Effects of immunomodulators on the response induced by vaccines against autoimmune diseases

A promising treatment for T-cell-mediated autoimmune diseases is the induction of immune tolerance by modulating the immune response against self-antigens, an objective that may be achieved by vaccination. There are two main types of vaccines currently under development. The tolerogenic vaccines, composed of proteins formed by a cytokine fused to a self-antigen, which usually induce tolerance by eliminating the T-cells that are immune reactive against the self-antigen. The immunogenic vaccines, comprised of a self-antigen plus a sole Th2 adjuvant either free or conjugated, that alleviate autoimmunity by switching the immune response against the self-antigen, from a damaging pro-inflammatory Th1/Th17 to an anti-inflammatory Th2 immunity. Another type of vaccines is the DNA vaccines, where cells transiently express the self-antigen encoded by DNA, which induces a Th2 immunity. Actually, DNA vaccines can benefit from the presence of an adjuvant that elicits a systemic sole Th2 immunity to enhance the initially weak immune response characteristic of these vaccines. While in the tolerogenic vaccines, cytokines are the endogenous immunomodulators, in the immunogenic vaccines, the adjuvants are exogenous agents that elicit Th2 immunity with a production of anti-inflammatory cytokines and antibodies against the self-antigen. Because the commonly used Th2 adjuvant alum, fails to induce an effective immunity in the elderly population, it is unlikely that it would be widely used. Another Th2 adjuvant, the oil/water emulsions mixed with the antigen, while effective in vaccines against infectious agents, due to potential aldehydes in their formulation may be not suitable for autoimmune vaccines. A unique compound is glatiramer, which seems to be both a random polypeptide antigen and an immune modulator that biases the response to Th2 immunity. Its mechanism of action seems to implicate binding to MHC-II, which alters the outcome of T-cell signaling, leading to anergy. Glatiramer, while effective in the treatment of multiple sclerosis has not shown efficacy in other autoimmune diseases. An important new group of promising sole Th2 adjuvants are the fucosylated glycans, which by binding to DC-SIGN bias dendritic cells to Th2 immunity while inhibiting Th1/Th7 immunities. These glycans are similar to those produced by parasitic helminths to prevent inflammatory responses by mammalian hosts. A novel group of sole Th2 adjuvants are some plant-derived fucosylated triterpene glycosides, which share the immune modulatory properties from the fucosylated glycans. These glycosides have also an aldehyde group that delivers an alternative co-stimulatory signal to T-cells, averting the anergy associated with aging due to the loss of the CD28 receptor on T-cells. Hence, the development of vaccines to treat and/or prevent autoimmune conditions and some proteopathies, will significantly benefit from the availability of new sole Th2 adjuvants that while inducing an anti-inflammatory immunity, they do not abrogate pro-inflammatory Th1/Th17 immunities.