Rational design of peptide vaccines for autoimmune disease: harnessing molecular recognition to fix a broken network

Autoreactive T-cells and antibodies are found at low levels in normal individuals and are thought to be kept at bay by regulatory T-cells and a network of idiotypic and anti-idiotype-bearing antigen receptors on lymphocytes as well as idiotypic anti-idiotypic antibodies. Disruption of this network by genetic, environmental and unknown factors is thought to result in autoimmune diseases. An obvious, ideal and specific therapy for such disorders would be to harness this regulatory network to re-establish immunologic homeostasis. In practice, however, this is not an easy task as most autoimmune diseases involve polyclonal responses to self antigen. Thus, we are faced with the conundrum of not knowing which autoreactive idiotype-bearing antibody or antigen receptor(s) to target in order to restore or induce network regulatory function. The thesis of this review is that understanding a fundamental property governing peptide/protein shape can be used in part to circumvent the problems of self reactivity and polyclonality in autoimmune disorders. More specifically, an algorithm has been developed to design peptide vaccines with shapes that are thought to be complementary in contour to self epitopes which seem to be the focus of autoimmunity. In theory, such complementary shapes should be engendered in certain autoreactive antigen receptors--these complementary constructs consequently represent receptor mimetics. By targeting an immune response against such mimetics, one generates a polyclonal anti-idiotype response that matches the complexity of the autoimmune response itself. This article will describe the algorithm for vaccine design, summarize the in vitro and in vivo evidence for its efficacy and discuss possible therapeutic utility in human autoimmune diseases.