No description available.

Immunological stressors, in the form of clinical and sub-clinical disease are currently controlled using both prophylactic antibiotics in-feed, and therapeutic antibiotic treatment. Respiratory disease, primarily Actinobacillus pleuropneumoniae (App) infection, is recognised as a major factor causing reduced productivity in pigs. This thesis reports investigations into the use of novel immunomodulators in particular Interleukin 4 (IL-4) and Interleukin 1 receptor antagonist (IL-1ra) as alternatives to antibiotics to treat App infection. Immunological and molecular biological assays were used to investigate and accumulate data. An in vitro study undertaken to find potential anti-inflammatory substances, revealed that Interleukin 8 (IL-8) mRNA production stimulated by PMA or LPS in whole pigs' blood was suppressed by IL-4. IL-1ra also suppressed stimulated IL-8 mRNA production by heat killed App bacteria (KB) in vitro. An acute LPS challenge in pigs in vivo however, showed no variation in illness or weight loss between pigs treated prophylactically with anti-inflammatory substance (IL-4 and IL-1ra) and saline treated pigs. The use of plasmids as a delivery system for anti-inflammatory substance did not show promise since it did not enhance growth or prolong the expression of the substances in the pigs. However, in the chronic App challenge model IL-4 and IL-1ra administered prophylactically in vivo showed an ability to improve growth. The therapeutic administration of IL-4 and IL-1ra to App challenged pigs showed no difference in pigs' growth, regardless of the treatment or control administered. To conclude, IL-4 and IL-1ra showed promise when administered prophylactically and improved growth and abrogated disease under conditions of App challenge. However when IL-4 and IL-1ra where administered therapeutically they did not perform as well. Moreover these compounds have potential as a commercial application to reduce the growth reduction caused by disease such as App.

Interleukin-1 (IL-1) is a prototypic multifunctional cytokine. IL-1 family include interleukin-1 a (IL-1 a), interleukin-1b (IL-1 b) and interleukin-1 receptor antagonist (IL-1 Ra). IL-1 b is the archetypeal pleiotropic cytokine which have been produced by many cells and exerting its biological effects on almost all cell types. IL-1 b is the most potent of known agents that are gastric cytoprotective, antiulcer, antisecretory and an inhibitor of gastric emptying. IL-1 Ra competes with IL-1 b for cell surface receptor occupancy. Host genetic factors that affect interleukin-1 (IL-1) have been reported to influence the susceptibility of Caucasians to gastric cancer. Whether Asians have the same genetic susceptibility remains unclear. In this study, the genetic associations of IL-1B and IL-1RN polymorphisms with gastric cancer and duodenal ulcer in Taiwan were evaluated. Genomic DNA from 140 unrelated Taiwanese patients with gastric adenocarcinoma, 94 with duodenal ulcer and 165 ethically matched healthy controls was typed for polymorphisms at positions ¡V31, -511, and +3954 in the IL-1B gene, and the variable number of tandem repeats polymorphisms in intron 2 of the IL-1RN gene. The allele frequencies of IL-1RN 2R in gastric cancer cases were much higher than those in healthy controls (9% vs. 3%, p = 0.781). The allele frequencies of IL-1B ¡V31, IL-1B ¡V511 and IL-1B +3954 did not differ. An increased risk of the development of intestinal type gastric carcinoma was found in IL-1RN 2R carriers with an odds ratio (OR) of 4.06 (95% confidence interval [CI]: 1.68 ¡V 9.79, p-value=0.085). And another increased risk of the development of diffuse type gastric carcinoma was found in IL-1RN 2R carriers with an odds ratio (OR) of 3.15 (95% confidence interval [CI]: 1.16 ¡V 8.56, p-value=0.061). A significant association was found in IL-1RN 2R/4R genotype and the risk of the development of duodenal ulcer, with an odds ratio (OR) of 2.57 (95% CI: 1.03 ¡V 6.38, p = 0.292). No significant relationship was noted in duodenal ulcer patients with IL-1B genotype examed in this study. Additionally, a synergistic interaction between blood type A and IL-1 RN 2R carriers existed in gastric cancer patients (OR= 4.51; 95% CI: 1.20 ¡V 16.88, p-value=0.516). The synergistic interaction was even stronger between blood type O and IL-1 RN 2R carriers of duodenal ulcer patients (OR= 10.3; 95% CI: 2.10 ¡V 50.61, p-value=0.160). In conclusion, the genetic polymorphisms of IL-1RN 2R and blood type A are associated with the development of gastric cancer. The genetic polymorphisms of IL-1RN 2R and blood type O are associated with the development of duodenal ulcer.

