Adjuvants, endocrines and conserved epitopes; factors to consider when designing "therapeutic vaccines".

Research into immunity to complex intracellular parasites has recently placed emphasis on the identification of peptide sequences recognised by T-cells, often with the dual objectives of finding species-specific protective epitopes, and of understanding selection of Th1 versus Th2 response patterns. In this review it is suggested that although such work is interesting, it will not achieve these objectives, which must, however, be addressed before we can design the new generation of therapeutic vaccines which may eventually replace antimicrobial drugs in the treatment of infection. First, we suggest that the balance of Th1 to Th2 lymphocyte activity is not determined by epitopes, but rather by adjuvant effects of microbial components which we have barely begun to define, and local endocrine effects mediated by conversion of prohormones into active metabolites by enzymes in lymph node macrophages. Cytokines play a role as mediators within these pathways. In chronic disease states there is a tendency for T-cell function to shift towards Th2. We describe immunopathological consequences of this tendency, including a putative role for agalactosyl IgG, and review evidence for involvement of changes in the endocrine system, brought about not only by the cytokine-hypothalamus-pituitary-adrenal axis, but also by direct actions on peripheral endocrine organs of excess levels of cytokines such as TNF alpha, TGF beta and IL-6. We summarise evidence that the epitopes that are targets for protective cell-mediated responses to complex organisms are usually not species specific. In tuberculosis, cellular responses to species-specific components appear to be associated with immunopathology rather than protection. Finally, we discuss how application of these principles has led to remarkable results in the immunotherapy of tuberculosis, including multidrug-resistant disease.