scholarly journals THE THYMUS AND RECOVERY FROM CYCLOPHOSPHAMIDE-INDUCED TOLERANCE TO SHEEP ERYTHROCYTES

1968 ◽  
Vol 128 (1) ◽  
pp. 35-46 ◽  
Author(s):  
Alan C. Aisenberg ◽  
Caroline Davis
Keyword(s):  
Proliferative Response ◽  
Tolerance Induction ◽  
Recovery Process ◽  
Immunological Tolerance ◽  
Base Line ◽  
Drug Injection ◽  
Sheep Erythrocytes ◽  
Lymphoid Depletion ◽  
Induced Tolerance ◽  
Specific Tolerance

Recovery from specific immunological tolerance to sheep erythrocytes induced with the drug cyclophosphamide was studied with the hemolytic plaque technique of Jerne. The base line plaque (19S antibody-forming cell of the unstimulated spleen) and the proliferative response to antigen, both of which had disappeared during tolerance induction, returned with the recovery of specific immunological reactivity. When cyclophosphamide is injected without sheep cells there is temporary immunological unreactivity and lymphoid depletion of the spleen, but specific tolerance is not induced. Recovery is largely complete at the end of 2 wk and does not require the participation of the thymus. When cyclophosphamide is injected together with sheep cells, 18 days after drug injection, tolerance is still complete. In nonthymectomized mice there is rapid recovery during the next 10 wk, followed by much slower restoration over the remaining 20–30 wk of observation. The entire recovery process evidently takes 40–50 wk. In thymectomized CBA mice only minimal recovery takes place in the first 10 wk and no further restoration occurs thereafter. Thymectomy performed 18 days after tolerance is induced, when tolerance is complete, is equally effective in preventing this recovery.

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.

Tolerogenic dendritic cells inhibit antiphospholipid syndrome derived effector/memory CD4+ T cell response to β2GPI

2011 ◽  
Vol 71 (1) ◽  
pp. 120-128 ◽  
Author(s):  
Honorio Torres-Aguilar ◽  
Miri Blank ◽  
Shaye Kivity ◽  
Mudi Misgav ◽  
Jacob Luboshitz ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Proliferative Response ◽  
Memory T Cells ◽  
Tolerance Induction ◽  
Effector Memory ◽  
Effector Memory T Cells ◽  
Tolerogenic Dendritic Cells ◽  
Specific Tolerance

ObjectivesThe importance of β2-glycoprotein I (β2GPI)-specific CD4+ T cells in the development of pathogenic processes in patients with antiphospholipid syndrome (APS) and APS mouse models is well established. Therefore, our objective is to manipulate the β2GPI specific CD4+ T cells using tolerogenic dendritic cells (tDCs) to induce tolerance. We aim to evaluate the capability of tDCs to induce antigen-specific tolerance in effector/memory T cells from patients with APS and to elucidate the involved mechanism.MethodsDCs and tDCs were produced from patients with APS peripheral-blood-monocytes, using specific cytokines. β2GPI-specific tolerance induction was investigated by coculturing control DC (cDC) or tDC, β2GPI-loaded, with autologous effector/memory T cells, evaluating the proliferative response, phenotype, cytokines secretion, viability and regulatory T cells.ResultsHuman monocyte-derived DCs treated with interleukin (IL)-10 and transforming growth factor β-1 (10/TGF-DC) induced β2GPI-specific-unresponsiveness in effector/memory CD4+ T cells (46.5%±26.0 less proliferation) in 16 of 20 analysed patients with APS, without affecting the proliferative response to an unrelated candidin. In five analysed patients, 10/TGF-DC-stimulated T cells acquired an IL-2lowinterferon γlowIL-10high cytokine profile, with just a propensity to express higher numbers of Foxp3+CTLA-4+ cells, but with an evident suppressive ability. In four of 10 analysed patients, 10/TGF-DC-stimulated T cell hyporesponsiveness could not be reverted and showed higher percentages of late apoptosis, p<0.02.ConclusionsThe inherent tolerance induction resistance of activated T cells present during the development of autoimmune diseases has delayed the application of tDC as an alternative therapy. This study highlights the 10/TGF-DC feasibility to induce antigen-specific unresponsiveness in autoreactive T cells generated in patients with APS by inducing apoptosis or T cells with regulatory abilities.

