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Immune Tolerance (immune + tolerance)
Terms modified by Immune Tolerance Selected AbstractsDNA Damage, Apoptosis and Langerhans Cells,Activators of UV-induced Immune Tolerance,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2008Laura Timares Solar UVR is highly mutagenic but is only partially absorbed by the outer stratum corneum of the epidermis. UVR can penetrate into the deeper layers of the epidermis, depending on melanin content, where it induces DNA damage and apoptosis in epidermal cells, including those in the germinative basal layer. The cellular decision to initiate either cellular repair or undergo apoptosis has evolved to balance the acute need to maintain skin barrier function with the long-term risk of retaining precancerous cells. Langerhans cells (LCs) are positioned suprabasally, where they may sense UV damage directly, or indirectly through recognition of apoptotic vesicles and soluble mediators derived from surrounding keratinocytes. Apoptotic vesicles will contain UV-induced altered proteins that may be presented to the immune system as foreign. The observation that UVR induces immune tolerance to skin-associated antigens suggests that this photodamage response has evolved to preserve the skin barrier by protecting it from autoimmune attack. LC involvement in this process is not clear and controversial. We will highlight some basic concepts of photobiology and review recent advances pertaining to UV-induced DNA damage, apoptosis regulation, novel immunomodulatory mechanisms and the role of LCs in generating antigen-specific regulatory T cells. [source] Immunomodulatory Effects of Mixed Hematopoietic Chimerism: Immune Tolerance in Canine Model of Lung TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009R. A. Nash Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n = 5) vs. nonchimeric (n = 7) recipients (p , 0.05, Fisher's test). There were histological changes consistent with low-grade rejection in 3/5 of the lung grafts in chimeric recipients at ,1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INF,+, CD4+IL-4+ and CD8+ INF,+ T-cell subsets in the blood (p < 0.0001 for each of the three T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGF, were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response. [source] Evidence of Immune Tolerance to Blood Group Antigens in a Case of ABO-Incompatible Pediatric Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2007H. Ohdan In a 12-year-old patient with blood group O, who had received a partial liver graft 10 years ago from his father with blood group A, the levels of anti-A-specific antibodies (Abs) were persistently undetectable after the transplantation, while the levels of anti-B-specific Abs gradually increased and attained a plateau. Peripheral blood mononuclear cells (PBMCs) from this patient were engrafted into NOD/SCID mouse in order to investigate the immune response to donor-type blood group antigens. Even after sensitization with blood group-A erythrocytes, no anti-A Abs were detected in the serum samples of the mouse that received PBMCs from the blood group-O recipient of group-A liver allograft, however, immunoglobulins specific for antigens other than the A antigens were produced. Thus, we provide a possible evidence of immune tolerance to blood group antigens in this ABO-incompatible pediatric liver transplantation. [source] Low-dose immune tolerance induction for paediatric haemophilia patients with factor VIII inhibitorsHAEMOPHILIA, Issue 2 2008A. UNUVAR Summary., The development of an inhibitor against factor VIII (FVIII) is a serious complication in children with haemophilia A. Immune tolerance induction (ITI) therapy is generally considered to be the best approach to eradicate the inhibitor. In this paper, the low-dose (,50 IU kg,1 twice or three times weekly with plasma-derived factor concentrates) ITI regimen used in Turkey is discussed. This regimen was given to 21 haemophilia A patients with high titer inhibitors. The median age at the beginning of ITI was 9 years and exposure days were 25. The median pre-ITI historical peak inhibitor titer, and inhibitor titer when ITI started were 80 BU (range 6.0,517), 19.2 BU (range 3.6,515), respectively. Complete immune tolerance was defined as the time at which at least two negative inhibitor assays was obtained with no anamnestic response. Our two cases were not reached in follow-up period. Immune tolerance could be achieved in 5 of 19 (26.3%) patients within a median time of 6 months. Partial tolerance was obtained in 7 patients while treatment failed in spite of significant decreased inhibitor levels in the other patients. A relapse developed in one immune-tolerized patient, one year later. The level of inhibitor titer at the beginning of ITI (,10 BU), the pre-ITI historical peak inhibitor titer (<50 BU), and the time between the first diagnosis inhibitor to starting ITI (<12 months) were main factors in the success (complete or partial tolerance) of ITI. In conclusion, the outcome of low-dose ITI protocol was not satisfactory in this retrospective study. [source] Immune tolerance: mechanisms and application in clinical transplantationJOURNAL OF INTERNAL MEDICINE, Issue 3 2007M. Sykes Abstract. The achievement of immune tolerance, a state of specific unresponsiveness to the donor graft, has the potential to overcome the current major limitations to progress in organ transplantation, namely late graft loss, organ shortage and the toxicities of chronic nonspecific immumnosuppressive therapy. Advances in our understanding of immunological processes, mechanisms of rejection and tolerance have led to encouraging