Induction of immunological tolerance to the penicilloyl antigenic determinant. II. Evaluation of stable and unstable penicilloyl dextrans

Publisher Website
Google Scholar
Abstract
A specific tolerant state to the major antigenic determinant of penicillin allergy, the penicilloyl group, was induced in C3H mice primarily immunized with penicilloylated bovine gamma globulin in complete Freund's adjuvant. Tolerance was obtained by intraperitoneal administration of either of two penicilloyl‐bearing dextrans of molecular weight 2 × 106. One conjugate contained penicilloyl groups stably bound via a 1,6‐diaminohexane spacer, the other bore the penicilloyl groups directly bound to the hydroxyl groups of the carrier. These directly bound penicilloyl groups undergo hydrolytic cleavage within 3 days under physiological conditions in neutral aqueous solution. Model experiments showed that the rapid cleavage into carrier and haptenic derivatives also applies to penicilloylated dextran in receptor‐bound and particulate form, as may be expected from the highly hydrophilic character of the conjugate. The stable conjugate at 1 mg and the cleavable conjugate at 4 mg doses induced comparable tolerance lasting for at least 8–12 weeks. For hapten‐dextran tolerance these findings make very unlikely any mechanism requiring the continuous presence of unmodified tolerogen on the membrane or in the interior of tolerant cells, and imply second‐stage processes to explain the long duration of unresponsiveness. They also show that cleavable penicilloyl tolerogens may be considered for prospective clinical use.
Keywords