Immunological Tolerance (immunological + tolerance)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

The mother's immune system is a balanced threat to the foetus, turning to protection of the neonate

Lars Hanson
Immunological tolerance by the mother prevents rejection of the foetus, but aberrations may increase risk of abnormalities like spontaneous abortion, or foetal growth restriction. The neonate is normally colonized with mother's gut microflora, mainly composed of protective anaerobes. This least threatening form of microbial colonization of the neonate, is impaired by sectio delivery, but supported by breastfeeding. Mother's transplacental IgG, secretory IgA and other milk components help protect the neonate together with its own slowly expanding immune system. Conclusion: The mother's immune system tolerates her foetus via several mechanisms. Failure to do so may cause foetal growth retardation, or spontaneous abortion. The mother and the neonate cooperate in preventing infections in the offspring. [source]

Preserving , Cells in Type 1 Diabetes mellitus: the role of immunological tolerance

Stanley R. Pillemer
Abstract Type 1 diabetes mellitus (T1DM) is characterized by an autoimmune attack on beta cells of the islets of Langerhans. This immunological attack is mediated by effector T-lymphocytes and results in the destruction of the , cells. One approach to abrogating the immunological attack is to use immunosuppressive treatments. Such treatments tend to broadly suppress the immune system. A better approach is to develop treatments that induce tolerance. Autoimmune diseases are associated with the presence of inadequate numbers of functionally active regulatory T cells (Tregs). Tregs can induce a state of immunological tolerance and suppress the inflammation and destruction of target tissues. Teplizumab, also known as hOKT3,1 (Ala-Ala), is a humanized monoclonal antibody that induces Tregs. In clinical trials, treatment with this antibody preserved insulin production and improved metabolic control during the first year of T1DM. A pivotal multinational trial is in progress to determine the efficacy and safety of teplizumab in the treatment of new onset T1DM. Drug Dev Res 69:153,157, 2008. 2008 Wiley-Liss, Inc. [source]

Abnormal CTLA-4 function in T cells from patients with systemic lupus erythematosus

Elizabeth C. Jury
Abstract CTLA-4 is a critical gatekeeper of T-cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA-4 in SLE. Our results reveal increased CTLA-4 expression in FOXP3, responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA-4 was unable to regulate T-cell proliferation, lipid microdomain formation and phosphorylation of TCR-, following CD3/CD28 co-stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co-stimulation, there was no parallel increase in CTLA-4 expression, which would normally provide a break on T-cell proliferation. These defects were associated with exclusion of CTLA-4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA-4 dysfunction as a potential cause for abnormal T-cell activation in patients with SLE, which could be targeted for therapy. [source]

Mechanism of T cell tolerance induction by murine hepatic Kupffer cells,

HEPATOLOGY, Issue 3 2008
Qiang 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 nave 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]

Can Turner syndrome teach us about the pathogenesis of chronic cholestasis?

HEPATOLOGY, Issue 5 2004
Piotr Milkiewicz
The mechanisms that cause the female predominance of primary biliary cirrhosis (PBC) are uncertain, but the X chromosome includes genes involved in immunological tolerance. We assessed the rate of X monosomy in peripheral white blood cells from 100 women with PBC, 50 with chronic hepatitis C, and 50 healthy controls, by fluorescence in-situ hybridisation. Frequency of X monosomy increased with age in all groups, but was significantly higher in women with PBC than in controls (p<0.0001); age-adjusted back-transformed mean frequencies were 0.050 (95% CI 0.046-0.055) in women with PBC, 0.032 (0.028-0.036) in those with chronic hepatitis C, and 0.028 (0.025-0.032) in controls. We suggest that haploinsufficiency for specific X-linked genes leads to female susceptibility to PBC. [source]

The use of genomewide ENU mutagenesis screens to unravel complex mammalian traits: identifying genes that regulate organ-specific and systemic autoimmunity

Gerard F. Hoyne
Summary:, T-cell development is perhaps one of the best understood processes of mammalian cell differentiation, as many of the genes and pathways have been identified. By contrast, relatively little is known about the genes and pathways involved in immunological tolerance to self-antigens. Here, we describe the challenges associated with a genomewide screen designed at identifying new immune regulatory genes that uses a model of organ-specific autoimmunity leading to type 1 diabetes. The successful propagation and identification of the new gene variants will shed light on the various developmental checkpoints in lymphocyte development that are crucial for establishing tolerance to self-antigens. [source]