developments in animal models, which are just beginning to be translated into clinical pilot studies. These advances are reviewed here and the appropriate timing for clinical trials is discussed. [source] New potential treatments for protection of pancreatic B-cell function in Type 1 diabetesDIABETIC MEDICINE, Issue 11 2008S. Cernea Abstract Type 1 diabetes mellitus results from the progressive and specific autoimmune destruction of insulin-secreting pancreatic B-cells, which develops over a period of years and continues after the initial clinical presentation. The ultimate goal of therapeutic intervention is prevention or reversal of the disease by the arrest of autoimmunity and by preservation/restoration of B-cell mass and function. Recent clinical trials of antigen-specific or non-specific immune therapies have proved that modulation of islet specific autoimmunity in humans and prevention of insulin secretion loss in the short term after the onset of disease is achievable. The identification of suitable candidates for therapy, appropriate dosage and timing, specificity of intervention and the side-effect profile are crucial for the success of any approach. Considering the complexity of the disease, it is likely that a rationally designed approach of combined immune-based therapies that target suppression of B-cell specific autoreactivity and maintenance of immune tolerance, coupled with islet regeneration or replacement of the destroyed B-cell mass, will prove to be most effective in causing remission/reversal of disease in a durable fashion. [source] Ecoimmunity: immune tolerance by symmetric co-evolutionEVOLUTION AND DEVELOPMENT, Issue 6 2007Uri Nevo SUMMARY It is widely accepted that immune tolerance toward "self" is established by central and peripheral adaptations of the immune system. Mechanisms that have been demonstrated to play a role in the induction and maintenance of tolerance include thymic deletion of self-reactive T cells, peripheral T cell anergy and apoptosis, as well as thymic and peripheral induction of regulatory T cells. However, a large body of experimental findings cannot be rationalized solely based on adaptations of the immune system to its environment. Here we propose a new model termed Ecoimmunity, where the immune system and the tissue are viewed as two sides of a continuously active and co-evolving predator,prey system. Ecoimmunity views self-tolerance, not as an equilibrium in which autoimmunity is chronically suppressed, but as a symmetrical balanced conflict between the ability of immune cells to destroy tissue cells by numerous mechanisms, and the capacity of adapted tissue cells to avoid predation. This balance evolves during ontogeny, in parallel to immune adaptations, embryonic tissue cells adapt their phenotype to the corresponding immune activity by developing the ability to escape or modulate damaging local immune responses. This phenotypic plasticity of tissue cells is directed by epigenetic selection of gene expression pattern and cellular phenotype amidst an ongoing immune pressure. Thus, whereas some immune cells prey predominantly on pathogens and infected cells, self-reactive cells continuously prey on incompetent tissue cells that fail to express the adapted phenotype and resist predation. This model uses ecological generalization to reconcile current contradictory observations as well as classical enigmas related to both autoimmunity and to tolerance toward foreign tissues. Finally, it provides empirical predictions and alternative strategies toward clinical challenges. [source] Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytesGLIA, Issue 15 2008Thomas Calzascia Abstract T cell mediated immunotherapies are proposed for many cancers including malignant astrocytoma. As such therapies become more potent, but not necessarily more tumor-specific, the risk of collateral autoimmune damage to normal tissue increases. Tumors of the brain present significant challenges in this respect, as autoimmune destruction of brain tissue could have severe consequences. To investigate local immune reactivity toward a tumor-associated antigen in the brain, transgenic mice were generated that express a defined antigen (CW3170,179) in astroglial cells. The resulting six transgenic mouse lines expressed the transgenic self-antigen in cells of the gastrointestinal tract and CNS compartments, or in the CNS alone. By challenging transgenic mice with tumor cells that express CW3, self/tumor-specific immune responses were visualized within a normal polyclonal T cell repertoire. A large expansion of the endogenous CW3170,179 -specific CD8 T cell population was observed in nontransgenic mice after both subcutaneous and intracerebral implantation of tumor cells. In contrast, CW3170,179 -specific immune responses were not observed in transgenic mice that exhibited extracerebral transgene expression. Importantly, in certain groups of mice in which transgene expression was restricted to the CNS, antigen-specific immune responses occurred when tumor was implanted subcutaneously, but not intracerebrally. This local immune tolerance in the brain was induced via peripheral (extrathymic) rather than central (thymic) tolerance mechanisms. Thus, this study highlights the role of regional immune regulation in the prevention of autoimmunity in the brain, and the potential impact of these mechanisms for brain tumor immunotherapy. © 2008 Wiley-Liss, Inc. [source] The relevance of the bleeding severity in the treatment of acquired haemophilia , an update of a single-centre experience with 67 patientsHAEMOPHILIA, Issue 102 2010H. ZEITLER Summary., Acquired haemophilia (AH), an autoimmune disorder with