Context-based therapy: A conceptual framework for transplantation tolerance

Allotransplantation has improved dramatically in the past 2 decades, mostly as a result of more potent immunosuppression and increasingly effective prophylaxis against opportunistic infections. It is likely, however, that the field has entered a period of diminishing returns, such that increased immunosuppression will minimally increase graft survival and markedly augment morbidity. The authors suggest that gains in graft and patient survival will best be achieved by pursuing strategies promoting immune tolerance and selecting therapies that enhance physiologic immune adaptation rather than those that indiscriminately suppress immune function. Principles of tolerance as they relate to allotransplantation are discussed. The authors introduce the concept of context-based therapy. This approach places an emphasis on preserving specificity during immune intervention by augmenting or avoiding interference with antigen receptor function. Graft acceptance is fostered by altering contextual signals influencing the outcome of antigen recognition such as intrinsic indicators of cell injury, costimulatory signals, the activation state of antigen presenting cells, or the local environment of immune engagement. The manipulation of immune thresholds is also introduced as an additional concept influencing tolerance. Supportive data from nonhuman primate and human trial are presented. This is a US government work. There are no restrictions on its use.