Cytokine/Antibody Complexes: An Emerging Class of Immunostimulants

In recent years, complexes formed from a cytokine and antibodies against that respective cytokine (cytokine/ Ab complex) have been shown to induce remarkable powerful changes in the immune system. Strong interest exists especially for complexes formed with Interleukin (IL)-2 and anti-IL-2-antibody (IL-2/Ab complex). IL-2/Ab complex activates maturation and proliferation in CD8+ T cells and natural killer (NK) cells to a much higher degree than conventional IL-2 therapy. In addition, IL-2/Ab complex does not stimulate regulatory T cells as much as IL-2 alone. This suggests the possibility to replace the conventional IL-2 therapy with a therapy using low-dose IL-2/Ab complex. Further synthetic cytokine/Ab complexes are studied currently, including IL-3/Ab complex for its effects on the mast cell population, and IL-4/Ab complex and IL-7/Ab complex for inducing B and T cell expansion and maturation. Cytokine complexes can also be made from a cytokine and its soluble receptor. Pre-association of IL-15 with soluble IL-15 receptor α produces a complex with strong agonistic functions that lead to an expansion of CD8+ T cells and NK cells. However, cytokine/ Ab complexes also occur naturally in humans. A multitude of auto-antibodies to cytokines are found in human sera, and many of these auto-antibodies build cytokine/Ab complexes. This review presents naturally occurring autoantibodies to cytokines and cytokine/Ab complexes in health and disease. It further summarizes recent research on synthetic cytokine/Ab complexes with a focus on the basic mechanisms behind the function of cytokine/Ab complexes.