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 PD-1/PD-L1 Interaction Maintains Allogeneic Immune Tolerance Induced by Administration of Ultraviolet B-Irradiated Immature Dendritic Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11
Author(s):  
Lanfang Zhang ◽  
Chang-Qing Xia
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Tolerance ◽  
Tolerance Induction ◽  
Ultraviolet B ◽  
Immature Dendritic Cells ◽  
Programmed Death ◽  
Induced Tolerance ◽  
Different Strains ◽  
Specific Tolerance

Our previous study demonstrated that transfusion of ultraviolet B-irradiated immature dendritic cells (UVB-iDCs) induced alloantigen-specific tolerance between two different strains of mice. Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have been suggested to play an important role in maintaining immune tolerance. In the present study, we seek to address whether PD-1/PD-L1 plays a role in the maintenance of UVB-iDC-induced tolerance. We first observe that the UVB-iDC-induced alloantigen-specific tolerance can be maintained for over 6 weeks. Supporting this, at 6 weeks after tolerance induction completion, alloantigen-specific tolerance is still able to be transferred to syngeneic naïve mice through adoptive transfer of CD4+ T cells. Furthermore, skin transplantation study shows that the survival of allogeneic grafts is prolonged in those tolerant recipients. Further studies show that PD-1/PD-L1 interaction is essential for maintaining the induced tolerance as blockade of PD-1/PD-L1 by anti-PD-L1 antibodies largely breaks the tolerance at both cellular and humoral immunological levels. Importantly, we show that PD-1/PD-L1 interaction in tolerant mice is also essential for controlling alloantigen-responding T cells, which have never experienced alloantigens. The above findings suggest that PD-1/PD-L1 plays a crucial role in maintaining immune tolerance induced by UVB-iDCs, as well as in actively controlling effector T cells specific to alloantigens.

scholarly journals Maternal IgG immune complexes induce food allergen–specific tolerance in offspring

2017 ◽  
Vol 215 (1) ◽  
pp. 91-113 ◽  
Author(s):  
Asa Ohsaki ◽  
Nicholas Venturelli ◽  
Tess M. Buccigrosso ◽  
Stavroula K. Osganian ◽  
John Lee ◽  
...  
Keyword(s):  
Breast Milk ◽  
Immune Complexes ◽  
Tolerance Induction ◽  
Specific Ige ◽  
Human Breast Milk ◽  
Maternal Supplementation ◽  
Induced Tolerance ◽  
And Control ◽  
Specific Tolerance ◽  
Maternal Igg

The role of maternal immune responses in tolerance induction is poorly understood. To study whether maternal allergen sensitization affects offspring susceptibility to food allergy, we epicutaneously sensitized female mice with ovalbumin (OVA) followed by epicutaneous sensitization and oral challenge of their offspring with OVA. Maternal OVA sensitization prevented food anaphylaxis, OVA-specific IgE production, and intestinal mast cell expansion in offspring. This protection was mediated by neonatal crystallizable fragment receptor (FcRn)–dependent transfer of maternal IgG and OVA immune complexes (IgG-IC) via breast milk and induction of allergen-specific regulatory T (T reg) cells in offspring. Breastfeeding by OVA-sensitized mothers or maternal supplementation with IgG-IC was sufficient to induce neonatal tolerance. FcRn-dependent antigen presentation by CD11c+ dendritic cells (DCs) in offspring was required for oral tolerance. Human breast milk containing OVA-IgG-IC induced tolerance in humanized FcRn mice. Collectively, we demonstrate that interactions of maternal IgG-IC and offspring FcRn are critical for induction of T reg cell responses and control of food-specific tolerance in neonates.

Address of the President Lord Blackett, O. M., C. H. at the Anniversary Meeting, 1 December 1969

1970 ◽  
Vol 174 (1037) ◽  
pp. 403-417
Keyword(s):  
Immunological Response ◽  
Immunological Tolerance ◽  
Cell Mediated Immunity ◽  
Specific Cell ◽  
Subsequent Work ◽  
The One ◽  
First Time ◽  
Improved Methods ◽  
Specific Tolerance ◽  
Immunological Barrier

The Copley Medal is awarded to Sir Peter Medawar, C. B. E., F. R. S. Medawar’s first major contribution was to prove conclusively that skin grafts made between different individuals usually fail because of an immunological response made by the recipient against foreign antigens in the donor’s cells, and then to show that the most important mechanism was a specific cell-mediated immunity due to lymphocytes. In attempting to find means of preventing the response against grafted tissues, without impairing immunological capacity in other respects, Medawar made a second major contribution by showing for the first time that it was possible to induce specific tolerance of foreign antigens by administering them to very young animals. His subsequent work, directed towards achieving practical means of overcoming the immunological barrier to tissue transplantation, led him on the one hand to investigate improved methods of inducing specific immunological tolerance and, on the other, to use antiserum against lymphocytes to suppress the damaging effects of these cells. His successful results in experimental animals have indicated the way to their possible application in Man. Medawar’s work has throughout been distinguished by a penetrating clarity of thought combined with insight, and by elegant and original experimental design. He also has a justly high reputation for his analyses and predictions in wider fields of biology, and his study of scientific method.

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.

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.

Sign in / Sign up

Export Citation Format

Share Document