T Regulatory Cells: An Overview and Intervention Techniques to Modulate Allergy Outcome

Dysregulated immune response results in inflammatory symptoms in the respiratory mucosa leading to asthma and allergy in susceptible individuals. The T helper type 2 (Th2) subsets are primarily involved in this disease process. Nevertheless, there is growing evidence in support of T cells with regulatory potential that operates in non-allergic individuals. These regulatory T cells occur naturally are called natural T regulatory cells (nTregs) and express the transcription factor Foxp3. They are selected in the thymus and move to the periphery. The CD4 Th cells in the periphery can be induced to become regulatory T cells and hence called induced or adaptive T regulatory cells. These cells can make IL-10 or TGF-b or both, by which they attain most of their suppressive activity. This review gives an overview of the regulatory T cells, their role in allergic diseases and explores possible interventionist approaches to manipulate Tregs for achieving therapeutic goals

T regulatory cells: an overview and intervention techniques to modulate allergy outcome

Dysregulated immune response results in inflammatory symptoms in the respiratory mucosa leading to asthma and allergy in susceptible individuals. The T helper type 2 (Th2) subsets are primarily involved in this disease process. Nevertheless, there is growing evidence in support of T cells with regulatory potential that operates in non-allergic individuals. These regulatory T cells occur naturally are called natural T regulatory cells (nTregs) and express the transcription factor Foxp3. They are selected in the thymus and move to the periphery. The CD4 Th cells in the periphery can be induced to become regulatory T cells and hence called induced or adaptive T regulatory cells. These cells can make IL-10 or TGF-b or both, by which they attain most of their suppressive activity. This review gives an overview of the regulatory T cells, their role in allergic diseases and explores possible interventionist approaches to manipulate Tregs for achieving therapeutic goals

Cellular Immune Responses to Nine Mycobacterium tuberculosis Vaccine Candidates following Intranasal Vaccination

BACKGROUND: The identification of Mycobacterium tuberculosis vaccines that elicit a protective immune response in the lungs is important for the development of an effective vaccine against tuberculosis. METHODS AND PRINCIPAL FINDINGS: In this study, a comparison of intranasal (i.n.) and subcutaneous (s.c.) vaccination with the BCG vaccine demonstrated that a single moderate dose delivered intranasally induced a stronger and sustained M. tuberculosis-specific T-cell response in lung parenchyma and cervical lymph nodes of BALB/c mice than vaccine delivered subcutaneously. Both BCG and a multicomponent subunit vaccine composed of nine M. tuberculosis recombinant proteins induced strong antigen-specific T-cell responses in various local and peripheral immune compartments. Among the nine recombinant proteins evaluated, the alanine proline rich antigen (Apa, Rv1860) was highly antigenic following i.n. BCG and immunogenic after vaccination with a combination of the nine recombinant antigens. The Apa-induced responses included induction of both type 1 and type 2 cytokines in the lungs as evaluated by ELISPOT and a multiplexed microsphere-based cytokine immunoassay. Of importance, i.n. subunit vaccination with Apa imparted significant protection in the lungs and spleen of mice against M. tuberculosis challenge. Despite observed differences in the frequencies and location of specific cytokine secreting T cells both BCG vaccination routes afforded comparable levels of protection in our study. CONCLUSION AND SIGNIFICANCE: Overall, our findings support consideration and further evaluation of an intranasally targeted Apa-based vaccine to prevent tuberculosis

Heterologous CD8 T Cell Immune Response to HSV Induced by Toll Like Receptor Ligands

A memory response is established following primary antigen exposure that stays more or less constant. It appears to adopt a set-point in magnitude but upon re-exposure the response is quicker and better and there is an upward shift in memory frequency that varies with individuals based on the exposure pattern to other microbes or its components. Our investigations were designed to test such differences of non-specific stimulation by PAMPs in lowering the threshold of activation. Neonatal mice were pre-exposed to TLR-ligands intermittently and later analyzed for its resilience to challenge with virus during adult-life. Secondly, adult mice with pre-existing memory to virus were exposed to various TLR-ligands and analyzed for their quality of memory response. The TLR-ligands exposed animals were better responders to a new agent exposure compared to the animals kept in sterile surroundings. Moreover, immune memory recall and the viral specific CD8+ T cells response with TLR-ligands were comparable to the recall response with the cognate antigen. The results provide insights into the role of hyper-sanitized environment versus PAMPs mediated signaling in adaptive immunity and long-term immune memory

