Therapeutic vaccines in autoimmunity.

Similarly to prophylactic vaccines whose purpose is to prevent infectious diseases, therapeutic vaccines against autoimmune diseases are based on their similarity to the putative causes of the disease. We shall describe here two such examples: a copolymer of amino acids related to myelin basic protein, in the case of multiple sclerosis, and a peptide derived from the nicotinic acetylcholine receptor (AChR), in the case of myasthenia gravis (MG). Copolymer 1 (Cop 1, glatiramer acetate, Copaxone) is a synthetic amino acid random copolymer, immunologically cross-reactive with myelin basic protein and suppresses experimental allergic encephalomyelitis in several animal species. Cop 1 slows the progression of disability and reduces relapse rate in exacerbating-remitting multiple sclerosis patients. It was approved by the Food and Drug Administration in 1996, and today is used by tens of thousands of patients. Cop 1 is a potent inducer of T helper 2 (Th2) regulatory cells in mice and humans, and Th2 cells are found both in the brains and spinal cords of Cop 1-treated mice. MG and experimental autoimmune MG are T cell-regulated, antibody-mediated autoimmune diseases. Two peptides, representing sequences of the human AChR alpha-subunit, p195-212 and p259-271, are immunodominant T cell epitopes in MG patients and in two strains of mice. Altered peptide ligand, composed of the tandemly arranged two single amino acid analogs, inhibits in vitro and in vivo MG-associated autoimmune responses. The active suppression is mediated by the CD4(+)CD25(+) immunoregulatory cells and is associated with the down-regulation of Th1-type cytokines and the up-regulation of the secretion of IL-10 and the immunosuppressive cytokine, transforming growth factor beta.