Oral Induction of Immunological Tolerance to Chromium in the Guinea Pig

1990 ◽  
Vol 69 (10) ◽  
pp. 1634-1639 ◽  
Author(s):  
K.J.J. Vreeburg ◽  
I.M.W. Van Hoogstraten ◽  
B.M.E. Von Blomberg ◽  
K. De Groot ◽  
R.J. Scheper
Keyword(s):  
Skin Testing ◽  
Tolerance Induction ◽  
Immunological Tolerance ◽  
Metal Alloys ◽  
High Dose ◽  
Allergic Reactions ◽  
Dose Frequency ◽  
Chromium Powder ◽  
Adverse Side Effects ◽  
Skin Contact

Metal alloys used in dentistry may elicit adverse side-effects. Contact allergic reactions to metals released from such alloys are among the most frequently encountered problems. In an earlier study, we observed that oral contacts with nickel or chromium salts did not sensitize, but rather decreased the risk of subsequent sensitization to these metals. In the present study, we focused on chromium allergy and extended our earlier observations by further dose-response studies. In addition, we compared different chromium valencies as to their potential oral tolerogenic effects. Development of immunological tolerance in chromium-fed guinea pigs was demonstrated by their inability to develop chromium hypersensitivity after a subsequent immunization attempt. For these studies, the techniques of immunization and skin testing were first improved. One feeding with a high dose of K2Cr2O7, (containing hexavalent chromium) was effective in full tolerance induction. In contrast, trivalent chromium (CrCl3) induced a distinctly lower degree of tolerance, whereas metallic chromium powder was not detectably tolerogenic after a limited number of feedings. Dose-frequency-response studies with K2Cr2O 7, showed that full tolerance could also be induced by an increase in the number of feedings with sub-optimal tolerogenic doses. The present results therefore support our hypothesis that long-lasting oral contact with chromium-releasing metal alloys may ultimately result in strong immune tolerance to this metal in subjects without previous skin contact with it. This view is further supported by recent insights into the unique tolerogenicity of oral, as compared with gastro-intestinal, allergenic contacts.

ITI with high-dose FIX and combined immunosuppressive therapy in a patient with severe haemophilia B and inhibitor

2009 ◽  
Vol 29 (02) ◽  
pp. 155-157 ◽  
Author(s):  
H. Hauch ◽  
J. Rischewski ◽  
U. Kordes ◽  
J. Schneppenheim ◽  
R. Schneppenheim ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Immunosuppressive Agents ◽  
Tolerance Induction ◽  
Intravenous Immunoglobulins ◽  
Factor Ix ◽  
High Dose ◽  
Allergic Reactions ◽  
Success Rates ◽  
Serious Infections ◽  
History Of

SummaryInhibitor development is a rare but serious event in hemophilia B patients. Management is hampered by the frequent occurrence of allergic reactions to factor IX, low success rates of current inhibitor elimination protocols and the risk of development of nephrotic syndrome. Single cases of immune tolerance induction (ITI) including immunosuppressive agents like mycophenolat mofetil (MMF) or rituximab have been reported. We present a case of successful inhibitor elimination with a combined immune-modulating therapy and high-dose factor IX (FIX). This boy had developed a FIX inhibitor at the age of 5 years and had a history of allergic reactions to FIX and to FEIBA→. Under on-demand treatment with recombinant activated FVII the inhibitor became undetectable but the boy suffered from multiple joint and muscle bleeds. At the age of 11.5 years ITI was attempted with a combination of rituximab, MMF, dexamethasone, intravenous immunoglobulins and high-dose FIX. The inhibitor did not reappear and FIX half-life normalized. No allergic reaction, no signs of nephrotic syndrome and no serious infections were observed.

scholarly journals STUDIES ON CYCLOPHOSPHAMIDE-INDUCED TOLERANCE TO SHEEP ERYTHROCYTES

1967 ◽  
Vol 125 (5) ◽  
pp. 833-845 ◽  
Author(s):  
Alan C. Aisenberg
Keyword(s):  
Tolerance Induction ◽  
Acid Synthesis ◽  
Progressive Increase ◽  
Immunological Tolerance ◽  
Receptor Sites ◽  
Deoxyribonucleic Acid Synthesis ◽  
Isotopic Methods ◽  
Radiation Induced ◽  
Immunological Suppression ◽  
Induced Tolerance

