Cognate interactions between immune effector cells and antigen-presenting cells (APCs) govern immune responses. Specific signals occur between the T-cell receptor peptide and APCs and nonspecific signals between pairs of costimulatory molecules. Costimulation signals are required for full T-cell activation and are assumed to regulate T-cell responses as well as other aspects of the immune system. As new discoveries are made, it is becoming clear how important these costimulation interactions are for immune responses. Costimulation requirements for T-cell regulation have been extensively studied as a way to control many autoimmune diseases and downregulate inflammatory reactions. The CD28:B7 and the CD40:CD40L families of molecules are considered to be critical costimulatory molecules and have been studied extensively. Blocking the interaction between these molecules results in a state of immune unresponsiveness termed 'anergy'. Several different strategies for blockade of these interactions are explored including monoclonal antibodies (mAbs), Fab fragments, chimeric, and/or fusion proteins. We developed novel, immune-specific approaches that interfere with these interactions. Using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis mediated by central nervous system (CNS)-specific T-cells, we developed a multi-targeted approach that utilizes peptides for blockade of costimulatory molecules. We designed blocking peptide mimics that retain the functional binding area of the parent protein while reducing the overall size and are thus capable of blocking signal transduction. In this paper, we review the role of costimulatory molecules in autoimmune diseases, two of the most well-studied costimulatory pathways (CD28/CTLA-4:B7 and CD40:CD40L), and the advantages of peptidomimetic approaches. We present data showing the ability of peptide mimics of costimulatory molecules to suppress autoimmune disease and propose a mechanism for disease suppression.

Oral tolerance refers to the oral administration of protein antigens, which induces a state of systemic nonresponsiveness specific for the fed antigen. This method of inducing immune non-responsiveness has been applied to the prevention and treatment of experimental animal models of autoimmune disease. Extensive research in this area over the past ten years has led to the conclusion that two mechanisms are operative in the mediation of oral tolerance--active suppression and clonal anergy/deletion. A number of factors have been identified that determine which mechanism of tolerance is operative--antigen dose, antigen form, and the timing of antigen administration. Work from these animal models has recently been extended into human clinical trials of multiple sclerosis, rheumatoid arthritis, diabetes, uveitis, and allergy, with differing degrees of success. In this review, a discussion is provided of the animal model systems where oral tolerance has been applied and the clinical trials where an oral tolerization approach has been attempted. Moreover, recent mechanistic studies are reviewed and a model proposed for the induction of oral tolerance.

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