Immunological stressors, in the form of clinical and sub-clinical disease are currently controlled using both prophylactic antibiotics in-feed, and therapeutic antibiotic treatment. Respiratory disease, primarily Actinobacillus pleuropneumoniae (App) infection, is recognised as a major factor causing reduced productivity in pigs. This thesis reports investigations into the use of novel immunomodulators in particular Interleukin 4 (IL-4) and Interleukin 1 receptor antagonist (IL-1ra) as alternatives to antibiotics to treat App infection. Immunological and molecular biological assays were used to investigate and accumulate data. An in vitro study undertaken to find potential anti-inflammatory substances, revealed that Interleukin 8 (IL-8) mRNA production stimulated by PMA or LPS in whole pigs' blood was suppressed by IL-4. IL-1ra also suppressed stimulated IL-8 mRNA production by heat killed App bacteria (KB) in vitro. An acute LPS challenge in pigs in vivo however, showed no variation in illness or weight loss between pigs treated prophylactically with anti-inflammatory substance (IL-4 and IL-1ra) and saline treated pigs. The use of plasmids as a delivery system for anti-inflammatory substance did not show promise since it did not enhance growth or prolong the expression of the substances in the pigs. However, in the chronic App challenge model IL-4 and IL-1ra administered prophylactically in vivo showed an ability to improve growth. The therapeutic administration of IL-4 and IL-1ra to App challenged pigs showed no difference in pigs' growth, regardless of the treatment or control administered. To conclude, IL-4 and IL-1ra showed promise when administered prophylactically and improved growth and abrogated disease under conditions of App challenge. However when IL-4 and IL-1ra where administered therapeutically they did not perform as well. Moreover these compounds have potential as a commercial application to reduce the growth reduction caused by disease such as App.

The overall aim of this thesis was to establish strategies to minimize secondary damage to the injured spinal cord. Secondary damage that follows spinal cord injury (SCI) involves inflammatory and excitotoxic pathways. Regulation of these pathways using immunomodulatory and neuroprotective substances potentially protects the injured spinal cord from further damage. We also developed and studied resorbable biomaterials to be used as carriers for potential neuroprotectants to the injured spinal cord. We used transversal spinal cord slice cultures (SCSCs) derived from postnatal mice as a model. SCSCs were maintained on different biomaterials and were studied after treatment with immunomodulatory and/or neurotrophic factors. They were further excitotoxically injured and subsequently treated with interleukin-1 receptor antagonist (IL1RA) or by neural crest stem cell (NCSC)-transplantation. The results show that biocompatible and resorbable hydrogels based on hyaluronic acid (HA) preserved neurons in SCSCs to a much higher extent than a conventional collagen-based biomaterial or standard polyethylene terephthalate (PET) membrane inserts. Glial activation was limited in the cultures maintained on HA-based hydrogel. The anti-inflammatory factor IL1RA protected SCSCs from degenerative mechanisms that occur during in vitro incubation, and IL1RA also protected SCSCs from excitotoxic injury induced by N-Methyl-d-Aspartate (NMDA). IL1RA specifically protected neurons that resided in the ventral horn, while other neuronal populations such as dorsal horn neurons and Renshaw cells did not respond to treatment. Finally, transplantation of NCSCs onto excitotoxically injured SCSCs protected from neuronal loss, apoptosis and glial activation, while NCSCs remained undifferentiated. The results presented in this thesis indicate that carriers based on HA seem to be more suitable than conventional collagen-based biomaterials since they enhance neuronal survival per se. The observed neuroprotection is likely due to biomechanical properties of HA. IL1RA protects SCSCs from spontaneous degeneration and from NMDA-induced injury, suggesting that excitotoxic mechanisms can be modulated through anti-inflammatory pathways. Different neuronal populations are affected by IL1RA to various degrees, suggesting that a combination of different neuroprotectants should be used in treatment strategies after SCI. Finally, NCSCs seem to protect SCSCs from excitotoxic injury through paracrine actions, since they remain undifferentiated and do not migrate into the tissue during in vitro incubation. It seems that combinations of neuroprotectants and carrier substances should be considered rather than one single strategy when designing future treatments for SCI. Incorporation of neuroprotectants such as IL1RA combined with stem cells in injectable biocompatible carriers based on HA is the final goal of our group in the treatment of SCI.