Complete immunological tolerance to sheep cells can be induced in mice when cyclophosphamide is injected together with sheep cells or up to 72 hr before or 48 hr after the antigen. As is true for radiation-induced immune suppression, the drug is most effective when given in the 24 hr prior to antigen. Complete cyclophosphamide-induced immunological suppression requires large doses of sheep cells (6.2 x 109 cells), presumably to enable antigen to reach sequestered receptor sites. The cyclophosphamide tolerance system has been analyzed with the Jerne technique to determine plaque-forming cells and with isotopic methods to measure rates of nucleic acid synthesis. This drug suppression has been found to consist of two components. The first is nonspecific injury to the lymphoid system caused by the cytotoxic drug and is related to the proportion of spleen cells killed. The second is antigen-specific immunological tolerance and appears to correlate with profound depression of deoxyribonucleic acid synthesis in the surviving cells. This tolerance is thought to be most consistent with a mechanism in which antigenic stimulation in the presence of cyclophosphamide-inhibited DNA synthesis and mitosis leads to the elimination or death of the specific immunological clone. Tolerance induction with cyclophosphamide is associated with loss of the 19S hemolysin plaques which are seen in nonstimulated mouse spleen, implicating these cells in immune responsiveness. The ability to induce tolerance is lost on the 3rd postantigen day at the end of a 24-hr period in which 19S cells have increased 8-fold and 7S cells 200-fold. The data suggest that loss of sensitivity is due to the emergence on day 3 of drug-resistant plaque-forming cells, particularly those of the 19S variety. In the succeeding days after antigen injection there is a progressive increase in the resistance of plaque-forming cells to cyclophosphamide administration.

scholarly journals Liver Transplant Tolerance and Its Application to the Clinic: Can We Exploit the High Dose Effect?

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Eithne C. Cunningham ◽  
Alexandra F. Sharland ◽  
G. Alex Bishop
Keyword(s):  
Liver Transplant ◽  
Tolerance Induction ◽  
Experimental Models ◽  
Dose Effect ◽  
Liver Graft ◽  
High Dose ◽  
Transplant Tolerance ◽  
Tissue Mass ◽  
Mhc Molecules ◽  
Specific Tolerance

The tolerogenic properties of the liver have long been recognised, especially in regard to transplantation. Spontaneous acceptance of liver grafts occurs in a number of experimental models and also in a proportion of clinical transplant recipients. Liver graft acceptance results from donor antigen-specific tolerance, demonstrated by the extension of tolerance to other grafts of donor origin. A number of factors have been proposed to be involved in liver transplant tolerance induction, including the release of soluble major histocompatibility (MHC) molecules from the liver, its complement of immunosuppressive donor leucocytes, and the ability of hepatocytes to directly interact with and destroy antigen-specific T cells. The large tissue mass of the liver has also been suggested to act as a cytokine sink, with the potential to exhaust the immune response. In this review, we outline the growing body of evidence, from experimental models and clinical transplantation, which supports a role for large tissue mass and high antigen dose in the induction of tolerance. We also discuss a novel gene therapy approach to exploit this dose effect and induce antigen-specific tolerance robust enough to overcome a primed T cell memory response.

scholarly journals Early Introduction of Multi-Allergen Mixture for Prevention of Food Allergy

2021 ◽  
Author(s):  
A. Zoe Quake ◽  
Taryn Audrey Liu ◽  
Rachel D’Souza ◽  
Katherine G Jackson ◽  
Margie Woch ◽  
...  
Keyword(s):  
Food Allergy ◽  
Total Protein ◽  
Low Risk ◽  
High Dose ◽  
Food Protein ◽  
Dose Frequency ◽  
Plasma Biomarkers ◽  
Early Introduction ◽  
High Doses ◽  
Serving Sizes

The incidence and prevalence of food allergy (FA) are increasing. While several studies have established the safety and efficacy of early introduction of single allergens in infants for the prevention of FA, the exact dose, frequency, and number of allergens that can be safely introduced to infants particularly in those at high or low risk of atopy are still unclear. This 1-year study evaluated the safety of early introduction of single foods (milk, egg, or peanut), vs. two foods (milk/egg, egg/peanut, milk/peanut), vs. multiple foods (milk/egg/peanut/cashew/almond/shrimp/walnut/wheat/fish/soy at low, medium, or high doses) vs no early introduction in infants between 4-6 months of age. At the end of the study, they were evaluated for plasma biomarkers associated with food reactivity with standardized blood tests. Two to four years after the start of the study, participants were evaluated by standardized food challenges. The serving sizes for the single, double, and low dose mixtures were 300 mg total protein per day. The serving sizes for the medium and high dose mixture was 900 mg and 3000 mg total protein, respectively. Equal parts of each protein were used for double or mixture foods. All infants were breastfed until at least 6 months of age. Results demonstrate that infants at either high or low risk for atopy were able to tolerate early introduction of multiple allergenic foods with no increases in any safety issues, including eczema, FA, or food protein induced enterocolitis. The mixtures of foods at either low, medium, or high doses demonstrated trends for improvement in food challenge reactivity and plasma biomarkers compared to single and double food introductions. The results of this study suggest that early introduction of foods, particularly simultaneous mixtures of many allergenic foods is efficacious for preventing FA and can occur safely.