One cell, one antibody: prelude and aftermath

G. J. V. Nossal
Summary: This essay seeks to summarize one scientist's pilgrim's progress through the world of antibody formation, attempting to capture the flavor of problems as encountered within their times. It seeks to portray a world where the direct template hypothesis ruled the day, where the function of lymphocytes was unknown, let alone the difference between T and B cells, and where antibody genes were but a dream. Struggles to establish the credentials of the clonal selection hypothesis are presented in some detail, as are the implications which followed the ,one cell , one antibody' discovery. The other two main preoccupations of the author are presented more briefly, namely the essential features of the germinal center and the cellular basis of immunological tolerance within the B lymphocyte compartment. Naturally, the experiments become more sophisticated as both knowledge and technology mature. A continuing thread within the unfolding story is that one must not shy away from developing new techniques when problems demand them. [source]

Regulatory T cells in human disease and their potential for therapeutic manipulation

IMMUNOLOGY, Issue 1 2006
Leonie S. Taams
Summary Regulatory T cells are proposed to play a central role in the maintenance of immunological tolerance in the periphery, and studies in many animal models demonstrate their capacity to inhibit inflammatory pathologies in vivo. At a recent meeting [Clinical Application of Regulatory T Cells, 7,8 April 2005, Horsham, UK, organized by the authors of this review, in collaboration with the British Society for Immunology and Novartis] evidence was discussed that certain human autoimmune, infectious and allergic diseases are associated with impaired regulatory T-cell function. In contrast, evidence from several human cancer studies and some infections indicates that regulatory T cells may impair the development of protective immunity. Importantly, certain therapies, both those that act non-specifically to reduce inflammation and antigen-specific immunotherapies, may induce or enhance regulatory T-cell function. The purpose of this review was to summarize current knowledge on regulatory T-cell function in human disease, and to assess critically how this can be tailored to suit the therapeutic manipulation of immunity. [source]

Modified ELISPOT assay may predict T-cell hyporesponsiveness to non-inherited maternal antigens

Summary Clinical reports have suggested the existence of immunological tolerance to noninherited maternal antigens (NIMA) in human leukocyte antigen (HLA) mismatched allogeneic stem cell transplantation (allo-SCT). We studied the T-cell reactivity using IFN-, enzyme-linked immunospot (ELISPOT) assay in three HLA fully matched allo-SCT cases and one healthy volunteer family case. In HLA fully matched allo-SCT cases, ELISPOT assay could detect the hyporesponsiveness of T cells from donors to the B cells from recipients. Moreover, ELISPOT assay showed that the T cells from an individual responded to B cell from his mother significantly weakly than those from an unrelated HLA-haploidentical individual. These observations suggest that our IFN-, ELISPOT assay-based method may predict the presence of immunological tolerance to NIMA. [source]

Autologous nucleus pulposus primes T cells to develop into interleukin-4-producing effector cells: An experimental study on the autoimmune properties of nucleus pulposus

Andrea Geiss
Abstract An autoimmune response to herniated nucleus pulposus has been proposed to constitute a pathophysiologic mechanism for inducing sciatica based on the fact that nucleus pulposus under normal conditions is excluded from the development of immunological tolerance. The manifestation of an autoimmune response comprises different steps starting with antigen capture, continuing with activation of T helper (TH) cells and ending with production of autoantibodies. Activated TH cells differentiate into either TH1 cells, predominately producing proinflammatory cytokines such as interferon , (IFN,) or a TH2 subset mainly producing anti-inflammatory cytokines such as interleukin-4 (IL-4). The aim of the present study was to examine if exposure of autologous nucleus pulposus (NP) to the immune system for 3 weeks is potent enough to prime TH cells to differentiate into TH2 cells. The study was performed in a pig model allowing the exposure of NP to the immune system. To assess the polarization of TH cells the intracellular production of IFN, and IL-4 was measured in T cells by using flow cytometry. The revealed predominant production of IL-4 together with low production of IFN, in T cells after NP exposure to the immune system indicates that nucleus pulposus may prime TH cells to develop into IL-4-producing TH2 cells after being exposed to the immune system, for example, in association with disc herniation. 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:97,103, 2009 [source]

Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report,

ALLERGY, Issue 7 2008
Steven O. Stapel
Serological tests for immunoglobulin G4 (IgG4) against foods are persistently promoted for the diagnosis of food-induced hypersensitivity. Since many patients believe that their symptoms are related to food ingestion without diagnostic confirmation of a causal relationship, tests for food-specific IgG4 represent a growing market. Testing for blood IgG4 against different foods is performed with large-scale screening for hundreds of food items by enzyme-linked immunosorbent assay-type and radioallergosorbent-type assays in young children, adolescents and adults. However, many serum samples show positive IgG4 results without corresponding clinical symptoms. These findings, combined with the lack of convincing evidence for histamine-releasing properties of IgG4 in humans, and lack of any controlled studies on the diagnostic value of IgG4 testing in food allergy, do not provide any basis for the hypothesis that food-specific IgG4 should be attributed with an effector role in food hypersensitivity. In contrast to the disputed beliefs, IgG4 against foods indicates that the organism has been repeatedly exposed to food components, recognized as foreign proteins by the immune system. Its presence should not be considered as a factor which induces hypersensitivity, but rather as an indicator for immunological tolerance, linked to the activity of regulatory T cells. In conclusion, food-specific IgG4 does not indicate (imminent) food allergy or intolerance, but rather a physiological response of the immune system after exposition to food components. Therefore, testing of IgG4 to foods is considered as irrelevant for the laboratory work-up of food allergy or intolerance and should not be performed in case of food-related complaints. [source]

Finnish Allergy Programme 2008,2018 , time to act and change the course

ALLERGY, Issue 6 2008
T. Haahtela
Background:, The prevalence of allergic diseases has grown in Finland, similarly to many other western countries. Although the origin of allergy remains unresolved, increasing body of evidence indicates that the modern man living in urban built environment is deprived from environmental protective factors (e.g. soil microorganisms) that are fundamental for normal tolerance development. The current dogma of allergen avoidance has not proved effective in halting the ,epidemic', and it is the Finnish consensus that restoring and strengthening tolerance should more be in focus. Aim:, The national 10-year programme is aimed to reduce burden of allergies. The main goals are to (i) prevent the development of allergic symptoms; (ii) increase tolerance against allergens; (iii) improve the diagnostics; (iv) decrease work-related allergies; (v) allocate resources to manage and prevent exacerbations of severe allergies and (vi) decrease costs caused by allergic diseases. Methods:, For each goal, specific tasks, tools and evaluation methods are defined. Nationwide implementation acts through the network of local co-ordinators (primary care physicians, nurses, pharmacists). In addition, three nongovernmental organizations (NGOs) take care of the programme implementation. The 21 central hospital districts carry out a three step educational process: (i) healthcare personnel; (ii) representatives and educators of NGOs and (iii) patients and the general population. For outcome evaluation, repeated surveys are performed and healthcare registers employed at the beginning, at 5 years, and at the end of the programme. The process will be evaluated by an independent external body. Conclusion:, The Finnish initiative is a comprehensive plan to reduce burden of allergies. The aim is to increase immunological tolerance and change attitudes to support health instead of medicalizing common and mild allergy symptoms. It is time to act, when allergic individuals are becoming a majority of western populations and their numbers are in rapid increase worldwide. The Programme is associated with the Global Alliance of Chronic Respiratory Diseases (GARD), WHO. [source]

ORIGINAL ARTICLE: The Persistence of Paternal Antigens in the Maternal Body is Involved in Regulatory T-Cell Expansion and Fetal-Maternal Tolerance in Murine Pregnancy

