Alteration of the humoral immune response against muscle acetylcholine receptor by timed administration of α(1 → 3)dextran

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Abstract
Previously, we discovered a profound idiotypic connectivity among antibodies involved in the immune responses to α(1 → 3)dextran (Dex) and the acetylcholine receptor (AChR). The present studies were undertaken to assess whether these connections represent functional pathways for regulation. It was found that immunization of mice with Dex prior to challenge with AChR reduced the subsequent response to receptor. The timing of the Dex administration was crucial for this effect with a 6‐day delay between Dex and AChR being optimal whereas 0‐or 12‐day delays proved ineffective. The suppressive effect was specific for Dex, as treatment with the closely related, but idiotypically distinct, α(1 → 6)dextran did not diminish the anti‐AChR response. Consistent with functional connections in the AChR‐Dex network, an inverse relationship between anti‐AChR and anti‐Dex antibodies was observed in these studies. Thus, high levels of anti‐AChR antibodies were associated with low levels of anti‐Dex antibodies and vice versa. A similar relationship was observed for serum antibodies from patients with myasthenia gravis. To investigate the mechanism for the antigen‐induced cross‐regulation, hybridomas were constructed from spleen cells of mice treated 6 days earlier with Dex. A variety of idiotypes (Id), anti‐Id and anti‐anti‐Id were obtained from this fusion. In addition, sera from day‐6 mice were examined for the expression of key anti‐Id which might provide regulation in the anti‐AChR response. The main feature of these sera was the presence of EB3‐7‐reactive antibodies which did not bind Dex, and hence were not identical to J558. A monoclonal antibody with similar properties was obtained from the day‐6 fusion (DX6) which had additional binding specificity for anti‐AChR antibodies. Antibodies induced by Dex immunization appear to participate in the crossregulation observed here. Understanding the mechanisms involved in this phenomenon will have important implications for network theory and for prediction of immune responsiveness.