Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are caused, in part, by the production of T-cell-dependent, autoantibodies against the main immunogenic region (MIR), amino acids 61-76, of the acetylcholine receptor (AChR) alpha-chain. In this application, the investigators describe a means to achieve the long sought therapeutic goal of specifically correcting aberrant immune responses in autoimmune diseases such as EAMG. Specifically, epitope sequence information, together with new knowledge of the role of the precise pattern of amino acid hydropathy in protein and peptide shape or structure, allows one to construct peptides which presumably assume shapes or structures complementary to disease-associated epitopes. As a consequence, vaccination with the novel peptides (termed complementary peptides) leads to the production of anti-idiotypic (Id) and anti-clonotypic antibody (Ab) whose combining sites are complementary to and therefore reactive with antigen (Ag) receptors on disease epitope specific B-cells and T-cells. This application is directed towards the study of two such peptides, denoted RhCA 67-16 and RhCA 611-001, designed to be complementary to the MIR and the dominant Lewis rat T-cell epitope (alpha-chain residues 100-116) of the Torpedo AChR, respectively. Both peptides are effective vaccines which prevent EAMG by lowering levels of AChR Ab. However, RhCA 67-16 Ab seems to act at the level of the AChR 61-76-specific B-cell, while RhCA 611-001 Ab acts on AChR 100-116-specific T-cells. Thus, the overall goal of this application is to expand on these provocative findings by evaluating the nature and contribution to disease of Id Abs and T-cells recognized by Ab to AChR complementary peptides. This will be accomplished through the following specific aims: 1. What is the relative contribution to EAMG of AChR-specific Ab that bear an Id recognized by a MAb (termed TCM 240) against RhCA 67-16? 2. What is the frequency, sequence and specificity of TCM 240 Id-bearing Ab? 3. Is the T-cell receptor (TCR) on AChR 100-116-specific T-cells recognized by MAb (termed CTCR8) against RhCA 611-001? 4. Does administration of polyclonal anti-RhCA 611-001 Ab or CTCR8 lower AChR Ab levels and prevent EAMG? 5. Is there restricted usage of TCR by AChR 100-116 specific T-cells recognized by CTCR8? 6. Can EAMG-associated T-cells of other specificities be identified with complementary peptides to different AChR T-cell epitopes?
| Galin, F Shawn; Chrisman, Cheryl L; Cook Jr, James R et al. (2007) Possible therapeutic vaccines for canine myasthenia gravis: implications for the human disease and associated fatigue. Brain Behav Immun 21:323-31 |
