Secondary infections are a major complication of sepsis and associated with a compromised immune state, called sepsis-induced immunoparalysis. Molecular mechanisms causing immunoparalysis remain unclear; however, changes in cellular metabolism of leukocytes have been linked to immunoparalysis. We investigated the relation of metabolic changes to antimicrobial monocyte functions in endotoxin-induced immunotolerance, as a model for sepsis-induced immunoparalysis. In this study, immunotolerance was induced in healthy males by intravenous endotoxin (2 ng/kg, derived from Escherichia coli O:113) administration. Before and after induction of immunotolerance, circulating CD14(+) monocytes were isolated and assessed for antimicrobial functions, including cytokine production, oxidative burst, and microbial (Candida albicans) killing capacity, as well metabolic responses to ex vivo stimulation. Next, the effects of altered cellular metabolism on monocyte functions were validated in vitro. Ex vivo ...
Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in given organism. It contrasts with conventional immune-mediated elimination of foreign antigens (see Immune response). Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced-in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar. Immune tolerance is important for normal physiology. Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.). Deficits in central or peripheral tolerance also cause autoimmune ...
microRNA-142-mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance.. J Clin Invest. 2019 Feb 11. pii: 124725. doi: 10.1172/JCI124725. [Epub ahead of print]. Anandagoda N, Willis JC, Hertweck A, Roberts LB, Jackson I, G kmen MR, Jenner RG, Howard JK, Lord GM.. Abstract. Tregs play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). This function is dependent on maintenance of a high intracellular cAMP concentration. A number of microRNAs are implicated in the maintenance of Tregs. In this study, we demonstrate that peripheral immune tolerance is critically dependent on posttranscriptional repression of the cAMP-hydrolyzing enzyme phosphodiesterase-3b (Pde3b) by microRNA-142-5p (miR-142-5p). In this manner, miR-142-5p acts as an immunometabolic regulator of intracellular cAMP, controlling Treg suppressive function. Mir142 was associated with a super enhancer bound by the Treg lineage-determining transcription factor ...
Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance. As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents (compare also tolerogenic therapy). In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease. Immune tolerance can be defined as the ability of the immune system to distinguish between self and non-self, or harmless and harmful. T-cells are able to distinguish between self and ...
Induction of B cell tolerance or activation was analyzed with vesicular stomatitis virus (VSV) glycoprotein (G) expressed as a neo-self Ag. A membrane form of VSV-G expressed in all tissues, including the bone marrow, induced unresponsiveness at both the Th and B cell level, whereas a soluble form of VSV-G expressed peripherally in liver and kidney did not tolerize B cells and only reversibly anergized Th cells. Interestingly, a similar correlation was found for activation of mature lymphocytes. When mature normal spleen cells were transferred into the two transgenic mouse lines, the membrane form of VSV-G was strongly immunogenic for both Th and B cells, and high VSV-G-specific IgG Ab titers were induced in these transgenic mice. In contrast, spleen cells transferred into mice expressing the soluble form of VSV-G were not activated, and no VSV-G specific Abs were induced. These results indicate that highly immunogenic Ags are strongly tolerogenic for both immature B and T cells.
For some time it has been thought that antigenic challenge in neonatal life is a tolerogenic rather than immunogenic event. Reexamination of the classic neonatal tolerance experiments of Billingham, Brent, and Medawar showed that tolerance is not an intrinsic property of the newborn immune system, but that the nature of the antigen-presenting cell determines whether the outcome is neonatal tolerance or immunization.