Maria Laura Zenclussen
Citation Zenclussen ML, Thuere C, Ahmad N, Wafula PO, Fest S, Teles A, Leber A, Casalis PA, Bechmann I, Priller J, Volk H-D, Zenclussen AC. The persistence of paternal antigens in the maternal body is involved in regulatory T-cell expansion and fetal-maternal tolerance in murine pregnancy. Am J Reprod Immunol 2010; 63: 200,208 Problem, Mammalian pregnancy is a state of immunological tolerance and CD4+ CD25+ regulatory T cells (Treg) contribute to its maintenance. Knowing that Treg act in an antigen-specific way during pregnancy, we hypothesized that they are generated after maternal immune cells encounter paternal antigens. Method of study, We mated wild type females with transgenic green fluorescent protein (GFP) males in an allogenic setting and killed them on different days of pregnancy. Results, Presence of paternal and maternal MHC class II+ cells in vaginal lavage on day 0.5 of pregnancy was confirmed. Thus, antigen presentation may take place early during pregnancy in the periphery either by the direct or indirect pathways. Foxp3+ cells known to have regulatory activity could be detected on day 2 of pregnancy in lymph nodes and shortly after implantation at the fetal-maternal interface. Conclusion, Our data suggest that paternal antigens are processed early during pregnancy, which leads to the generation of Treg. The continuous release of placental antigens into the maternal circulation allows the maintenance of a Treg population which is specific for paternal antigens and mediates tolerance toward the semi-allogeneic fetus until the time point of birth. [source]

ORIGINAL ARTICLE: Selective Downregulation of Phosphoinositide 3-Kinase alpha in Leukocytes During Pregnancy

Anne Rohrbach
Problem, During pregnancy, it is crucially important that the mother's immune system tolerates the developing embryo. Although a number of mechanisms of immunological tolerance have been described, little is known about intracellular signaling events, causing a decrease in the mother's leukocyte activity. Method of study, We investigated the expression and activity of phosphoinositide 3-kinases (PI3K) in maternal blood cells of healthy volunteers by Reverse Transcription PCR and Western blotting. Results, Our data reveal a selective downregulation of the p110, catalytic isoform. This correlated with a slight decrease in PI3K activity as judged by the levels of phosphorylated Akt. Conclusion, As PI3K are involved in signal transduction of various leukocyte receptors, this downregulation may comprise a means of holding immune functions at bay. [source]

1140915445 Increased numbers of FoxP3+ cells in vaginal mucus from normal pregnant mice suggest early antigen-specific tolerance mechanism during pregnancy

C Thuere
The fetal survival within the maternal uterus is thought to be due to a transient immunological tolerance, being CD4+CD25+ T regulatory cells (Tregs) crucial players. Former studies confirmed diminished total numbers of this unique population in abortion-prone mice (DBA/2J-mated CBA/J females) as compared to a control with normal pregnancy outcome (BALB/c-mated CBA/J females) and suggested that Tregs act in an antigen-specific fashion. This hypothesis led us to investigate the kinetics of Tregs during pregnancy (day 0, 2, 5, 8, 10 or 12 of pregnancy) in abortion-prone mice and the control group. Our data confirmed diminished number of Tregs in immunological relevant organs such as lymph nodes and thymus within the abortion-prone mice. The enormous augmentation in the number of FoxP3+ cells in vaginal mucus already on day 0.5 after conception, followed by increased Tregs levels at early pregnancy stages, suggest, that Tregs need to be activated by male antigens for being protective. Notably, the abortion-prone mice displayed again a lower total amount of Tregs as compared to the control. Similar progesterone levels in spite of different pregnancy outcome reinforce the theory of antigen specificity of pregnancy-induced Tregs. The antigen presentation would take place in the periphery e.g. in vaginal mucus, the first site of contact with paternal antigens, directly after insemination. Interestingly the transfer of Tregs from normal pregnant mice at this time point prevented fetal rejection. Our results suggest the crucial role of Tregs already shortly after conception. [source]

During Pregnancy, in the Context of a Th2-Type Cytokine Profile, Serum IL-6 Levels Might Condition the Quality of the Synthesized Antibodies

