Cytokine adjuvants: lessons from the past--guidelines for the future?

Formulation of vaccines has for the most part relied on simple adjuvants which are able to enhance the immune response to the immunogen. Cytokines are an attractive alternative to conventional preparations, and have been tested in a number of different systems. However, experience has indicated that there are a number of guidelines that must be followed. The dose of cytokine administered is critical for optimal effect. Too little will have no effect, and too much will have undesirable side effects. For instance, at high doses IL-2 can induce autoimmune disease and interferon gamma can have a suppressive effect. Cytokines may also have to be administered at the same site or even to the same cell as the antigen for optimal effect. Conjugation or molecular chimerization of antigens and cytokines can achieve this effect efficiently. Formulation of cytokine with antigen may overcome any detrimental effect that the antigen may have. Should the antigen have any suppressive epitopes or have a direct effect on essential intracellular mechanisms, cytokines may be used to overcome these effects. In some cases, Th1 or Th2 cytokines have been used to enhance a protective Th1 or Th2 response. However, the paradigm does not always hold, and Th1 cytokines can enhance Th2 responses, or have no overall effect on phenotype. Further, in some host species, there is evidence that there may be no Th1/Th2 dichotomy. The most important aspect of using cytokines as adjuvants is in ensuring that there is a balanced response.