Thesis (Ph.D. in Pharmaceutical Sciences) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 133-143). Online version available via ProQuest Digital Dissertations.

No description available.

A candidíase vulvovaginal corresponde a uma das mais frequentes infecções do trato reprodutivo. Estima-se que 75% das mulheres na idade reprodutiva experimentarão pelo menos um episódio de candidíase vulvovaginal durante suas vidas, a maioria evoluirá com episódios infrequentes, entretanto, 5% sofrerão recorrência, ou seja, quatro ou mais episódios de candidíase vulvovaginal comprovadas clínica e laboratorialmente no período de 1ano. Os mecanismos pelos quais as recorrências ocorrem ainda são pouco conhecidos, estando provavelmente relacionados à alterações na imunidade local. O presente estudo teve como objetivo avaliar as associações entre os polimorfismos nos genes que codificam a lecitina ligadora de manose (MBL) e do antagonista do receptor da interleucina 1 (IL1-Ra) com a candidíase vulvovaginal recorrente (CVVR) em mulheres brasileiras. Foram estudadas 100 mulheres portadoras de CVVR atendidas no Serviço de Imunologia Genética e Infecções do Trato Reprodutivo da Disciplina de Ginecologia da Faculdade de Medicina da Universidade de São Paulo. Para a análise dos polimorfismos nos genes que codificam para a MBL e o IL1-Ra realizou-se coleta de células bucais que foram enviadas para Division of Immunology and Infectious Diseases of Weill Medical College of Cornell University Resultados: Mulheres com candidíase vulvovaginal recorrente apresentaram maior frequência de polimorfismo no códon 54 do gene que codifica a MBL quando comparadas a mulheres saudáveis. Não foram observadas diferenças estatisticamente significativas na frequência do polimorfismo do gene que codifica o IL1-Ra entre os grupos estudados / Vulvovaginal candidiasis is the most common genital infection in women during their childbearing years. About 75% of women suffer at least one syntomatic episode during their lives. Most of them will have infrequent episodes, but 5% will suffer recurrent episode of vulvovaginal candidiasis. The mechanisms responsible for recurrent vulvovaginal candidiasis (RVCC) remain a matter of speculation, although an alteration in local immunity appears to be a major factor. The aim of this study was to assess the correlation between polymorphisms in the genes coding for mannose-binding lectin (MBL) and interleukin-1 receptor antagonist (IL1-Ra) and RVCC in women from São Paulo, Brazil. The study population consisted of 100 women with RVCC, who were seen at Serviço de Infecções do Trato Reprodutivo da Disciplina de Ginecologia da Faculdade de Medicina da Universidade de São Paulo. To analyse for the MBL códon 54 gene polymorphism and for IL1-Ra, buccal cells were obtained with a cotton swabs and shipped to New York at ambient temperature. The polymorphisms were identified in the Division of Immunology and Infectious Diseases of Weill Medical College of Cornell University. Results: Women with RVVC present a high frequency of polymorphisms at codon 54 in the gene coding for MBL; on the other hand there were no differences in polymorphism frequency in the gene coding for IL1-Ra when compared to control women

