scholarly journals HAPTEN-SPECIFIC TOLERANCE

1972 ◽  
Vol 136 (3) ◽  
pp. 426-438 ◽  
Author(s):  
Joseph M. Davie ◽  
William E. Paul ◽  
David H. Katz ◽  
Baruj Benacerraf
Keyword(s):  
Immune Response ◽  
Guinea Pig ◽  
Individual Cell ◽  
Tolerance Induction ◽  
High Affinity ◽  
Individual Plaque ◽  
Specific Tolerance ◽  
Marked Suppression ◽  
Antibody Secreting Cells ◽  
Induction Of Tolerance

The induction of tolerance in guinea pigs with a 2,4-dinitrophenyl (DNP) derivative of a copolymer of copolymer of D-glutamic acid and D-lysine (D-GL) leads to a preferential depression of the capacity to produce high affinity anti-DNP antibody in response to immunization with DNP-guinea pig albumin. Thus, immunization 2 wk after tolerance induction with 3 mg of DNP-D-GL results in an immune response in which individual plaque-forming cells (PFC) secreting high affinity anti-DNP antibody are absent and in which the affinity of circulating anti-DNP antibody is reduced. A similar, but less marked, suppression is seen when 0.3 mg of DNP-D-GL is used for tolerance induction. If immunization is delayed until 2 months after tolerance induction, then suppression is restricted to the highest avidity PFC group. Our data is consistent with a state of tolerance in the pool of precursors of anti-DNP antibody-secreting cells induced as a result of their interaction with DNP-D-GL in the absence of specific "helper" cells, which appear to be lacking for DNP-D-GL. In such a situation, the affinity of receptors on precursor cells for tolerogen and the concentration of tolerogen appear to be crucial determinants of whether an individual cell will become tolerant.

scholarly journals RECEPTORS ON IMMUNOCOMPETENT CELLS

1971 ◽  
Vol 134 (2) ◽  
pp. 517-531 ◽  
Author(s):  
Joseph M. Davie ◽  
Alan S. Rosenthal ◽  
William E. Paul
Keyword(s):  
Immune Response ◽  
Guinea Pig ◽  
Heavy Chain ◽  
Guinea Pigs ◽  
Bovine Serum ◽  
Antigen Binding ◽  
Agarose Beads ◽  
Cellular Immune ◽  
Draining Lymph Nodes ◽  
Antibody Secreting Cells

Guinea pigs immunized with 2,4-dinitrophenyl-guinea pig albumin (DNP-GPA) possess lymphocytes which specifically bind sufficient DNP-GPA-125I to their surface to be detected by radioautography. These lymphocytes are present in the draining lymph nodes in a frequency of ∼50/1000 lymphocytes in animals immunized 2–4 wk earlier with DNP-GPA in complete Freund's adjuvant. Nonimmunized animals have ∼0.4 DNP-GPA antigen-binding cells (ABC) per 1000 lymphocytes. An increase in the frequency of DNP-GPA ABC in peripheral blood is detectable by 5 days after immunization, which is before the time that serum anti-DNP antibody is measurable. The receptors of these ABC are hapten specific in that free ϵ-DNP-L-lysine, at low concentration, inhibits the binding of DNP-GPA-125I; DNP bovine serum alumbin (DNP-BSA) is equivalent to DNP-GPA in the inhibition of binding of DNP-GPA-125I to ABC; and both DNP-GPA agarose beads and DNP-BSA agarose beads specifically adsorb DNP-GPA-125I ABC. Anti-immunoglobulin antisera, particularly anti-γ2 sera, inhibit the binding of DNP-GPA-125I to these cells implying that the receptors are immunoglobulin, primarily of the γ2 heavy chain class. DNP-GPA-125I ABC appear to represent precursors of antibody-secreting cells and have specificity characteristics which are very different from cells, of similarly immunized guinea pigs, which mediate a cellular immune response to DNP-GPA.

Blockade of Inhibitor Formation by B-Cell Delivered Tolerance to Immunodominant A2 and C2 Domains.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3187-3187
Author(s):  
Tei Chi Lei ◽  
David W. Scott
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Tolerance Induction ◽  
Full Length ◽  
Great Promise ◽  
C2 Domain ◽  
Gene Therapy Protocol ◽  
Inhibitory Antibodies ◽  
Induced Tolerance ◽  
Specific Tolerance

Abstract A major impediment in the treatment of hemophilia is the formation of inhibitory antibodies, which occurs in approximately 25–30% of Hemophilia A patients treated with therapeutic Factor VIII (fVIII). We have focused on the development of a gene therapy protocol for tolerance induction, with an emphasis on the elimination of inhibitor production. Our lab has demonstrated that LPS-stimulated B-cell blasts, transfected with a retrovirus encoding an IgG-peptide fusion protein, such as fVIII domains, are tolerogenic in both normal and primed recipients. Last year, we reported (http://www.abstracts-on-line.com/abstracts/hemphiladelphia03; Scott and Lei 2003) that specific tolerance to the immunodominant epitopes in the C2 domain of fVIII (a major target of inhibitors) could be induced by our protocol. However, the immune response to full length fVIII was only modestly affected. Most inhibitory antibodies are reactive with conformational epitopes on the exposed surfaces of the A2, as well as the C2, domain of fVIII. Therefore, in this study, we inserted residues S2173-Y2332 of the C2 domain and S373-R740 of the A2 domain onto the IgG heavy chain backbone, respectively, to induce tolerance in hemophilic mice. Specific tolerance to each domain was induced by this protocol. Importantly, a combination of A2-IgG and C2-IgG expressing B cells induced tolerance to the full length fVIII molecule, a result which supports the dominance of these domains in the immune response to fVIII. Tolerance was manifested in terms of ELISA, T-cell proliferation and especially Bethesda Unit titers (95% reduction). Similar results were obtained even when treatment was initiated after priming injections of fVIII. In conclusion, this protocol offers great promise for prevention and potential reversal of this serious complication of fVIII replacement therapy. (Supported by HL61883 and a Laboratory Grant from the National Hemophilia Foundation).