MOLECULAR LINK BETWEEN TOLL LIKE RECEPTORS, TUMOROGENESIS AND OBESITY (135.61)

Abstract Hygiene hypothesis states that "Lack of early childhood exposure to infectious agents and symbiotic microbes increases the susceptibility to allergic diseases by modulating the immune system". We predicted that neonate's exposure to microbes or its components will have long term protective effect against infectious diseases and cancer. To this end, we simulated dirty environment (exposure to microbial components) for a group of neonatal mice and compared them to mice kept in sterile conditions. The mice were allowed to grow up to 5-6 weeks after which they were analyzed for their ability to resist infection and tumor challenge. The mice that were in a simulated dirty environment were better able to resists HSV disease manifestation and tumor challenge with adeno carcinoma cells. Interestingly, the mice kept in sterile conditions gained significant body weight. Taken together, mice in cleaner environment became obese and were prone to infection and cancer indicating a similarity with human epidemiological data. We found that microbial exposure resulted in the 2.5 times more bone morphogenetic protein -7 in microbes exposed mice compared to mice kept in cleaner environment. BMP-7 is involved in the generation of brown fat that is known to be efficient in energy utilization, metabolism and weight reduction. Hence we conclude that bmp-7 induced by exposure to microbial components may be the molecular link between the microbial exposure pattern, obesity development and immune-protection. Increasing the levels of BMP-7 may well be employed as a therapeutic tool. Acknowledgements: ETSU-College of Medicine-Start up funds</jats:p

Timing, dose and combination impact immune memory recall with TLR ligands (47.30)

Abstract The hygiene hypothesis and the study of probiotic and prebiotic effects have emphasized the need to understand, and ultimately to manipulate, our physiological interactions with commensal flora, and with other transient but harmless organisms from the environment that affect immunoregulatory circuits. A long-term memory response is established following primary antigen exposure that stays more or less constant. It appears to adopt a set-point in magnitude but upon re-exposure the response is quicker and better and there is an upward shift in memory frequency. This new set-point is likely higher than the primary set-point and varies with individuals based on the exposure pattern to other microbes or its components. Our investigations have been designed to test such differences of non-specific stimulation by PAMPs in lowering the threshold of activation. Accordingly, young mice were pre-exposed to TLR stimulation intermittently and later analyzed for its resilience to challenge with virus during later part of their life. Secondly, adult mice with pre-existing memory to virus were exposed to various TLR ligands in the presence and absence of cognate antigen and analyzed for their quality and frequency of the memory response. Animals that are constantly reminded of the danger in a subtle way are better responders to a new agent exposure compared to the animals kept in sterile surroundings. However, immune memory recall with TLR ligands differed based on the dose, timing and combination of ligands used. Taken together, results provide insights into the role of hyper-sanitized environment versus PAMP mediated signaling in adaptive immune response and long term memory.</jats:p

Resistance training and aerobic exercise alters immune function (87.25)

Abstract Exercise affects various components of the immune system that could be clinically beneficial or deleterious. Accordingly, moderate exercise stimulates the immune system, while intense exercise suppresses certain immune cell activities. Some of the immune-regulation observed may be due to the regulatory T cells. This could also explain the difference between moderate and strenuous exercisers and the probable reason for lower incidence of autoimmunity in active individuals. Intense exercisers (Trained -regular) and Moderate exercisers (untrained- occasional) were recruited as volunteers from of our university community after IRB approval. Blood samples were collected. PBMCs were used for immune cell profile analysis and the plasma was used for cytokine estimation. Results suggest recruitment of all lymphocyte subpopulations to the vascular compartment: CD4, CD8, B, and Natural killer (NK) cells. Depending on intensity of exercise, the CD4-to-CD8 ratio decreased, reflecting the greater increase in CD8s than CD4s. Both memory and naive phenotype were found, while memory type prevailed. The number of Tregs was increased in all subjects and inversely correlated with IL-6 concentration. Resistant training associated initiation of inflammatory cytokine suggest metabolic link between skeletal muscles and the lymphoid system. It is therefore to be expected that moderate exercise protects against malignancy or infection whereas exhaustive exercise is linked to increased pathology.</jats:p