The immune idiotype:anti-idiotype (Id:anti-Id) network is important in immunoregulation and tolerance. Its analysis in experimental autoimmune myasthenia gravis (EAMG) should provide insight into the abnormal immunoregulation in a defined antibody-mediated autoimmune disease, We have produced isogeneic monoclonal anti-Id antibodies directed against EAMG-inducing anti-acetylcholine receptor (AChR) monoclonal antibodies (mAbs) to be used as tools to analyze the immune network in EAMG. We have purified and characterized five anti-Id mAbs directed against two of these anti-AChR mAbs. Immunochemical analysis reveals that these anti-Ids are noncompetitive inhibitors of antigen (Ag) (i.e., ACHR) binding to the anti-AChR mabs. The Ids defined by the anti-Ids are moderately crossreactive with other anti-AChR mabs and with EAMG sera without being present in dominant levels. We have, nonetheless, suppressed the total serum anti-AChR antibody levels and prevented the development of EAMG by pretreating animals, prior to immunization with AChR, with physiologic doses of individual anti-Id mAb. These anti-Id thus play a major immunoregulatory role in EAMG. In our present proposal, the aim is to analyze the mechanism(s) involved in this observed suppression of the total anti-AChR response induced by manipulating an Id that is moderately crossreactive but not dominant in EAMG sera. Experiments are proposed to: a) further analyze the parameters important to the development of suppression (animal age, Ag dose, adjuvants used, and dose and timing of anti-Id) in order to characterize this biological system and to maximize the suppression; b) analyze the structural and cellular mechanisms involved in the observed suppression. To analyze structural mechanisms at a molecular level, we will clone and sequence the variable regions of the anti-AChR mAb 132A and the corresponding anti-Id-mAb HC-4A. To analyze cellular mechanisms, altered B cell secretions of Ab by anti-Id, and the role of specific B cell populations (Id + and anti-Id +) will be determined. This analysis of the immune network in EAMG should have implications for the understanding and treatment of human MG and other autoimmune diseases.
| Agius, M A; Yuen, E (1998) Effect of anti-idiotopic antibody on the course of experimental autoimmune myasthenia gravis. Ann N Y Acad Sci 841:584-6 |
| Agius, M A; Kirvan, C A; Sanyal, B (1998) Homology of an antiacetylcholine receptor monoclonal antibody with a monoclonal antibody to Campath-1 antigen suggests usage of the same VH genes. Ann N Y Acad Sci 841:469-70 |
| Kirvan, C A; Zhu, S; Richman, D P et al. (1998) Expression and initial characterization of recombinant antiacetylcholine receptor antibodies in experimental autoimmune myasthenia gravis. Ann N Y Acad Sci 841:466-8 |
| Agius, M A; Sanyal, B; Richman, D P (1993) Molecular structure of a monoclonal antiacetylcholine receptor antibody and of a corresponding monoclonal antiidiotopic antibody. Ann N Y Acad Sci 681:274-5 |