A candidíase vulvovaginal corresponde a uma das mais frequentes infecções do trato reprodutivo. Estima-se que 75% das mulheres na idade reprodutiva experimentarão pelo menos um episódio de candidíase vulvovaginal durante suas vidas, a maioria evoluirá com episódios infrequentes, entretanto, 5% sofrerão recorrência, ou seja, quatro ou mais episódios de candidíase vulvovaginal comprovadas clínica e laboratorialmente no período de 1ano. Os mecanismos pelos quais as recorrências ocorrem ainda são pouco conhecidos, estando provavelmente relacionados à alterações na imunidade local. O presente estudo teve como objetivo avaliar as associações entre os polimorfismos nos genes que codificam a lecitina ligadora de manose (MBL) e do antagonista do receptor da interleucina 1 (IL1-Ra) com a candidíase vulvovaginal recorrente (CVVR) em mulheres brasileiras. Foram estudadas 100 mulheres portadoras de CVVR atendidas no Serviço de Imunologia Genética e Infecções do Trato Reprodutivo da Disciplina de Ginecologia da Faculdade de Medicina da Universidade de São Paulo. Para a análise dos polimorfismos nos genes que codificam para a MBL e o IL1-Ra realizou-se coleta de células bucais que foram enviadas para Division of Immunology and Infectious Diseases of Weill Medical College of Cornell University Resultados: Mulheres com candidíase vulvovaginal recorrente apresentaram maior frequência de polimorfismo no códon 54 do gene que codifica a MBL quando comparadas a mulheres saudáveis. Não foram observadas diferenças estatisticamente significativas na frequência do polimorfismo do gene que codifica o IL1-Ra entre os grupos estudados / Vulvovaginal candidiasis is the most common genital infection in women during their childbearing years. About 75% of women suffer at least one syntomatic episode during their lives. Most of them will have infrequent episodes, but 5% will suffer recurrent episode of vulvovaginal candidiasis. The mechanisms responsible for recurrent vulvovaginal candidiasis (RVCC) remain a matter of speculation, although an alteration in local immunity appears to be a major factor. The aim of this study was to assess the correlation between polymorphisms in the genes coding for mannose-binding lectin (MBL) and interleukin-1 receptor antagonist (IL1-Ra) and RVCC in women from São Paulo, Brazil. The study population consisted of 100 women with RVCC, who were seen at Serviço de Infecções do Trato Reprodutivo da Disciplina de Ginecologia da Faculdade de Medicina da Universidade de São Paulo. To analyse for the MBL códon 54 gene polymorphism and for IL1-Ra, buccal cells were obtained with a cotton swabs and shipped to New York at ambient temperature. The polymorphisms were identified in the Division of Immunology and Infectious Diseases of Weill Medical College of Cornell University. Results: Women with RVVC present a high frequency of polymorphisms at codon 54 in the gene coding for MBL; on the other hand there were no differences in polymorphism frequency in the gene coding for IL1-Ra when compared to control women

<p>Adult prostate stem cells (PSC) are a rare epithelial progenitor population in the prostate. While essential for normal homeostasis, they have also been implicated in hyperplasia and cancer initiation. While studies have shown that inflammatory growth factors and cytokines can fuel stem cell expansion, the impact of inflammation on PSC is not well understood. To study the impact of inflammation on the prostate, the Ratliff laboratory developed the Prostate Ovalbumin Expressing Transgenic 3 (POET3), an inducible mouse model of abacterial T cell mediated prostate inflammation, which functions as a model for human autoimmune prostatitis. Previous studies using the POET3 demonstrated that inflammation increased proliferation and differentiation of PSC enrichments. Based on these findings, it was speculated that inflammation impacts prostate stem cells to enhance mechanisms of survival, possibly as a means of tissue protection.</p><p>Since androgen receptor (AR) signaling is the major driver of cellular differentiation and survival in the prostate, it was further hypothesized that inflammation promotes AR signaling in the PSC. To address this hypothesis, PSC and their resulting organoids from inflamed and non-inflamed (naïve) POET3 mice as well as human patient samples were assessed for AR and its signaling components.</p><p>These data were expanded by single cell mRNA sequencing using Fluidigm’s C1 platform, which revealed changes in stem cell populations, differential expression of interleukin 1 alpha (IL-1⍺) and its signaling components, and upregulation of various genes associated with immune regulation. Thus, experiments described herein probed the impacts of inflammation on AR, IL-1⍺, and T cell regulatory abilities in the PSC.</p>The results of these studies indicate that indeed, inflammation increases PSC survival. Inhibition of IL-1⍺ via inflammation-mediated up-regulation of IL-1 receptor antagonist (IL-1RA) promotes AR signaling, resulting in proliferation, differentiation, and AR target gene expression which can be modulated by Enzalutamide (a clinical AR inhibitor). Furthermore, PSC from inflamed mice are able to suppress cytotoxic T cell function in <i>ex vivo</i> assays. These studies set the foundation for new ways to treat proliferative diseases of the prostate by targeting IL-1⍺, AR, and immune regulation in the PSC.