clinical features ranging from harmless haematomas to life-threatening bleedings, still has a mortality rate of up to 25%. Owing to its low frequency (1,4 × 106), standardized treatment protocols for its variable manifestations are not available. In case of prominent severe bleedings, the treatment should aim at rapid elimination of the antibody to protect patients from bleedings and on reinduction of long-term immune tolerance. Clinical data, short- and long-term treatment results of 67 patients diagnosed by our centre are presented. Patients were treated depending on their bleeding severity either by an immunosuppressive treatment alone, or in case of life-threatening bleedings, by a combined protocol (modified Bonn,Malmö protocol, MBMP) consisting of antibody depletion through immunoadsorption, intravenous immunoglobulin treatment, immunosuppression and high-dose factor VIII (FVIII) substitution. Mild bleedings occurred in two patients who were treated successfully alone by immunosuppression. Complete remission (CR) was achieved in 90% of the patients treated with MBMP (60). Of the six patients (10%) who achieved a partial remission (PR), four suffered from cancer. Mortality under MBMP was not seen. In contrast, five patients, in whom diagnosis of AH was delayed, experienced fatal outcome during surgical interventions before initiation of MBMP treatment. Prognosis in AH depends mainly on its prompt diagnosis. Treatment procedures should be adapted to bleeding severity and inhibitor titres. Under these conditions, AH is a potentially curable autoimmune disorder with an excellent prognosis. [source] Risk factors for inhibitor formation in haemophilia: a prevalent case,control studyHAEMOPHILIA, Issue 5 2009M. V. RAGNI Summary., Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case,control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Cases experienced higher intensity factor, 455 vs. 200 U per exposure, P < 0.005, more frequent central nervous system (CNS) bleeding, seven of 20 (35.0%) vs. one of 57 (1.7%), P = 0.001 and more commonly from inhibitor families, seven of 20 (35.0%) vs. zero of 57 (0%), P < 0.001, and African-American, 12 of 63 (19.0%) vs. six of 117 (5.1%), P = 0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, P < 0.001, and survival was shorter, 14 vs. 38 yr, P = 0.025. Inhibitor formation was uncommon in those with missense mutations, two of 65 (3.1%) vs. 31 of 119 (26.0%), P = 0.008, and unrelated to factor VIII immunogenic epitope, P = 0.388, or HLA type, P > 0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titres <120 vs. ,120 BU/mL, six vs. 16 months, P < 0.01, but unaffected by tolerizing dose regimen, P > 0.50. Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies. [source] Low-dose immune tolerance induction for paediatric haemophilia patients with factor VIII inhibitorsHAEMOPHILIA, Issue 2 2008A. UNUVAR Summary., The development of an inhibitor against factor VIII (FVIII) is a serious complication in children with haemophilia A. Immune tolerance induction (ITI) therapy is generally considered to be the best approach to eradicate the inhibitor. In this paper, the low-dose (,50 IU kg,1 twice or three times weekly with plasma-derived factor concentrates) ITI regimen used in Turkey is discussed. This regimen was given to 21 haemophilia A patients with high titer inhibitors. The median age at the beginning of ITI was 9 years and exposure days were 25. The median pre-ITI historical peak inhibitor titer, and inhibitor titer when ITI started were 80 BU (range 6.0,517), 19.2 BU (range 3.6,515), respectively. Complete immune tolerance was defined as the time at which at least two negative inhibitor assays was obtained with no anamnestic response. Our two cases were not reached in follow-up period. Immune tolerance could be achieved in 5 of 19 (26.3%) patients within a median time of 6 months. Partial tolerance was obtained in 7 patients while treatment failed in spite of significant decreased inhibitor levels in the other patients. A relapse developed in one immune-tolerized patient, one year later. The level of inhibitor titer at the beginning of ITI (,10 BU), the pre-ITI historical peak inhibitor titer (<50 BU), and the time between the first diagnosis inhibitor to starting ITI (<12 months) were main factors in the success (complete or partial tolerance) of ITI. In conclusion, the outcome of low-dose ITI protocol was not satisfactory in this retrospective study. [source] Cyclosporin A can achieve immune tolerance in a patient with severe haemophilia B and refractory inhibitorsHAEMOPHILIA, Issue 1 2007D. C. A. CROSS Summary., Immune tolerance induction (ITI) is described in a patient with severe haemophilia B complicated by the presence of an inhibitor. A number of ITI regimes were attempted without success and the patient suffered from frequent relapses and bleeding episodes. Successful ITI was achieved with the additional use of cyclosporin A. The patient developed nephrotic syndrome although had a negative Bethesda titre at this time. When cyclosporin A therapy was ceased, the inhibitor titre rose and the patient suffered again from bleeding episodes. Cyclosporin A was reintroduced at a lower dose. The patient has now received cyclosporin A for 10 years, during which time he has relapsed three times for short periods (2 weeks). He is also on prophylaxis with factor IX three times a week with preinfusion levels >1% and without bleeding. [source] The management of inhibitors in haemophilia A: introduction and systematic review of current practiceHAEMOPHILIA, Issue 4 2003S. Paisley Summary., Haemophilia is the commonest bleeding disorder in the UK, affecting approximately 