Congenital T cell (T)-deficient mice, such as RAG-1- or SCID mice, succumb to inflammatory bowel disease (IBD) upon adoptive transfer of syngenic naive T cells as a consequence of chronic inflammation in the intestine from unfettered response to commensal bacterial antigens. Although the prevailing view for the onset of IBD is believed to be the absence of regulatory T cells (Tregs), the finding that donor T cells undergo considerable chronic activation even in the presence of Tregs suggests an abnormality in the presentation of enteric antigens also appears to be involved. To study if such a defect is also evident during the lymphopenic neonatal period, we compared the induction of oral tolerance between B6 neonates and adults to host commensal or exogenously provided nominal Ags by adoptively transferring polylconal or Ag-specific donor T cells. Strikingly, donor T cells in neonatal hosts proliferated much faster and more readily acquired effector function than donor T cells in adults. These ...
The Immune Tolerance Network seeks to provide funding and strategic support for clinical trials designed to induce immune tolerance in allergy and asthma, autoimmune disease, transplantation, and type 1 diabetes. The ITN is currently seeking proposals for clinical trials of immune tolerance in transplantation using deceased-donor organs.
Argyris, B F. and Lustro, F D., "Immunologic unresponsiveness of mouse spleen sensitized to allogeneic tumors." (1977). Subject Strain Bibliography 1977. 1705 ...
Conclusions Apoptosis of epithelial cells leads to translocation of SS-autoantigens and single-stranded hy1-RNA to apoptotic blebs and membrane particles. The apoptotic particles are internalized by pDCs, which in response mature and produce proinflammatory cytokines. Androgens affect to redistribution of autoantigens and diminish the particle-elicited increase of TLR expression in pDCs. Apoptosis of salivary gland cells lead to formation of apoptotic particles, which might affect immunotolerance, production of autoantibodies and onset of autoinflammation. This event might describe how the immunologic tolerance is broken in the early stages of SS. ...
TY - JOUR. T1 - Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3. AU - Ostroukhova, Marina. AU - Seguin-Devaux, Carole. AU - Oriss, Timothy B.. AU - Dixon-McCarthy, Barbara. AU - Yang, Liyan. AU - Ameredes, Bill. AU - Corcoran, Timothy E.. AU - Ray, Anuradha. PY - 2004/7. Y1 - 2004/7. N2 - Under normal circumstances, the respiratory tract maintains immune tolerance in the face of constant antigen provocation. Using a murine model of tolerance induced by repeated exposure to a low dose of aerosolized antigen, we show an important contribution by CD4+ T cells in the establishment and maintenance of tolerance. The CD4+ T cells expressed both cell surface and soluble TGF-β and inhibited the development of an allergic phenotype when adoptively transferred to naive recipient mice. While cells expressing cell surface TGF-β were detectable in mice with inflammation, albeit at a lower frequency compared with that in tolerized mice, only those from ...
Incubation of unprimed spleen B cells with high concentrations of hapten-conjugates resulted in the induction of specific unresponsiveness or tolerance to a subsequent encounter with the hapten on a potentially immunogenic carrier. This process of tolerance induction could occur in the absence of extracellular calcium. In contrast B-cell activation to both proliferation and subsequent antibody secretion is known to be calcium dependent. This means that either (1) the decisions which determine immunity and tolerance in B cells are mediated through totally distinct signalling pathways, or that (2) if tolerance and immunity depend on same common signalling events, then the commitment of B cells to switch on or off must be determined at a very early stage.
While emerging proof indicates that dendritic cells (DC) play a central part in the pathogenesis of multiple sclerosis (MS), their modulation with immunoregulatory providers provides potential customer as disease-modifying therapy. 1,25(Oh yea)2D3-treated DC nor their capability to induce Capital t cell hyporesponsiveness. In addition, the Capital t cell hyporesponsiveness caused by 1,25(Oh yea)2D3-treated DC is definitely antigen-specific and powerful since Capital t cells maintain their capability to react to an unconnected antigen and perform not really reactivate upon rechallenge with completely mature standard DC, respectively. These findings underline the medical potential of tolerogenic DC (tolDC) to right the immunological. ...
