Browsing by Subject "immunology"

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    Mechanisms Underlying Opioid Modulation of Gut Immunity
    (2014-08) Meng, Jingjing
    Opioids are used widely by clinicians due to their potent analgesic activities and sedative properties. However, opioid use or abuse is associated with multiple adverse gastrointestinal (GI) symptoms and higher susceptibility to infection caused by pathogens with gut origin. Both clinical and laboratory studies implied that opioids showed suppressive effects on gut immunity and predisposed critically sick patients to infections while the mechanism underlying this defect is still unknown. In the present study we investigated how opioids modulate gut epithelial barrier function and immune responses of gut associated lymphoid tissue (GALT). We demonstrated significant bacterial translocation from gut lumen to mesenteric lymph node (MLN) and liver following morphine treatment in wild-type (WT) animals that was significantly attenuated in Toll-like receptor (TLR2 and 4) knockout mice. We further observed significant disruption of tight junction protein organization only in the ileum but not in the colon of morphine treated WT animals. Inhibition of myosin light chain kinase (MLCK) blocked the effects of both morphine and TLR ligands, suggesting the role of MLCK in tight junction modulation by TLR. Additionally we determined the immune responses of GALT to polymicrobial sepsis in the presence and absence of opioids by using a murine cecal ligation and puncture model. The results showed that opioids accelerated the mortality rate of polymicrobial sepsis. During sepsis progression, morphine treatment altered gut microbiome and subsequently promoted gram-positive bacterial dissemination, which induced excess IL-17A production in a TLR2-dependent manner, resulting in increased gut permeability, sustained inflammation and higher mortality. This study improved our understanding of the role of morphine in modulating gut barrier functions and the roles of GALT in infection susceptibility, which may provide the potential therapeutic targets for novel drug development and lead to more powerful strategy to control or prevent severe infectious diseases like sepsis especially in the opioid using and abusing population.
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    The porcine memory B cell in conferring long term adaptive immunity to viral pathogens
    (2017-06) Rahe, Michael
    Porcine reproductive and respiratory syndrome virus (PRRSV) is the most important pathogen of swine health and well-being worldwide. Discovered nearly thirty years ago, there is still no vaccine capable of producing a broadly protective immune response against the virus. This deficiency is due in large part to a failure to understand how the adaptive immune system responds to vaccination or infection. Specifically, there is little to no knowledge regarding the all-important memory immune response to PRRSV. The objective of this dissertation was to fill in this significant gap in knowledge by identifying and characterizing the memory B cell response to PRRSV vaccination. First, we identified the presence of memory B cells against PRRSV non-structural protein 7 (nsp7) through the use of a novel in vitro B cell culture system. Next, we created and validated a novel reagent, a B cell tetramer, against nsp7 to enhance the speed and sensitivity of memory cell identification. Finally, through the utilization of the nsp7 tetramer, we evaluated the regional specificity and dynamic nsp7 specific B cell response to PRRSV MLV vaccination within select secondary lymphoid organs. These results constitute the first evidence of regional specialization of the B cell response to vaccination in an outbred animal species. Furthermore, the presented methods are a blueprint for the study of antigen specific cellular responses to any significant pathogen of animals important for food or fiber.