PROBLEM: In recent years, the central role of cytokines in the immune response has been widely studied. It is considered that a T helper (Th)1-type cytokine profile is associated with the rejection phenomenon, whereas a Th2-type cytokine profile is associated with immunological tolerance. In pregnancy, the enhanced Th2/Th1 ratio seems to be necessary to fetal protection. Taking into account that a Th2-type response means antibody production by B cells, and that these antibodies could induce degradation of the paternal antigens, we investigated the quality of the antibodies produced during pregnancy and their regulation. METHOD OF STUDY: Review of previous data. RESULTS: The regulation of protective antibodies by IL-6 in a dose-dependent fashion is proposed as a hypothesis. CONCLUSION: Cytokines play a central role in the success (or failure) of pregnancy. However, the quality of the synthesized antibodies is also a regulatory key. The preferential synthesis of asymmetric immunoglobulin G antibodies during pregnancy could be one of the several pathways that lead to a successful pregnancy [source]

Partially circumventing peripheral tolerance for oncogene-specific prostate cancer immunotherapy

THE PROSTATE, Issue 7 2008
Yilin C. Neeley
Abstract BACKGROUND Failure of cancer immunotherapy is essentially due to immunological tolerance to tumor-associated antigens (TAAs), as these antigens are also expressed in healthy tissues. METHODS Here, we used transgenic adenocarcinoma of mouse prostate (TRAMP) mice, which develop lethal prostate cancer due to prostate-specific expression of SV40 T antigen (Tag), to evaluate effects of prostatic transformation on oncogene TAA-specific tolerance and to test the possibility of breaking such tolerance using a modified recombinant vaccinia virus. RESULTS We showed that Tag expression in TRAMP mice is uniquely extra-thymic, and levels of prostatic Tag expression positively correlate with malignant transformation of the prostate. Yet, young tumor-free TRAMP mice were tolerant to Tag antigen. We therefore attempted overcoming such peripheral oncogene-specific T cell tolerance through immunization with a vaccinia construct encoding Tag immunogenic epitopes. This vaccination modality showed that oncogene-specific tolerance was successfully overcome by effective in vivo priming of Tag-specific cytotoxic T cells (CTLs). However, this was restricted to young TRAMP mice. Tag-specific CTL from "tumor nave" young TRAMP mice showed significant anti-tumor efficacy in vivo by eliminating established heterotopic prostate tumors and prolonging survival in SCID mice harboring Tag-expressing tumors. In contrast, older TRAMP mice with established prostate tumors exhibited oncogene-specific tolerance as evidenced by failure to generate Tag-specific CTL following Tag-specific immunization. CONCLUSIONS Peripheral tolerance can be overcome for effective anti-tumor therapy following oncogene-specific immunization. However, this ability to elicit oncogene-specific CTL is impeded in the tumor-bearing host, in the context of increased oncogene expression associated with tumor progression. Prostate 68: 715,727, 2008. 2008 Wiley-Liss, Inc. [source]

Combined Coinhibitory and Costimulatory Modulation with Anti-BTLA and CTLA4Ig Facilitates Tolerance in Murine Islet Allografts

W. Truong
Complex interactions between positive and negative cosignaling receptors ultimately determine the fate of the immune response. The recently identified coinhibitory receptor, B and T lymphocyte attenuator (BTLA), contributes to regulation of autoimmune and potentially alloimmune responses. We investigated the role of BTLA in a fully major histocompatibility complex-mismatched mouse islet transplant model. We report that anti-BTLA mAb (6F7) alone does not accelerate graft rejection. Rather, while CTLA4Ig alone improved allograft survival, the addition of anti-BTLA mAb to CTLA4Ig led to indefinite (>100 days) allograft survival. Immediately after treatment with anti-BTLA mAb and CTLA4Ig, islet allografts showed intact islets and insulin production despite a host cellular response, with local accumulation of Foxp3+ cells. We clearly demonstrate that combined therapy with anti-BTLA mAb and CTLA4Ig mice induced donor-specific tolerance, since mice accepted a second donor-specific islet graft without further treatment and rejected third party grafts. CTLA4Ig and anti-BTLA mAb limited the initial in vivo proliferation of CFSE-labeled allogeneic lymphocytes, and anti-BTLA mAb enhanced the proportion of PD-1 expressing T cells while depleting pathogenic BTLA+ lymphocytes. We conclude that targeting the BTLA pathway in conjunction with CTLA4Ig costimulatory blockade may be a useful strategy for promoting immunological tolerance in murine islet allografts. [source]