Bode, K.; Bujupi, F.; Link, C.; Hein, T.; Zimmermann, S.; Peiris, D.; Jaquet, V.; Lepenies, B.; Weyd, H.; Krammer, P. H.: Dectin-1 binding to annexins on apoptotic cells induces peripheral immune tolerance via NADPH oxidase-2. Cell Reports 29 (13), S. 4435 - 4446.e9 (2019 ...
The Immune Tolerance Network is dedicated to the clinical evaluation of novel tolerance-inducing therapies that will ¿re-educate¿ the immune system to eliminate injurious immune responses. The ITN is conducting clinical trials in autoimmune diseases such as Type 1 Diabetes. In addition, to understand the underlying mechanisms of action of the candidate therapies and to monitor tolerance, the ITN has established state of the art core laboratory facilities to conduct integrated mechanistic studi...
The lollipop plot above illustrates recurrent (observed in 3 or more out of 4440 TCGA tumor samples from 15 cancer types) and therefore potentially oncogenic missense mutations (click on Show Cancer Mutations). The bar plot below shows the proportion of tumor samples that have any kind of altering mutation(s) in the given protein. ...
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor-initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses. Negatively regulates B cell proliferation and also has an important function in self-antigen induced B cell tolerance induction. Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53. In the case of ER stress or DNA damage-induced ...
Searching For The Secrets Of Drug-Free Transplants: University Of Pittsburgh, Through Immune Tolerance Network, To Develop Tests Predictive Of Transplant Tolerance
The 4th Antigen Specific Immune Tolerance Digital Summit (ASIT) brings together industry representatives from the fields of autoimmunity, al...
Immune suppressive mechanisms in HCV infection. HCV mutates its amino acid sequence to escape from immune surveillance, inhibits type 1 IFN production, and supp
Margaret Petroff believes that decoding additional secrets to immune tolerance could lead to treatment breakthroughs for a variety of conditions.
Japanese drugmaker Astellas and Swiss biotech Anokion have hooked up in a deal worth $760 million to create a new US-based firm focused on developing novel immune tolerance therapeutics. - News - PharmaTimes
Immune responses and their modulation within the liver are critical to the outcome of liver malignancies. In late-stage tumors, secreted TGF-β promotes oncogenic functions and can confer tolerogenicity to some immune cells like DCs. The TGF-β signaling pathway is involved in the control of several biological processes, including immunosurveillance. The aim of the present study was to assess CD1a(+) and CD83(+) DCs and to evaluate the impact of TGF-β pathway on DCs maturation and distribution in the liver metastases from gastric and colorectal tumors. The percentage of CD83(+) DCs in the liver tissue, surrounding metastasis and in the metastasis-free liver was measured by flow cytometry, and TGF-β levels were assessed in the tissue supernatant from the peritumoral liver after mononuclear cell isolation and in the sera of the same patients. CD1a(+) and CD83(+) DCs were observed in the tumor stroma and border. Out of 73 patients, there was cytoplasmic reactivity: of TGF-β1 in 37 (50.7%); of ...
Tolerance induction to self antigens in the peripheral lymphoid tissues: blood, lymph nodes, spleen, and mucosal-associated lymphoid tissues.
Furthermore, it has also been shown that a distinct population of antigen-specific, non-Qa-1-restricted CD8+CD28- cells can suppress immune responses by directly interacting with antigen-presenting DCs and rendering these cells tolerogenic (64-66). The suppression involves the upregulation of inhibitory Ig-like transcript 3 (ILT3) and ILT4 receptors expressed on the DCs. APCs tolerized by CD8+ T cells show reduced expression of costimulatory molecules and induce antigen-specific unresponsiveness in CD4+ T helper cells. The precise function of these cells in vivo is not clear, and it is not known whether they interact with the Qa-1-restricted CD8+ suppressor cells or, alternatively, whether Qa-1-restricted T cells induce tolerogenic DCs.. Finally, the Qa-1-dependent regulatory CD8 pathway has begun to be translated from mice to humans with the in vitro findings that human CD8+ T cells can be induced to differentiate into regulatory cells whose function is dependent on HLA-E, the human homolog of ...