scholarly journals CUTANEOUS BASOPHIL (JONES-MOTE) HYPERSENSITIVITY AFTER "TOLEROGENIC" DOSES OF INTRAVENOUS OVALBUMIN IN THE GUINEA PIG

1971 ◽  
Vol 134 (3) ◽  
pp. 630-641 ◽  
Author(s):  
Hal B. Richerson
Keyword(s):  
Immune Response ◽  
Guinea Pig ◽  
Functional Relationship ◽  
Early Period ◽  
Tolerance Induction ◽  
High Dose ◽  
Significant Heterogeneity ◽  
Incomplete Freund’S Adjuvant ◽  
Cellular Immune ◽  
Low Dosage

Cutaneous basophil hypersensitivity (CBH) was studied for tolerogenic requirements. Graded doses of intravenous ovalbumin (OA) were given to guinea pigs which were subsequently immunized appropriately to produce CBH, classic delayed hypersensitivity (classic DH), and/or antibodies of both passive cutaneous anaphylaxis (PCA) and hemolytic types. Results showed that doses of intravenous antigen sufficient to induce subsequent tolerance for classic DH and hemolytic antibody actually stimulate CBH reactivity and PCA antibody production. Other studies of dose-route relationships for CBH production demonstrated that optimal immunogenic dosage requirements for CBH varied widely with route of antigen employed. OA in incomplete Freund's adjuvant (IFA) injected into footpads had low dosage requirements, intravenous OA had high dose requirements, and intradermal soluble OA dosage requirements were intermediate. The observation that blatant immunogenic responses occur during the early period of tolerance induction amplifies the significant heterogeneity of the cellular immune response and may be of importance in understanding tolerogenesis. Similar immunogenic-tolerogenic requirements and the prime role played by the basophil suggest a developmental or functional relationship between CBH and PCA antibody response.

scholarly journals RECEPTORS ON IMMUNOCOMPETENT CELLS

1972 ◽  
Vol 135 (3) ◽  
pp. 660-674 ◽  
Author(s):  
Joseph M. Davie ◽  
William E. Paul
Keyword(s):  
Immune Response ◽  
Guinea Pig ◽  
Detailed Analysis ◽  
Serum Antibody ◽  
Antigen Binding ◽  
High Avidity ◽  
Cell Type ◽  
Parallel Increase ◽  
Individual Plaque ◽  
Sequential Appearance

During the course of the immune response to dinitrophenylated guinea pig albumin (DNP-GPA), a striking and parallel increase in avidity for ϵ-DNP-L-lysine occurs in the receptors on antigen-binding lymphocytes, antibody secreted by individual plaque-forming cells, and serum antibody molecules. A detailed analysis of the avidity distribution of antibody produced by plaque-forming cells indicates that this "immunologic maturation" is primarily due to a preservation of the high avidity subpopulation and a striking loss in the low avidity population rather than to sequential appearance of these cells. Moreover, the demonstration of the increased avidity of receptors of antigen-binding lymphocytes, which appear to be precursors of antibody-synthesizing cells, strongly suggests that the antigen-driven selectional process operates primarily on this cell type.

High level expression of the Drosophila Toll receptor ectodomain and crystallization of its complex with the morphogen Spätzle

2013 ◽  
Vol 394 (8) ◽  
pp. 1091-1096 ◽  
Author(s):  
Marco Stelter ◽  
Uwe Fandrich ◽  
Kati Franzke ◽  
Angelika Schierhorn ◽  
Constanze Breithaupt ◽  
...  
Keyword(s):  
Immune Response ◽  
High Level Expression ◽  
Receptor Ligand ◽  
High Affinity ◽  
Cystine Knot ◽  
Toll Receptor ◽  
Cystine Knot Protein ◽  
High Yields ◽  
High Level ◽  
Affinity Interaction

Abstract Drosophila Toll receptors are involved in embryonic development and in the immune response of adult flies. In both processes, the Toll receptor ligand is the NGF-like cystine knot protein Spätzle. Here we present the expression of Toll receptor ectodomain in Schneider cells at high yields and demonstrate a high affinity interaction with the refolded and trypsin-processed Spätzle cystine knot domain dimer. Poorly and anisotropically diffracting crystals of the complex could be improved by deglycosylation and dehydration, paving the way for structural analyses of the Toll-Spätzle interaction.

Specific Immunoregulation of the Induction and Effector Stages of Relapsing EAE via Neuroantigen-Specific Tolerance Induction

1991 ◽  
Vol 636 (1 Antigen and C) ◽  
pp. 79-94 ◽  
Author(s):  
STEPHEN D. MILLER ◽  
L. J. TAN ◽  
MARY K. KENNEDY ◽  
MAURO C. CANTO
Keyword(s):  
Tolerance Induction ◽  
Specific Tolerance

scholarly journals Normal Incidence of Diabetes in NOD Mice Tolerant to Glutamic Acid Decarboxylase

2003 ◽  
Vol 197 (12) ◽  
pp. 1635-1644 ◽  
Author(s):  
Elmar Jaeckel ◽  
Ludger Klein ◽  
Natalia Martin-Orozco ◽  
Harald von Boehmer
Keyword(s):  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
Tolerance Induction ◽  
Nod Mice ◽  
Normal Incidence ◽  
Invariant Chain ◽  
Acid Decarboxylase ◽  
Β Cells ◽  
Nonobese Diabetic ◽  
Specific Tolerance

Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in β cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

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