeutic regimens. However, as several authors have pointed out, the drugs presently available provide little margin between the dosages required for therapeutic effects and those which will produce serious toxicity. Very little is available in the way of comparative effects of several antimetabolites in a given disease. Moreover, on the basis of present results, one is unable to sort out in a given situation the relative importance of effects on circulating antibodies, delayed hypersensitivity, and anti-inflammatory activities, although there are some indications that these effects may be at least partially separable.
One may reasonably inquire, in view of their less marked effects on established immunity than on the induction of the primary response, why these drugs influence autoimmune disease at all. Perhaps another apparent anomaly might be mentioned. The induction of tolerance requires a high initial dose of antigen, and tolerance is maintained only in the continuing presence of antigen. The persistence of a simple antigen is significantly increased when a carrier, such as Freund's adjuvant, is given simultaneously. One might expect that by this means the induction and maintenance of tolerance to the antigen would be facilitated, but the opposite is true. Whether this is the result of the route or site of administration or the nature of the carrier, it appears that the adjuvant may have altered the antigenic stimulus in some fundamental way. One clue which may provide future information is the observation of Mathé et al. (222) that different cell types are stimulated by different antigens and indeed by the same antigen with and without adjuvant. Similarly, Bieber (23) observed that the repressive effects of purine antagonists as opposed to those of thymidine affected different portions of the cellular response of the spleen to heterologous erythrocytes. Studies such as these eventually may aid in the classification of drugs by their effects on specific antigenic stimuli and may aid in the understanding of some of the species differences in responsiveness and in the interpretation of the responses obtained in the autoimmune diseases.
The mechanism of action of the antimetabolites in their effects on the immune response cannot be defined with any certainty at this time. Since most of the drugs which inhibit immune processes are also "anticancer" agents, a mechanism involving cellular destruction first comes to mind. It can be shown that effects on immunity can be obtained at levels of drug which produce no obvious effects on the numbers of circulating lymphocytes, but this does not exclude the possibility of a selective destruction of a small clone of cells in which the rate of multiplication has increased in response to an antigenic stimulus. An evaluation of these factors may be facilitated if new drugs become available which show a greater separation of "anti-immune" and "antitumor" effects (161). Alternative explanations might involve a metabolic block of some informational process through inhibition of the biosynthesis of a nucleic acid. This might take the form of an inhibition of the synthesis de novo of the purine and thymine moieties of the nucleic acids. In the case of the base analogs, a direct incorporation might occur into one or more of the nucleic acid fractions, either deoxyribonucleic acid, or informational, soluble, or microsomal ribonucleic acid. The principal hindrance to a direct attack on these problems is the present inability to obtain the cell line concerned with a specific immune response in anything like a pure culture. It is impossible to carry out meaningful biochemical studies on cell populations in which only a small percentage of the cells is participating in the reaction to be studied. This may be summed up by saying that there is no solid foundation for an interpretational structure, but that a multitude of challenging problems exists. It is predictable that the solutions to many of these will come with further progress in studies of the immune response in vitro, as further advances are made in achieving uniformity in pertinent cell populations.