5400 people, almost all of them male. In haemophiliacs, reduced levels, or absence, of factor VIII (FVIII) cause bleeding episodes, typically into joint spaces or muscles. Haemophilia is generally treated with exogenous FVIII. However, in some haemophiliacs, therapeutically administered FVIII comes to be recognized as a foreign protein, stimulating the production of antibodies (inhibitors), which react with FVIII to render it ineffective. Alternative treatment strategies then have to be used to manage bleeding episodes. In addition, strategies have been developed to attempt to abolish inhibitor production through the induction of immune tolerance. A systematic review was undertaken of current international practice for the clinical management of haemophilia A patients with inhibitors to FVIII, concentrating on literature published from 1995 onwards. Although it can be difficult to determine what constitutes current practice, current guidelines indicate that immune tolerance induction is seen as desirable, with the choice of regimen dependent on patient characteristics, familiarity with regimens and cost. Various approaches, based on similar factors, are used to control bleeding episodes. [source] Immune tolerance induction in patients with haemophilia A with inhibitors: a systematic reviewHAEMOPHILIA, Issue 4 2003J. Wight Summary., In some patients with haemophilia A, therapeutically administered factor VIII (FVIII) comes to stimulate the production of antibodies (inhibitors) which react with FVIII to render it ineffective. As a result, FVIII cannot be used prophylactically and patients become liable to recurrent bleeds. There are two elements to the management of patients with inhibitors: the treatment of bleeding episodes, and attempts to abolish inhibitor production through the induction of immune tolerance. This paper reports a systematic review of the best available evidence of clinical effectiveness in relation to immune tolerance induction (ITI) in patients with haemophilia A with inhibitors. Owing to the lack of randomized controlled trials on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. As a result of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. The International Registry provides the most reliable estimate of the proportion of successful cases of ITI [48.7%, 95% confidence interval (CI) 42.6,52.7%]. The duration of effect is unclear, but relapses appear to be infrequent. The International Registry shows a rate of relapse of 15% at 15 years. The comparative effectiveness of different protocols is uncertain, as no trials have been undertaken which compare them directly. However, the evidence suggests that the Bonn protocol may be more effective than the Malmö or low-dose protocols. There is no good evidence that immunosuppressive drug regimens are effective. [source] Putting flesh and polish on autoimmune hepatitis and moving the disease of exclusion to inclusion,HEPATOLOGY, Issue 4 2010Albert J. Czaja Autoimmune hepatitis emerged during an era when concepts of neonatal immune tolerance, clonal selection of lymphocytes, and "forbidden clones" of activated immune cells were forming. The diagnosis had to be deduced from circumstantial evidence and by exclusion of other conditions. The goals of this review are to demonstrate how a clinician nonscientist can contribute to the maturation of autoimmune hepatitis and to illustrate the principles of clinical investigation that can be applied broadly to other projects. Autoimmune hepatitis initially had to be distinguished from other diseases, and improvements in the tests for viral and immune markers were instrumental in this regard. Diversification of the clinical phenotype to accommodate acute severe, asymptomatic, elderly, and variant forms enhanced the pertinence of the disease, and the formation of the International Autoimmune Hepatitis Group standardized the diagnosis, interconnected investigators, and promoted global acceptance of the condition. Subsequent studies refined current corticosteroid-based therapies, identified prognostic markers, assessed genetic predispositions, explored new pharmacological agents, and forecast the emergence of cellular and molecular interventions. Good fortune, stimulating mentors, career dedication, practical goal selection, protocol compliance, compulsive record keeping, personal resilience, and strong collaborations were the bases for progress. Autoimmune hepatitis exemplifies an evolutionary process in the science of autoimmunity and the people committed to its study. Lessons derived from this experience can be far-reaching. (HEPATOLOGY 2010;52:1177-1184) [source] Mechanism of T cell tolerance induction by murine hepatic Kupffer cells,HEPATOLOGY, Issue 3 2008Qiang You The liver is known to favor the induction of immunological tolerance rather than immunity. Although Kupffer cells (KC) have been indicated to play a role in liver tolerance to allografts and soluble antigens, the mechanisms involved remain unclear. We hypothesized that KCs could promote immune tolerance by acting as incompetent antigen-presenting cells (APC), as well as actively suppressing T cell activation induced by other potent APCs. The expression of antigen presentation-related molecules by KCs was phenotyped by flow cytometry. The abilities of KCs to act as APCs and to suppress T cell activation induced by splenic dendritic cells (DC) were examined by in vitro proliferation assays using CD4+ OVA-TCR (ovalbumin T cell receptor) transgenic T cells. We found that, compared with DCs, KCs expressed significantly lower levels of major histocompatibility complex (MHC) II, B7-1, B7-2, and CD40. This result is consistent with our observation