Induction of B cell tolerance to polysaccharides by exhaustive immunization and during immunosuppression with cyclophosphamide

Howard, J. G.; Courtenay, Barbara M.

doi:10.1002/eji.1830040905

Cited by 38 publications

(11 citation statements)

References 22 publications

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“…(b) That DNP-FIC and DNP-OEt starch,elicited very prolonged IgM anti-DNP responses over a wide dose range (Table 1). Dextran B512-2000 [9] and dextran B1355 [lo] also elicit prolonged IgM antibody responses at comparable doses, although at high doses (10 mg) or at much lower doses given during cyclophosphamide suppression they are tolerogenic.…”

Section: Discussionmentioning

confidence: 99%

Tolerogenic or immunogenic activity of hapten‐conjugated polysaccharides correlated with cellular localization

Humphrey

1981

Eur J Immunol

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Dinitrophenylated (DNP) conjugates of Ficoll, hydroxyethyl starch, levan, dextran, type 3 pneumococcal capsular polysaccharide SIII, pectin, alginic and hyaluronic acid at various epitope densities were tested for their capacity to inhibit secondary IgG anti-DNP antibody responses using an in vivo transfer system. Some aminobenzylarsonate conjugates were examined similarly. Conjugates of the acidic polysaccharides were markedly more effective than those of uncharged polysaccharides. Conjugated with high epitope densities were particularly tolerogenic. DNP conjugates of Ficoll and hydroxyethyl starch elicited prolonged IgM responses over a wide dose range, and there are indications in the literature that conjugates of dextran do likewise. All the polysaccharide conjugates, labeled with radioiodine, persisted in the body for long periods (half-lives 8.5--63 days), and all were cleared rapidly from, but remained detectable in the blood for many days. Gross tissue distributions varied markedly from one conjugate to another, and autoradiography revealed unexpected differences in cellular localization. Despite substantial retention in the liver, some uncharged polysaccharides were localized only in parenchymal and not in Kupffer cells. In the spleen, only the acidic polysaccharides were predominantly localized in red pulp macrophages, and the neural polysaccharides were detectable exclusively, and in the case of Ficoll, hydroxyethyl starch and some dextrans very intensely in macrophages of the marginal zone of the white pulp. It is suggested that retention of thymus-independent antigens in marginal-zone macrophages favors, whereas trapping in red-pulp macrophages diminishes immunogenicity, and that tolerogenic effectiveness depends upon a balance between tolerization of B cells by free antigen and stimulation by antigen presented by marginal-zone macrophages. The distinction between functionally different macrophages in the spleen is elaborated in the following report.

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Section: Discussionmentioning

confidence: 99%

Tolerogenic or immunogenic activity of hapten‐conjugated polysaccharides correlated with cellular localization

Humphrey

1981

Eur J Immunol

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“…We report here o n the effect of epitope density variations t W on the primary in vivo immunogenicity and "high zone" tolerogenicity of DNP conjugates with SIII, levan and dex-n ul trans (B512 and B1299), together with their capacities to induce tolerance via immunization ("exhaustion") and du-: 1 0 2 k 2 n ring suppression with cyclophosphamide (CP) [8].…”

Section: 'mentioning

confidence: 99%

Role of epitope density in the induction of immunity and tolerance with thymus‐independent antigens. II. Studies with 2,4‐dinitrophenyl conjugates in vivo

Desaymard

Howard

1975

Eur J Immunol

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The immunogenicity and tolerogenicity of 2,4-dinitrophenyl (DNP) conjugates of levan, type 3 pneumococcal polysaccharide (SIII), dextran B512 and dextran B 1299 with different levels of substitution were assessed in vivo. It was confirmed that, as in vitro, conjugates with low epitope density are solely immunogenic for Bmu cells, whereas higher density conjugates are both immunogenic and tolerogenic according to dosage. The maximal anti-DNP plaque-forming cell responses attainable varied by 2 log10 according to the carrier, being greatest with dextrans and least with SIII. The effect of the carrier on immunogenicity was not attributable to B cells responding to it, as concurrent tolerization by either free polysaccharide or the conjugate itself was without effect. Optimal immunization was succeeded by varying degrees of responsiveness ("exhaustion") which was greatest with the more immunogenic conjugates. In contrast, reduction of tolerizing dose by cyclophosphamide suppression was only a feature of more highly substituted conjugates.

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“…Studies have shown that treatment with high doses of dextran itself can tolerize mice (16), and it was possible that the chemical manipulation that was used to prepare the toxogen had produced a modified dextran that was an unusually good tolerogen. To eliminate this possibility, cytidine, a noncytotoxic analog of araC, was coupled to oxidized dextran by the same procedures as those used to prepare the toxogen.…”

Section: Resultsmentioning

confidence: 99%

Antigen-specific drug-targeting used to manipulate an immune response in vivo.

Abu-hadid

Bankert

Mayers

1987

Proc. Natl. Acad. Sci. U.S.A.

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The administration of dextran-conjugated cytosine arabinonucleoside (araC) to BALB/c mice at various times prior to but not subsequent to immunization with native dextran renders mice unresponsive to this thymic-independent antigen. These results demonstrate that the primary immune response to an antigen can be selectively and efficiently suppressed or eliminated in vivo by the delivery of a single dose of an appropriate antigen-cytotoxic drug conjugate. Evidence presented here indicates that the dextran-araC conjugate (toxogen) acts directly and selectively upon unprimed dextranspecifc antibody-forming cell precursors, presumably by binding to their receptors and subsequent internalization of the resultant receptor-toxogen complexes. The resistance of antigen-primed mice to the cytotoxic effect of the toxogen could result from the failure of dextran-primed cells to reexpress antigen-specific receptors, from an alternative processing of the toxogen, or from the inability of the antigen-primed cells to internalize a second round of receptor-ligand complexes. We also determined that B cells responding to thymic-dependent antigens were not affected by the prior exposure to a toxogen. The inability to eliminate or suppress the primary response to a thymic-dependent antigen via the administration of a cytotoxic drug-antigen conjugate distinguishes the thymicindependent set of B cells from the thymic-dependent B-cell repertoire. The difference between these two B-cell compartments could be due either to differences in the amount of ligand bound to receptors or to differences in the trafficking patterns of receptor-ligand complexes within each cell type.In this report we demonstrate that the primary immune response to dextran can be efficiently manipulated in vivo by the selective elimination of a defined population of immunocompetent cells (in this case, thymic-independent antigen-binding B cells). This has been accomplished with a minimal degree of disruption to the physiology and microenvironment of the host's immune system by targeting to the antigen-specific B-cell receptor a conjugate ofthe antigen and a cytotoxic drug. Dextran-binding antibody-forming cell precursors were removed by administering a conjugate of a cytotoxic drug and dextran prior to immunization with the unmodified immunogenic form of dextran.

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Induction of B cell tolerance to polysaccharides by exhaustive immunization and during immunosuppression with cyclophosphamide

Cited by 38 publications

References 22 publications

Tolerogenic or immunogenic activity of hapten‐conjugated polysaccharides correlated with cellular localization

Tolerogenic or immunogenic activity of hapten‐conjugated polysaccharides correlated with cellular localization

Role of epitope density in the induction of immunity and tolerance with thymus‐independent antigens. II. Studies with 2,4‐dinitrophenyl conjugates in vivo

Antigen-specific drug-targeting used to manipulate an immune response in vivo.

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