Immunosuppression and Regulation

Research and clinical trials aimed at prolonging allograft survival have historically been viewed as promoting either immunosuppression or tolerance. However, new studies reveal that some immunosuppressive agents may also promote tolerance through enhanced generation of regulatory T cells (Treg). These findings lead to new ways of thinking about these agents and how they might be combined to promote tolerance while suppressing the immune response. This requires a new view of tolerance and immunosuppression as a continuum rather than a dichotomy. The outcome of kidney transplantation continues to improve through judicious use of potent drugs that prevent rejection by “nonspecifically” suppressing the immune system while trying to avoid deleterious consequences of overimmunosuppression. In contrast, research, including pilot clinical trials, continues to focus on achieving immunologic tolerance, where the immune system is rendered specifically unresponsive to the allograft in the absence of ongoing therapy. Tolerance promises to reduce rejection and improve long-term outcome, while avoiding the dangers of chronic immunosuppression. Conventional wisdom holds that tolerance has only been achieved in rodents and that standard immunosuppressive agents may actually hinder its development. However, a truth lies between these extremes. First, tolerance may be viewed as a balance rather than “all or none” and intermediate levels are still clinically useful. Whatever the mechanisms, most allograft recipients require much less immunosuppression after six months than they did initially. Patients whose immune systems lean toward tolerance may suffer fewer rejections and require less maintenance immunosuppression. Second, some patients, albeit a minority, on standard therapy do actually develop tolerance. If we could only identify these patients, immunosuppression could be stopped or tapered with anticipation of a favorable outcome