that KCs were not as potent as DCs in eliciting OVA-specific T cell proliferation. However, KCs isolated from polyinosinic:polycytidylic acid,treated mice expressed significantly higher levels of MHC II and costimulatory molecules than did naïve KCs and could stimulate stronger T cell responses. More importantly, we found that KCs could inhibit DC-induced OVA-specific T cell activation. Further investigation of the underlying mechanism revealed that prostaglandins produced by KCs played an important role. The results ruled out the possible involvement of interleukin-10, nitric oxide, 2,3-dioxygenase, and transforming growth factor , in KC-mediated T cell suppression. Conclusion: Our data indicate that KCs are a tolerogenic APC population within the liver. These findings suggest that KCs may play a critical role in regulating immune reactions within the liver and contributing to liver-mediated systemic immune tolerance. (HEPATOLOGY 2008.) [source] Covalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouseHEPATOLOGY, Issue 6 2004Jeremy M. Palmer The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by the breakdown of normal immune self tolerance to pyruvate dehydrogenase complex (PDC). How tolerance is broken to such a central and highly conserved self antigen in the initiation of autoimmunity remains unclear. One postulated mechanism is that reactivity arises to an altered form of self antigen with subsequent cross-reactivity to native self. In this murine study, we set out to examine whether sensitization with a covalently modified form of self PDC can give rise to the pattern of breakdown of B-cell and T-cell tolerance to self PDC seen in PBC patients. The notion that altered self can lead to tolerance breakdown was studied by sensitizing SJL/J mice with a covalently modified (biotinylated) preparation of self murine PDC (mP/O-B). Subsequently, antibody and T-cell reactivities to unmodified self mP/O were studied. Sensitization with mP/O-B elicited high-titre, high-affinity antibody responses reactive with both the mP/O-B immunogen and, importantly, native mP/O. In addition, significant MHC class II restricted splenic T-cell responses to native mP/O (i.e., true autoimmune responses) were seen in mP/O-B sensitized animals. The breakdown of T-cell self tolerance to mP/O was not seen in animals sensitized with irrelevant biotinylated antigens. In conclusion, this study provides evidence to support the concept that exposure to covalently modified self PDC can, in the correct proimmune environment, replicate the full breakdown of B-cell and T-cell immune tolerance to PDC seen in PBC. One potential etiological pathway in PBC therefore could be the breakdown of tolerance to self PDC occurring after exposure to self antigen covalently modified in the metabolically active environment of the liver. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;39:1583,1592.) [source] Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escapeIMMUNOLOGICAL REVIEWS, Issue 1 2008Jessica B. Katz Summary: Indoleamine 2, 3-dioxygenase (IDO) degrades the essential amino acid tryptophan in mammals, catalyzing the initial and rate-limiting step in the de novo biosynthesis nicotinamide adenine dinucleotide (NAD). Broad evidence implicates IDO and the tryptophan catabolic pathway in generation of immune tolerance to foreign antigens in tissue microenvironments. In particular, recent findings have established that IDO is overexpressed in both tumor cells and antigen-presenting cells in tumor-draining lymph nodes, where it promotes the establishment of peripheral immune tolerance to tumor antigens. In the normal physiologic state, IDO is important in creating an environment that limits damage to tissues due to an overactive immune system. However, by fostering immune suppression, IDO can facilitate the survival and growth of tumor cells expressing unique antigens that would be recognized normally as foreign. In preclinical studies, small-molecule inhibitors of IDO can reverse this mechanism of immunosuppression, complementing classical cytotoxic cancer chemotherapeutic agents' ability to trigger regression of treatment-resistant tumors. These results have encouraged the clinical translation of IDO inhibitors, the first of which entered phase I clinical trials in the fall of 2007. In this article, we survey the work defining IDO as an important mediator of peripheral tolerance, review evidence of IDO dysregulation in cancer cells, and provide an overview of the development of IDO inhibitors as a new immunoregulatory treatment modality for clinical trials. [source] Central and peripheral autoantigen presentation in immune toleranceIMMUNOLOGY, Issue 2 2004Alberto Pugliese Summary Recent studies in both humans and experimental rodent models provide new insight into key mechanisms regulating tolerance to self-molecules. These recent advances are bringing about a paradigm shift in our views about tolerance to self-molecules with tissue-restricted expression. There is, indeed, mounting evidence that selected antigen-presenting cells (APCs) have the ability to synthesize and express self-molecules, and that such expression is critical for self-tolerance. Insulin is a key hormone produced exclusively by pancreatic ,-cells and a critical autoantigen in type 1 diabetes. It provides an excellent example of a molecule with tissue-restricted expression that is expressed ectopically by APCs. The fact that APCs expressing insulin have been demonstrated in both thymus and peripheral lymphoid tissues suggests that they may play a role in insulin presentation in both the central and peripheral immune system. Experimental mice, in which insulin expression