In a healthy individual, the immune system uses several different immune tolerance mechanisms in order to prevent the development of autoimmune disease. For T c...
ASIT 2020 is specifically dedicated to realizing the commercial potential of antigen specific immunotherapies with a focus on novel approaches to tolerance induction, assay development and tolerance delivery.
Impaired T cell tolerance is the cause of all types of autoimmune diseases, which suffers more than 23 million Americans. Since Sir Frank Macfarlane Burnet firs...
The immune system exists to protect the host against pathogenic organisms and highly complex pathways of recognition, response, elimination and memory have evolved in order to fulfil this role. The immune system also acts to ensure tolerance to self, to food and other environmental components, and to commensal bacteria. A breakdown in the tolerogenic pathways can also lead to inflammatory diseases. The prevalence of inflammatory diseases, including atopic disorders, has increased over the last 60 years. The development of tolerance is the result of active immune mechanisms and both development and maintenance of tolerance are lifelong processes which start very early in life, even prenatally. Profound immunologic changes occur during pregnancy, involving a polarization of T helper (Th) cells towards a dominance of Th2 and regulatory T cell effector responses in both mother and fetus. This situation is important to maintain pregnancy through avoidance of the rejection of the immunologically ...
A state of unresponsiveness to a specific antigen (immune stimulus) or group of antigens to which a person is normally responsive. Immune tolerance can result from a number of causes, including: {{}}Prior contact with the same antigen in fetal…
The RESTARRT study is being conducted by the Immune Tolerance Network (ITN) and leading transplant centers throughout the U.S. The ITN is a resesarch consortium sponsored by the National Institute of Allergy and Infectious Diseases (NIH funded). ...
Tregs play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). This function is dependent on maintenance of a high intracellular cAMP concentration. A number of microRNAs are implicated in the maintenance of Tregs. In this study, we demonstrate that peripheral immune tolerance is critically dependent on posttranscriptional repression of the cAMP-hydrolyzing enzyme phosphodiesterase-3b (Pde3b) by microRNA-142-5p (miR-142-5p). In this manner, miR-142-5p acts as an immunometabolic regulator of intracellular cAMP, controlling Treg suppressive function. Mir142 was associated with a super enhancer bound by the Treg lineage-determining transcription factor forkhead box P3 (FOXP3), and Treg-specific deletion of miR-142 in mice (TregΔ142) resulted in spontaneous, lethal, multisystem autoimmunity, despite preserved numbers of phenotypically normal Tregs. Pharmacological inhibition and genetic ablation of PDE3B prevented autoimmune disease and reversed the ...
The release of Otto Warmbier, still in an unresponsive state, from North Korean imprisonment has left his family struggling to understand the mysterious circumstances surrounding the 22-year-olds medical condition. He spent at least 17 months in pri…
A paradigm shift in immunology has been the recent discovery of regulatory T cells (T reg cells), of which CD4(+)Foxp3(+) cells are proven as essential to self-tolerance. Using transgenic B6.Foxp3(hCD2) mice to isolate and ablate Foxp3(+) T reg cells with an anti-hCD2 antibody, we show for the first time that CD4(+)Foxp3(+) cells are crucial for infectious tolerance induced by nonablative anti-T cell antibodies. In tolerant animals, Foxp3(+) T reg cells are constantly required to suppress effector T cells still capable of causing tissue damage. Tolerated tissue contains T cells that are capable of rejecting it, but are prevented from doing so by therapeutically induced Foxp3(+) T reg cells. Finally, Foxp3(+) cells have been confirmed as the critical missing link through which infectious tolerance operates in vivo. Peripherally induced Foxp3(+) cells sustain tolerance by converting naive T cells into the next generation of Foxp3(+) cells. Empowering Foxp3(+) regulatory T cells in vivo offers a tractable
The Immune Tolerance Network (ITN) is an international clinical research consortium sponsored by NIAID, part of the National Institutes of Health. Our mission is to accelerate the clinical development of immune tolerance therapies.. Immune tolerance therapies reprogram the immune system in a highly specific manner so that disease-causing immune responses are stopped while maintaining the immune systems ability to combat pathogen infection. The ITN develops and conducts clinical trials and mechanistic studies of specialized immune tolerance therapies in the following areas:. ...
