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Suppression of Reaginic Antibody Formation

III. Relationship Between Immunogenicity and Tolerogenicity of Hapten-Carrier Conjugates¹

From the MRC Group for Allergy Research, Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

Abstract

From the study of the effect of epitope density on the immunogenicity of haptenated ovalbumin (DNP-OA) it was concluded that the lightly haptenated conjugate, DNP_0.5-OA, induced, on the one hand, only low titers of anti-DNP hemagglutinating antibody and no reaginic antibodies to the hapten and, on the other, high reaginic and high hemagglutinating antibody responses to the carrier. The conjugate with a slightly higher degree of haptenation, i.e., DNP_2.3-OA, induced both reaginic and hemagglutinating antibodies to both the hapten and the carrier. By contrast, the heavily haptenated conjugate, DNP₂₀-OA, elicited reaginic and hemagglutinating antibodies only against the hapten but not against the carrier.

Specific suppression of anti-hapten reaginic antibody formation had been achieved by treatment of mice with a tolerogen consisting of the hapten (DNP) conjugated covalently to isologous globulins (MG). The epitope density of the DNP_x-MG conjugates was shown to play a dominant role in determining whether or not the conjugate was tolerogenic. Thus, lightly haptenated conjugates (DNP_0.5-MG, DNP_1.3-MG or DNP_1.9-MG) were not tolerogenic, moderately haptenated conjugates (DNP_4.2-MG, DNP₈-MG, and DNP₁₄-MG) were tolerogenic, and heavily haptenated conjugates (DNP₃₂-MG and DNP₅₃-MG) were immunogenic, being capable of priming the recipients for the DNP hapten.

Further evidence for the nonimmunogenicity of DNP₈-MG conjugate was inferred from its rate of clearance in tolerized and normal mice. Thus, the half-life of ¹²⁵I-labeled DNP₈-MG in circulation was not significantly different for normal and tolerized mice; it was 3.7 and 3.5 days, respectively, which is within the range of data reported for clearance of normal MG. These results suggest that DNP₈-MG was catabolized at a rate similar to that of nonconjugated, isologous MG. Moreover, there was no significant difference in the localization of DNP₈-MG in identical organs (spleen, thymus, kidney, and liver) of normal and tolerized mice.

All the multivalent DNP_x-MG conjugates were shown to be able to elicit passive cutaneous anaphylaxis (PCA) reaction on i.v. Challenge of rats which had been pre-sensitized i.d. with anti-DNP reaginic antibodies.

Footnotes

¹ This investigation was supported by grants from the Medical Research Council of Canada and the Sellers Foundation. The results of this study were presented at the 18th Annual Meeting of the Canadian Federation of Biological Societies, Winnipeg, Manitoba, Canada, June, 1975.

² Holder of a Scholarship from the Medical Research Council of Canada.

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