was altered, provide functional data that help to dissect the role of insulin presentation by APCs of the immune system. This review addresses recent literature and emerging concepts about the expression of self-molecules in the thymus and peripheral lymphoid tissues and its relation to self-tolerance. [source] Intestinal dendritic cells: Their role in bacterial recognition, lymphocyte homing, and intestinal inflammationINFLAMMATORY BOWEL DISEASES, Issue 10 2010S.C. Ng PhD Abstract Dendritic cells (DCs) play a key role in discriminating between commensal microorganisms and potentially harmful pathogens and in maintaining the balance between tolerance and active immunity. The regulatory role of DC is of particular importance in the gut where the immune system lies in intimate contact with the highly antigenic external environment. Intestinal DC constantly survey the luminal microenvironment. They act as sentinels, acquiring antigens in peripheral tissues before migrating to secondary lymphoid organs to activate naive T cells. They are also sensors, responding to a spectrum of environmental cues by extensive differentiation or maturation. Recent studies have begun to elucidate mechanisms for functional specializations of DC in the intestine that may include the involvement of retinoic acid and transforming growth factor-,. Specialized CD103+ intestinal DC can promote the differentiation of Foxp3+ regulatory T cells via a retinoic acid-dependent process. Different DC outcomes are, in part, influenced by their exposure to microbial stimuli. Evidence is also emerging of the close interaction between bacteria, epithelial cells, and DC in the maintenance of intestinal immune homeostasis. Here we review recent advances of functionally specialized intestinal DC and their mechanisms of antigen uptake and recognition. We also discuss the interaction of DC with intestinal microbiota and their ability to orchestrate protective immunity and immune tolerance in the host. Lastly, we describe how DC functions are altered in intestinal inflammation and their emerging potential as a therapeutic target in inflammatory bowel disease. (Inflamm Bowel Dis 2010) [source] CD4+CD25hi regulatory T-cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasiaINTERNATIONAL JOURNAL OF CANCER, Issue 8 2007Johan W. Molling Abstract CD4+CD25hiCTLA4+FoxP3+ regulatory T cells (Treg) have been shown to maintain immune tolerance against self antigens and increased circulating frequencies have been reported in various types of cancers. Circulating invariant natural killer T-cells (iNKT) are reduced in cancer patients and low iNKT frequency is related to poor prognosis. It is not yet clear whether high Treg numbers and low iNKT cell numbers pose an increased risk for the progression of premalignant lesions or whether Treg and iNKT cell numbers are influenced by dysplasia. We therefore studied prospectively the relation between iNKT cell and Treg frequencies and the natural course of human papillomavirus type 16 (HPV16) induced pre-malignant cervical dysplasia in 82 patients who participated in a nonintervention cohort study of women with abnormal cytology. Treg frequencies were significantly increased in women who had persistent HPV16 infection. Within the HPV16 persistence group there was no difference in Treg frequencies among patients who developed a CIN3 lesion and patients who did not progress to CIN3. Furthermore, Treg frequencies were increased in patients who had detectable HPV16 E7 specific IL-2 producing T-helper cells, which suggests a causal role of HPV infection in Treg development in parallel with HPV16 specific T helper cells. No evidence was found for a role for iNKT cells in persistence of HPV16 and progression of HPV16 induced CIN lesions. However, HPV-persistence-associated Tregs may explain the inefficacy of concomitant persistence associated immunity and may contribute to subsequent progression to neoplasia. © 2007 Wiley-Liss, Inc. [source] Immunosuppressive drug-free operational immune tolerance in human kidney transplant recipients: Part I. blood gene expression statistical analysisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008Christophe Braud Abstract Survival of solid organ grafts depends on life-long immunosuppression, which results in increased rates of infection and malignancy. Induction of tolerance to allografts would represent the optimal solution for controlling both chronic rejection (CR) and side effects of immunosuppression. Although spontaneous "operational tolerance" can occur in human kidney transplantation, the lack of noninvasive peripheral blood biological markers of this rare phenomenon precludes the identification of potentially tolerant patients in whom immunosuppression could be tapered as well as the development of new tolerance inducing strategies. Here, the potential of high throughput microarray technology to decipher complex pathologies allowed us to study the peripheral blood specific gene expression profile and corresponding EASE molecular pathways associated to operational tolerance in a cohort of human kidney graft recipients. In comparison with patients with CR, tolerant patients displayed a set of 343 differentially expressed genes, mainly immune and defense genes, in their peripheral blood mononuclear cells (PBMC), of which 223 were also different from healthy volunteers. Using the expression pattern of these 343 genes, we were able to classify correctly >80% of the patients in a cross-validation experiment and classified correctly all of the samples over time. Collectively, this study identifies a unique PBMC gene signature associated with human operational tolerance in kidney transplantation by a classical statistical microarray analysis and, in the second part, by a nonstatistical analysis. J. Cell. Biochem. 