Overcoming immunological tolerance to melanoma: Targeting CTLA-4

F Stephen HODI
Abstract The use of immunotherapeutics in melanoma has received much attention, and recent advances to further characterize the regulatory components of the immune system and the importance of co-stimulatory molecules have opened a new area for clinical investigation. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) serves as a negative regulator of immunity. Recent trials administering fully human anti-CTLA-4 monoclonal antibodies to melanoma patients have demonstrated clinically meaningful responses. Treatment with CTLA-4 blocking antibodies, however, is not without potential toxicities. Autoimmune side-effects, the most common being colitis-associated diarrhea, are frequently associated with clinical responses. In efforts to build upon prior vaccination efforts as well as attempt to offer patients clinically meaningful immune responses with a CTLA-4 blockade but without significant toxicities, we conducted a clinical trial in patients who previously received autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GVAX; Cell Genesys, South San Francisco, CA, USA) with periodic infusions of CTLA-4 blocking antibodies. This sequential treatment resulted in clinically significant anti-tumor immunity without grade 3 or 4 toxicity in most patients. Pathological analyses following treatment of pre-existing tumors revealed a linear correlation between tumor necrosis and the ratio of intra-tumoral CD8+ effector cells to FoxP3+ regulatory cells (Tregs). Effective anti-tumor immunity and serious autoimmunity can be disassociated. Further targeting of anti-tumor Tregsin combinatorial therapy approaches may be a rich avenue of future investigation. [source]

IgE-Mediated Asthma and Rhinitis I: A Role of Allergen Exposure?

Gunnar D. Nielsen
The IgE antibodies and associated cellular responses are responsible for the allergic airway diseases, allergic rhinitis and allergic asthma, which are increasing in societies with Western life style. Aeroallergens may have different potential to sensitize exposed subjects. Thus, there are only a limited number of important groups of aeroallergens, which are those from house dust mites, cockroaches, pets, pollens, and moulds. Allergy follows to a certain extent the pharmacological/toxicological paradigm of dose-response relationship. Unlike effects of pharmacologically and toxicologically active substances, allergens elicit their adverse effects in a two-stage process. In the first stage the immunologically nave individual is sensitized to the allergen. In the second stage renewed exposure to the allergen elicits the disease response. Also, high concentrations of aeroallergens may induce immunological tolerance. The scientific literature suggests that many environmental factors contribute to the increase in sensitization and development of airway allergies. Nevertheless, the dose-response relationships apply (within certain limits) both to the sensitization itself and to the exacerbation of the diseases. This suggest that exposure reduction may be one of the methods for reduction of risk, in relation to control of the allergic airway diseases. [source]

The ,microflora hypothesis' of allergic diseases

M. C. Noverr
Summary Increasingly, epidemiologic and clinical data support the hypothesis that perturbations in the gastrointestinal (GI) microbiota because of antibiotic use and dietary differences in ,industrialized' countries have disrupted the normal microbiota-mediated mechanisms of immunological tolerance in the mucosa, leading to an increase in the incidence of allergic airway disease. The data supporting this ,microflora hypothesis' includes correlations between allergic airway disease and (1) antibiotic use early in life, (2) altered fecal microbiota and (3) dietary changes over the past two decades. Our laboratory has recently demonstrated that mice can develop allergic airway responses to allergens if their endogenous microbiota is altered at the time of first allergen exposure. These experimental and clinical observations are consistent with other studies demonstrating that the endogenous microbiota plays a significant role in shaping the development of the immune system. Data are beginning to accumulate that a ,balanced' microbiota plays a positive role in maintaining mucosal immunologic tolerance long after post-natal development. Other studies have demonstrated that even small volumes delivered to the nasopharynx largely end up in the GI tract, suggesting that airway tolerance and oral tolerance may operate simultaneously. The mechanism of microbiota modulation of host immunity is not known; however, host and microbial oxylipins are one potential set of immunomodulatory molecules that may control mucosal tolerance. The cumulative data are beginning to support the notion that probiotic and prebiotic strategies be considered for patients coming off of antibiotic therapy. [source]