Browsing by Subject "mycoplasma"
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Item Setting Us Up to Fail: Pulmonary Dendritic Cells Promote Immunopathology during Mycoplasma Respiratory Disease(2010-08-01) Dobbs, Nicole A.; Jerry SimeckaThe purpose of these studies was to define the contributions of T helper 2 cells and dendritic cells toward the development of immunopathology during mycoplasma respiratory disease. IFN-γ+ CD8+ T cells, IFN-γ+ Th1 cells and IL-13+ Th2 cells developed over the course of mycoplasma infection. By day 14 post-infection, the results demonstrated a significant and preferential increase of an IL-13+ Th2 cell sub-population in the LRNs. Additional studies using STAT4-/- animals, which have a Th2 polarized environment, demonstrated no difference in disease compared to the wild-type animals. Absence of STAT6, which strongly contributes to a Th1 polarized environment, conveyed significantly more protection from mycoplasma disease in immunized mice compared to STAT4-/- and WT mice. By day 14 post-infection, all mice had significantly more IL-13+ Th2 cells than IFN-γ+ Th1 in the LRN compared to STAT6-/- immunized mice, thus suggesting that the reduction in the IL-13+ Th2 population leads to protection, while an increase in Th2 is pathogenic. Additional studies demonstrated that pulmonary dendritic cells support the mycoplasma-specific CD4+ and CD8+ T cell activation when stimulated with mycoplasma antigen. Knowing that T cells and DCs have an intimate relationship during mycoplasma disease, sub-classes of cytokine differentiated BMDCs were created to attempt to skew to the protective arm of immunity against mycoplasma disease. However, in vivo adoptive transfer studies demonstrated antigen pulsed DCs accelerated and exacerbated the pathological effects of mycoplasma disease. The exacerbation was antigen-specific and lymphocyte dependent. Mice that received antigen pulsed DCs demonstrated a significant increase in IL-13+ Th2 cell sub-population in the LRNs with a similar trend found in the lungs prior to infection. The same exacerbation was seen when antigen pulsed pulmonary DCs were adoptively transferred into mice, but not with antigen pulsed splenic DCs. Prior to infection, mice that received antigen-pulsed pulmonary DC, not splenic DC, had a significant increase in a IL-13+ Th2 population in the LRNs. Taken collectively, these studies demonstrate two key players in the development of the detrimental response against mycoplasma disease. This knowledge will assist in the development of targeted vaccines that will promote protection over pathology.Item The Role of Regulatory T Cells in Mycoplasma Respiratory Infection(2011-05-01) Odeh, Adam N.; Jerry SimeckaThe purpose of these studies was to examine the role of regulatory T cells (Tregs) in mycoplasma respiratory disease. Depletion of Tregs resulted in increased disease severity. Tregdepleted mice lost significantly more weight over the course of the experiment, and displayed a significantly higher incidence of both gross lung lesions and histological lung lesions at day 14 post-infection. Treg depletion resulted in increased cell infiltration into the lungs by day 14 postinfection, and significant increases in the serum levels of mycoplasma-specific antibodies. Treg depletion also led to an increase in the percentage of IL-13+ T cells in the LRNs, meaning that the immune response was skewed towards a Th2 phenotype. There were no differences observed in lung CFU. These data demonstrate that Tregs in mycoplasma respiratory disease play a role in inflammation and disease severity, but have no effect on bacterial clearance. Importantly, depletion of Tregs causes a Th2-directed shift in the immune response. Additional studies demonstrated that Tregs from mycoplasma-infected mice secreted IFN-γ or IL-17. IFN-γ + and IL-17+ Treg populations both preferentially expanded in response to M. pulmonis infection. Depletion of Tregs resulted in decreased secretion of IFN-γ and IL-17 by CD4+ non-Treg cells. Cocultures of Tregs and T helper cells from mycoplasmainfected mice secreted large amounts of IFN-γ and IL-17 when stimulated with mycoplasma membrane antigen. Levels of IL-4, IL-10, and IL-13 did not significantly increase in response to antigen. Together these studies demonstrate that mycoplasma respiratory disease is influenced by Tregs. These data further suggest that mycoplasma-specific Tregs include two unique subpopulations that express either IFN-γ or IL-17, and that these Tregs may promote the secretion of IFN-γ and IL-17 by T helper cells. This may represent a novel mechanism of Tregmediated immune suppression. This knowledge can assist in the development of treatments for mycoplasma respiratory disease and in the development of Treg-mediated therapies for a number of diseases.Item The Roles of IFN-y and IL-4 in the Upper and Lower Respiratory Tracts Immune Responses Toward Mycoplasma Infection(2003-12-01) Woolard, Matthew D.; Jerry SimeckaWoolard, Matthew D., The Roles of IFN-γ and IL-4 in the Upper and Lower Respiratory Tracts Immune Responses Toward Mycoplasma Infection. Doctor of Philosophy (Biomedical Sciences), December, 2003, 136 pp., 1 table, 16 illustrations, bibliography, 152 titles. The purpose of these studies was to evaluate the roles of IFN-γ and IL-4 during the development of immune responses of the upper and lower respiratory tracts, during mycoplasma respiratory disease. To study their roles, we took advantage of IFN-γ and IL-4 knockout (KO) mice. The loss of IL-4 did not impact the development of disease or the clearance of mycoplasma from either respiratory tracts during mycoplasma infection. However, IL-4 mediated responses dampen mycoplasma induced bronchial hyperresponsiveness (BHR), which are in direct contrast to theories that state that IL-4 is critical for the development of BHR. This suggests that mycoplasma exacerbation of asthma is a synergism between IL-4 and non-IL-4 mediated responses. Thus, IL-4 does not impact mycoplasma disease development, but dampens detrimental non-IL-4 mediated responses that exacerbate BHR during mycoplasma disease. The loss of IFN-γ did not affect disease or the number of mycoplasma organisms in the upper respiratory tract; this is in contrast to the lungs where the loss of IFN-γ led to a defect in innate immune responses. A significant increase in mycoplasma organisms were seen by day 3 post-infection which led to exacerbation of disease pathology. By three days after infection, only the number of IFN-γ+ NK cells increase in numbers in response to mycoplasma infection. However, the depletion NK cells by anti-asialo GM1 antibody treatment did not affect the clearance of mycoplasma from lungs of BALB/c mice, however, NK cell depletion from IFN-γ KO mice lead to increased clearance of mycoplasma organisms from the lung. Further studies demonstrated that NK cells in an IFN-γ deficient environment lead to increased secretion of IL-10, G-CSF, and TNF-α and increased numbers of cell infiltrated into the alveoli and airways. These results suggest that NK cells of the lung have anti-inflammatory roles that IFN-γ counteracts in BALB/c mice. Regardless, these studies demonstrate that NK cells in an IFN-γ deficient environment impair innate immune responses from clearing mycoplasma organisms from the lung. These studies demonstrated diverse but novel functions for IFN-γ and IL-4 during respiratory infections that will have significant impact on future studies of respiratory immunology.