103: 1681,1692, 2008. © 2007 Wiley-Liss, Inc. [source] Immune tolerance: mechanisms and application in clinical transplantationJOURNAL OF INTERNAL MEDICINE, Issue 3 2007M. Sykes Abstract. The achievement of immune tolerance, a state of specific unresponsiveness to the donor graft, has the potential to overcome the current major limitations to progress in organ transplantation, namely late graft loss, organ shortage and the toxicities of chronic nonspecific immumnosuppressive therapy. Advances in our understanding of immunological processes, mechanisms of rejection and tolerance have led to encouraging developments in animal models, which are just beginning to be translated into clinical pilot studies. These advances are reviewed here and the appropriate timing for clinical trials is discussed. [source] Dysfunction of CD4+CD25high T regulatory cells in patients with recurrent aphthous stomatitisJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 8 2008Natalia Lewkowicz Background:, Recurrent aphthous stomatitis (RAS) is a chronic inflammatory disease of unknown etiology characterized by recurring formation of painful oral ulcers. RAS may result from oral epithelium damage caused by T-cell-mediated immune response. CD4+CD25+ T regulatory (Treg) cells suppress proliferation and effector functions of other immune cells, and therefore are crucial in regulating the immune response. Methods:, We tested the function of peripheral CD4+CD25high Treg cells in active RAS through their ability to inhibit proliferation and cytokine production of conventional CD4+ T cells. We also attempted to detect the presence of FOXP3 and indoleamine 2,3-dioxygenase (IDO) mRNA in the lesional and non-lesional oral mucosa of RAS patients and healthy individuals using real-time PCR assay. Results:, Treg cells derived from RAS patients were less efficient in the suppression of cytokine production of CD4+ T effector cells than Treg cells from healthy individuals. Moreover, in RAS, Treg cells were nearly twice less potent in the inhibition of CD4+CD25, T cell proliferation than in healthy donors. Furthermore, we have demonstrated the decreased proportion of CD4+CD25+FOXP3+ Treg cells in peripheral blood of RAS patients compared with controls. We failed to detect FOXP3 mRNA, while IDO mRNA expression was decreased in non-lesional mucosa biopsies from RAS patients compared with ulcer biopsies or normal mucosa from healthy donors. Conclusions:, These findings suggest that CD4+CD25high Treg cells are both functionally and quantitatively compromised in RAS and that decreased constitutive expression of IDO in oral mucosa in RAS may lead to the loss of local immune tolerance. [source] Extracellular vesicles are key intercellular mediators in the development of immune dysfunction to allergens in the airwaysALLERGY, Issue 10 2010T.-S. Shin To cite this article: Shin T-S, Kim JH, Kim Y-S, Jeon SG, Zhu Z, Gho YS, Kim Y-K. Extracellular vesicles are key intercellular mediators in the development of immune dysfunction to allergens in the airways. Allergy 2010; 65: 1256,1265. Abstract Background:, Previous evidence indicates that inhalation of lipopolysaccharide (LPS)-containing with allergens induced mixed Th1 and Th17 cell responses in the airways. Extracellular vesicles (EVs) are nanometer-sized spherical, lipid-bilayered structures and are recently in the public eye as an intercellular communicator in immune responses. Objective:, To evaluate the role of EVs secreted by LPS inhalation in the development of airway immune dysfunction in response to allergens. Methods:, Extracellular vesicles in bronchoalveolar lavage fluids of BALB/c mice were isolated and characterized 24 h after applications to the airway of 10 ,g of LPS for 3 days. To evaluate the role of LPS-induced EVs on the development of airway immune dysfunction, in vivo and in vitro experiments were performed using the isolated LPS-induced EVs. Results:, The inhalation of LPS enhanced EVs release into the BAL fluid, when compared to the application of PBS. Airway sensitization with allergens and LPS-induced EVs resulted in a mixed Th1 and Th17 cell responses, although that with allergens and PBS-induced EVs induced immune tolerance. In addition, LPS-induced EVs enhanced the production of Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) by lung dendritic cells. Moreover, the immune responses induced by the LPS-induced EVs were blocked by denaturation of the EV-bearing proteins. Conclusion:, These data suggest that EVs (especially, the protein components) secreted by LPS inhalation are a key intercellular communicator in the development of airway immune dysfunction to inhaled LPS-containing allergens. [source] Effector and regulatory mechanisms in allergic contact dermatitisALLERGY, Issue 12 2009M. Vocanson Allergic contact dermatitis (ACD), one of the commonest occupational diseases, is a T-cell-mediated skin inflammation caused by repeated skin exposure to contact allergens, i.e. nonprotein chemicals called haptens. Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten. Subsets of CD4+ T cells endowed with suppressive activity are responsible for both the down-regulation of eczema in allergic patients and the prevention of priming to haptens in nonallergic individuals. Therefore, ACD should be considered as a breakdown of the skin immune tolerance to haptens. Recent advances in the pathophysiology of ACD have demonstrated the important role of skin innate immunity in the sensitization process and have revisited the dogma that Langerhans cells are mandatory for CD8+ T-cell priming. They have also introduced mast cells as a pivotal actor in the magnitude of the inflammatory reaction. Finally, the most recent studies address the nature, the mode and the site of action of the regulatory T cells that control the skin inflammation with the aim of developing new strategies of tolerance induction in allergic patients. [source] Cross-talk of human gut with bifidobacteriaNUTRITION REVIEWS, Issue 2 2009Ilja Trebichavsky The gut constitutes a prominent part of the immune system. Its commensal microflora plays an important role in defense and in tolerance to diet allergens. Disturbances in immune regulations may lead to food allergy. Among commensal bacteria, bifidobacteria are able to induce mechanisms of immune tolerance. Comprehension of their mutual cross-talk with the host is necessary for understanding their role in the diet and in food supplements. [source] Induction of IL-10+ CD4+ CD25+ regulatory T cells with decreased NF-,B expression during immunotherapyPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 1-Part-II 2010Yi-Giien Tsai Tsai Y-G, Chiou Y-L, Chien J-W, Wu H-P, Lin C-Y. Induction of IL-10+ CD4+ CD25+ regulatory T cells with decreased NF-,B expression during immunotherapy. Pediatr Allergy Immunol 2010: 21: e166,e173. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard MyD88 is a major toll-like receptor (TLR) adaptor to activate NF-,B, which acts as a mater switch for allergic inflammation disease. Sterile hust dust extracts have been reported with TLR-dependent immunostimulatory activities. The aim of this study was to evaluate whether Dermatophagoides pteronyssinus (Der p) immunotherapy may increase IL-10+ CD4+ CD25+ T cells with modulating MyD88 signaling proteins, to decrease NF-,B expression. Peripheral blood mononuclear cells were isolated from patients before and after 1 yr of Der p immunotherapy, and also from matched control subjects. After 2 days of Der p-2 stimulation, intracellular IL-10 and Foxp3 expression of CD4+ CD25+ T cells were measured by flow-cytometry. The expression of IL-1 receptor-associated kinase (IRAK)-1 in cytoplasm and IFN-regulator factor-3 (IRF-3) with NF-,B/p65 in nuclei was determined by Western-blot analysis. Patients undergoing immunotherapy produced more soluble CD14, IL-10, and TGF-, that correlated with FEV1improvement (p < 0.05). In the immunotherapy group, the number of Foxp3+ CD4+ Treg cells increased more than the baseline status (25.06 ± 4.19 vs. 16.08 ± 3.54, p < 0.05). Additionally, increased IL-10 production with decreased IRAK-1 and NF-,B/p65 nuclear translocation was observed in sorted-purified Treg cells. IL-10+ CD4+ CD25+ Treg cells may respond to Der p-2 and down-regulate NF-,B/p65 expression to maintain immune tolerance during immunotherapy. [source] Successful ABO-incompatible heart transplantation in a child despite blood-group sensitization after ventricular assist device supportPEDIATRIC TRANSPLANTATION, Issue 6 2009S. Urschel Abstract:, In the first two yr of life blood-group incompatible (ABO-incompatible) heart transplantation can be performed leading to immune tolerance to donor blood group. Antibody titers should be below 1:4. VAD use is correlated with sensitization toward blood-group antigens. A boy was diagnosed with dilated cardiomyopathy at nine months of age and listed for 0-compatible transplantation. Progressive heart failure required implantation of a left VAD. His listing was extended for ABO-incompatible transplantation despite antibody titers of 1:32 anti-A and 1:8 anti-B. After 26 days on VAD, he was transplanted with a B donor heart. No hyperacute or acute rejection occurred in 12 months post-transplant. Anti-B antibodies rose to a maximum of 1:2. No use of rituximab or plasmapheresis was required. There are no signs of graft vasculopathy. This indicates that inclusion criteria for ABO-incompatible transplantation may be extended to immediate cases. This is the first case with a healthy immune system to show signs of tolerance development after ABO-incompatible heart transplantation with increased prior antibody titers and without specific treatment. [source] DNA Damage, Apoptosis and Langerhans Cells,Activators of UV-induced Immune Tolerance,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2008Laura Timares Solar UVR is highly mutagenic but is only partially absorbed by the outer stratum corneum of the epidermis. UVR can penetrate into the deeper layers of the epidermis, depending on melanin content, where it induces DNA damage and apoptosis in epidermal cells, including those in the germinative basal layer. The cellular decision to initiate either cellular repair or undergo apoptosis has evolved to balance the acute need to maintain skin barrier function with the long-term risk of retaining precancerous cells. Langerhans cells (LCs) are positioned suprabasally, where they may sense UV damage directly, or indirectly through recognition of apoptotic vesicles and soluble mediators derived from surrounding keratinocytes. Apoptotic vesicles will contain UV-induced altered proteins that may be presented to the immune system as foreign. The observation that UVR induces immune tolerance to skin-associated antigens suggests that this photodamage response has evolved to preserve the skin barrier by protecting it from autoimmune attack. LC involvement in this process is not clear and controversial. We will highlight some basic concepts of photobiology and review recent advances pertaining to UV-induced DNA damage, apoptosis regulation, novel immunomodulatory mechanisms and the role of LCs in generating antigen-specific regulatory T cells. [source] | ||||||||||||||||||||||||||||||||||