Innowacyjna metoda prowadzenia ITI za pomocą preparatu czynnika VIII z frakcją Fc u pacjentów z hemofilią A z obecnością inhibitora czynnika VIII – przegląd literaturowy

2018 ◽  
Vol 22 (3) ◽  
Author(s):  
Maciej Trzaska ◽  
Marek Karwacki ◽  
Paweł Łaguna ◽  
Michał Matysiak
Keyword(s):  
Factor Viii ◽  
Tolerance Induction ◽  
Standard Of Care ◽  
Preliminary Evidence ◽  
Immunological Tolerance ◽  
Therapeutic Benefit ◽  
High Titre ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
First Time

Eradication of factor VIII inhibitors using Immune tolerance induction (ITI) treatment is the standard of care for severe haemophilia A patients presenting with factor VIII inhibitors, but is not always effective. A description of the potential immunological tolerance effect of the IgG Fc domain of recombinant factor VIII Fc fusion protein (rFVIIIFc), as well as published experience with rFVIIIFc for ITI in patients with severe haemophilia A and high-titre inhibitors. Review of published literature describing cases of ITI with rFVIIIFc in patients with severe haemophilia A and high-titre inhibitors between November 2015 and June 2018. Four publications has been found. Of 56 patients with haemophilia A who presented with FVIII inhibitors, 28 achieved a negative Bethesda titre (< 0.6) after ITI treatment using rFVIIIFc. Additional patients continued on rFVIIIFc ITI at the time of publication, while a few were reported to have switched to bypass therapy alone or other factors . For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events were reported. Based on literature review, preliminary evidence of FVIIIFc use in high risk, first-time ITI suggests rapid time to tolerization. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI. These findings give hope but highlight the need for further evaluation in ongoing clinical trials.

ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and Low-Responding Inhibitors: Evidence from a PedNet Study

2020 ◽  
Vol 120 (08) ◽  
pp. 1166-1172
Author(s):  
H. Marijke van den Berg ◽  
Maria Elisa Mancuso ◽  
Christoph Königs ◽  
Roseline D'Oiron ◽  
Helen Platokouki ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Real Life ◽  
Tolerance Induction ◽  
High Dose ◽  
Severe Hemophilia ◽  
Limited Data ◽  
Treatment Regimens ◽  
First Choice ◽  
Lost To Follow Up

Abstract Background Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype. Methods The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry. It included unselected children with severe hemophilia A (factor VIII [FVIII] < 0.01 IU/mL) born between January 1, 1990 and December 31, 2009 who developed clinically relevant inhibitors and were followed-up for at least 3 years after the first positive inhibitor test. Results A total of 260 patients with inhibitors were identified and 68 of them (26%) had low-responding inhibitors (peak < 5 BU/mL). Five patients were lost to follow-up and 63 were included in this study. The median follow-up was 3.7 years (interquartile range: 3.0–7.5). ITI was started in 51/63 (81%) patients. The median time from ITI start to first negative inhibitor titer was similar with low-dose and high-dose ITI regimens (2.5 and 3.1 months, respectively). Ten of the 12 patients who did not receive ITI were treated with regular prophylaxis and reached a negative titer after a median of 6.5 months. Bleeding rate was low in all patients with no difference between treatment regimens. Conclusion In children with low-responding inhibitors negative titers were reached with regular FVIII treatment irrespective of the regimen (i.e., prophylaxis or ITI).

Partial Immunological Tolerance Induction with Extracorporeal Photopheresis

2018 ◽  
Vol 102 ◽  
pp. S261
Author(s):  
Aleksei Zulkarnaev ◽  
Andrey Vatazin ◽  
Alexander Kildushevsky ◽  
Veronika Fedulkina ◽  
Alexander Faenko
Keyword(s):  
Tolerance Induction ◽  
Immunological Tolerance ◽  
Extracorporeal Photopheresis

scholarly journals Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 378-383 ◽  
Author(s):  
IM Nilsson ◽  
E Berntorp ◽  
O Zettervall ◽  
B Dahlback
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Protein A ◽  
Gel Filtration ◽  
Tolerance Induction ◽  
Factor Ix ◽  
High Dose ◽  
Void Fractions ◽  
Igg4 Antibody ◽  
Induction Of Tolerance

Abstract We recently described tolerance induction with factor VIII/IX, cyclophosphamide, and high-dose intravenous IgG in hemophilia A or B patients with coagulation inhibitory antibodies. Circulating noninhibitory antibodies complexed with factor IX have been demonstrated in tolerant hemophilia B patients. Similar findings are now described in six tolerant hemophilia A patients. Complexes between factor VIII and the ‘tolerant’ antibody were demonstrated by subjecting plasma to gel filtration chromatography, void fractions containing factor VIII/vWF complexes being collected and adsorbed to protein A. Using 125I-labeled F(ab')2 fragments against IgG subclass and factor VIII antigen, complexes between an IgG4 antibody and factor VIII were found to adsorb to protein A. After infusion of factor VIII to tolerant patients, all factor VIII circulated in complex with IgG4 antibody. In three of the patients, the ‘tolerant’ antibodies inhibited an ELISA specific for factor VIII light chain but, unlike the pretolerant antibodies, did not bind radiolabeled factor VIII heavy chain. Although after induction of tolerance the patients still have circulating IgG4 antibodies against factor VIII, the antibodies differ in specificity, lack coagulation inhibitory activity, and do not enhance the rate of elimination of factor VIII.

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