Dendritic cells (DCs) are known to regulate immune responses by inducing both central and peripheral tolerance. DCs play a vital role in negative selection of developing thymocytes by deleting T cells with high-affinity for self-peptide-major histocompatibility complexes. In the periphery, DCs mediate peripheral tolerance by promoting regulatory T-cell development, induction of T-cell unresponsiveness, and deletion of activated T cells. We studied whether allogeneic DCs, obtained from bone marrow cultured with either Flt3L (FLDCs) or granulocyte-macrophage colony-stimulating factor (GMDCs), could induce allospecific central and peripheral tolerance after IV injection; B cells were used as a control. The results showed that only FLDCs reached the thymus after injection and that these cells induced both central and peripheral tolerance to donor major histocompatibility complexes. For central tolerance, injection of FLDCs induced antigen-specific clonal deletion of both CD8 and CD4 single-positive
The atheroprotective effect paralleled an induction of Treg suppression of apoB-100-specific effector T cells and an increase in IL-10+ CD4+ T cells. Therefore, our data suggest that nasal immunization with p210-CTB protects against atherosclerosis by inducing antigen-specific, IL-10+ regulatory Tr1 cells. It is unlikely that atheroprotection involved the immunosuppressive cytokine TGF-β because nasal immunization with p210-CTB also reduced atherosclerosis in mice lacking a functional TGF-β receptor on T cells.. Antigen-specific as well as antigen-independent effects have been reported in studies of Treg.25 Several studies of autoimmune diseases support the regulation model according to which Treg suppresses conventional effector T cells with the same antigen specificity. Other investigators report that Treg exerts major effects on antigen-presenting cells in an antigen-independent manner. Our data clearly show that antigen-specific atheroprotection was paralleled by inhibition of ...
The administration of antigens into the anterior chamber (AC) of the eye induces a special form of antigen-specific peripheral immune tolerance termed AC-associated immune deviation (ACAID), which prevents delayed-type hypersensitivity (DTH) responses and other inflammatory responses. Type-II collagen (CII) is highly expressed in cartilage tissues and has been linked to Rheumatoid arthritis, aging, and osteoarthritis. To explore the potential for ACAID induction via CII, we checked for different signs of ACAID generation following the AC injection of CII in BALB/c mice. We hypothesized that the mechanism of ACAID induction involves efferent T regulatory cells (Tregs). Both local adoptive transfer (LAT) assays and DTH assays were performed. Results indicated that ACAID induction was driven by the AC injection of CII. Spleen cells of mice injected with CII in the AC significantly suppressed DTH responses. ACAID induction was mediated by efferent Tregs in the spleen. CII-mediated ACAID induction ...
Background: Dendritic cells (DCs) are professional antigen-presenting cells able to induce immunity or tolerance. The interactions of immature DCs with naive T lymphocytes induce peripheral tolerance through mechanisms that include anergy or deletion of lymphocytes or the generation of regulatory T cells. Because of the central role of DCs in the immune response, they are potential targets for the induction of experimental tolerance. Thus, the generation of immature (tolerogenic) DCs able to capture and present alloantigens to T cells represents an important aim in our efforts to achieve better transplant acceptance. Methods: In this work, we generated immature DCs by using vitamin D 3 (VD3) during the process of DC differentiation. Results: The VD3DCs showed an immature phenotype characterized by a low expression of major histocompatibility complex antigens of class II, CD86, and CD80 molecules and the secretion of a tolerogenic cytokine pattern. Furthermore, we showed that VD3DCs ...
Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system and is considered to be a T-cell mediated autoimmune disease. The "ideal" method in treating MS would be an antigen-specific therapy that does not require generalized immunosuppression. To date there are no definitive treatments for MS but there are several licensed therapies such as -interferon. Unfortunately the effect of interferon (IFN) is reduced by the development of neutralizing antibodies (NAbs) in up to 35% of MS patients within two years of starting treatment. An immunization schedule was developed in the BALB/c mice by subcutaneous administration of recombinant human IFN, and this resulted in development of high incidence of NAbs to the protein in the BALB/c model termed "NAbs model". The mechanism of NAbs formation in this model is believed to be similar to that observed in IFN-treated MS patients with NAbs, which is as a result of an immune response to the protein. We elected ...
The induction of T-cell responses involves the recognition of extrinsic antigen in association with antigens of the major histocompatibility complex (MHC), in mice and man, with different T cells recognizing antigen in association with either class I (H-2K/D, HLA-A, B, C) or class II (Ia, HLA-D/DR) MHC antigens. However, the requirement of MHC recognition in the induction of immunological tolerance remains ill defined. With human T helper clones recognizing synthetic peptides of influenza haemagglutinin (HA-1), we have investigated the nature of antigen-induced stimulation, and antigen-induced antigen-specific unresponsiveness, immunological tolerance. Tolerance is not due to cell death, as the cells remain responsive to interleukin-2 and is associated with the loss of T3 antigen from the cell surface. Using monoclonal antibodies to the non-polymorphic regions of human class II antigens to inhibit the induction of T-cell tolerance we report here that induction of tolerance requires the recognition of
Little is know about the nature of peripheral B cell tolerance or how it may vary in distinct lineages. Although autoantibody transgenic studies indicate that anergy and apoptosis are involved, some studies claim that receptor editing occurs. To model peripheral B cell tolerance in a normal, polyclonal immune system, we generated transgenic mice expressing an Igκ-light chain-reactive superantigen targeted to the plasma membrane of hepatocytes (pAlb mice). In contrast to mice expressing κ superantigen ubiquitously, in which κ cells edit efficiently to λ, in pAlb mice, κ B cells underwent clonal deletion. Their κ cells failed to populate lymph nodes, and the remaining splenic κ cells were anergic, arrested at a semi-mature stage without undergoing receptor editing. In the liver, κ cells recognized superantigen, down-regulated surface Ig, and expressed active caspase 3, suggesting ongoing apoptosis at the site of B cell receptor ligand expression. Some, apparently mature, κ B1 and ...
Cell based therapies have been studied extensively in the context of transplantation tolerance induction. The most successful protocols have relied on transfusion of bone marrow prior to the transplantation of a renal allograft. However, it is not clear that stem cells found in bone marrow are required in order to render a transplant candidate immunologically tolerant. Accordingly, mesenchymal stem cells, regulatory myeloid cells, T regulatory cells, and other cell types, are being tested as possible routes to tolerance induction, in the absence of donor derived stem cells. Early data with each of these cell types have been encouraging. However, the induction regimen capable of achieving consistent tolerance, whilst avoiding unwanted sided effects, and which is scalable to the human patient, has yet to be identified. Here we present the status of investigations of various tolerogenic cell types and the mechanistic rationale for their use in in tolerance induction protocols.
Orally induced tolerance is a physiologically relevant form of peripheral tolerance, which is believed to be important for the prevention of pathological immune responses in the gut. Of several mechanisms proposed to mediate oral tolerance, one that has received much attention recently is the concept of regulatory CD4+ T cells. As recent studies have suggested that interleukin (IL)-15 may be important for the differentiation and maintenance of regulatory CD4+ T cells, we have examined the role of IL-15 in oral tolerance, using a soluble form of the IL-15 receptor (sIL-15R) which blocks the biological effects of IL-15 in vivo. Oral tolerance induced by feeding mice ovalbumin (OVA) in a low-dose regimen believed to induce regulatory T cell activity was not affected by the administration of sIL-15R during either the induction or maintenance phase of tolerance. Thus, oral tolerance does not involve an IL-15-dependent mechanism.. ...
Although oral tolerance was first described in 1911 (1), it was not until the later 1970s that investigators started to address the mechanisms involved (2-4). An expansion of interest has evolved in the past 20 years as various laboratories have attempted to use this form of induced immunosuppression to counteract various chronic inflammatory/autoimmune diseases. A clearer understanding of the parameters regulating oral tolerance has emerged. First and foremost is the observation that multiple forms of tolerance exist. Initial studies by Challacombe et al. (2), Mowat et al. (3), and Waksman et al (4) all documented that regulatory CD8+ T cells existed in the spleen following oral antigen administration and that these cells, but not CD4+ T cells, could transfer the tolerant state to a naive animal. The mechanism whereby these CD8+ T cells were activated was not elucidated. Richman et al. (5) and Santos et al. (6) subsequently demonstrated that tolerance could also be transferred with Peyers ...
Principal Investigator:SEKINE Yasuo, Project Period (FY):2003 - 2005, Research Category:Grant-in-Aid for Scientific Research (C), Section:一般, Research Field:Thoracic surgery
We have used a novel hu-mouse model expressing a human-specific surrogate self-Ag to formally demonstrate that developing human B cells use receptor editing as a mechanism of central B cell tolerance. Central B cell tolerance in hu-mice is stringent but incomplete. Although the selection of autoreactive B cells into the periphery is rare, variations in the extent of tolerance were observed and shown to depend on the amount of self-Ag as well as the individual genetics of the source of CB.. To date, most studies of human B cell tolerance have focused on limited repertoire analyses of B cell subsets present in peripheral blood (Meffre and Wardemann, 2008; Meffre, 2011). These studies have been invaluable in establishing the presence of tolerance checkpoints, but they have been limited to a poorly defined set of self-Ags without a clear understanding of how these Ags directly affect B cells in vivo. In fact, although a significant reduction in the frequency of autoreactive clones in the human B ...
TGF-beta-induced myelin peptide-specific regulatory T cells mediate antigen-specific suppression of induction of experimental autoimmune encephalomyelitis.
The induction of peripheral tolerance to alloantigen is accompanied in many cases by a decrease in the production of cytokines such as IL-2 and IFN gamma, yet a sustained production of cytokines such as IL-10 and IL-4. Whether or not this altered pattern of cytokine production in tolerant animals is causally related to the induction and/or maintenance of the tolerant state has yet to be fully determined, although experiments blocking selectively the action of IL-2 with CD25 antibodies suggest that manipulation of cytokine production may at least be a route to tolerance. Alternative methods for directly influencing the cytokine balance are sought and recent experiments on the CD28/CTLA-4-B7 interaction suggest a possible approach.
Control of immune damage at the effector phase is a crucial and perhaps the most realistic therapeutic target in clinical intervention of immune-mediated diseases (Chatenoud, 2011). Improvement of therapeutic interventions will require in-depth understanding of the immune cell behavior in target tissues and of the reaction of target tissue cells in response to insult. The current study suggests that the contact-dependent mode of immune cell interaction in the target tissue is a critical part of pathophysiology at the effector phase of immune responses, and immune tolerance induction may be facilitated by promoting intimacy between pathogenic and protective immune cells. In this regard, it is highly relevant that tissue antigen-specificity, as opposed to bystander killing (Tite and Janeway, 1984), shapes tissue fate in the effector phase.. With the tools currently available for longitudinal imaging of antigen-specific T cells in target tissues, we uncovered some basic behaviors of different ...