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Vor Einführung der direkt antiviralen Kombinationstherapien war die Kombination aus pegyliertem Interferon plus Ribavirin die Standardbehandlung für Patienten mit chronischer Hepatitis-C-Infektion. Bei 30% der Patienten zeigten sich neurokognitive sowie depressive Nebenwirkungen, die das dauerhafte Therapieansprechen negativ beeinflussen können. Vor diesem Hintergrund untersuchten wir in unserer Arbeit bei 93 Patienten mit chronischer Hepatitis-C-Infektion den Zusammenhang zwischen drei Single Nucleotide Polymorphismen im Bereich des IL28B-Gens und der Verträglichkeit sowie dem Therapieerfolg einer interferonbasierten Behandlung. Der Vergleich zwischen den Ergebnissen im HADS-(Hospital Anxiety and Depression Scale) sowie TAPS- (Testbatterie zur Aufmerksamkeitsprüfung) Testverfahren mit den Genotypen der drei SNPs zeigte im Studienkollektiv keinen signifikanten Zusammenhang. Hinsichtlich des Therapieerfolges konnten wir bei einem der drei SNPs das C-Allel als positiven Prognosefaktor für das dauerhafte Therapieansprechen nachweisen. / Prior to the introduction of direct antiviral combination therapies, the combination of pegylated interferon plus ribavirin was the standard treatment for patients with chronic hepatitis C infection. In 30% of the patients, neurocognitive and depressive side effects were observed, which could negatively influence the sustained virological response. Against this background, the central question that motivates our work was to investigate the association between three single nucleotide polymorphisms in the IL28B gene and the tolerability and therapeutic outcome of interferon-based treatment in 93 patients with chronic hepatitis C infection. The comparison between two test procedures, the HADS (hospital anxiety and depression scale) and TAPS (test battery for attention testing), with the genotypes of the three SNPs showed no significant association in the study population. In terms of therapeutic success, we were able to demonstrate the C allele in one of the three SNPs as a positive prognostic factor for the sustained virological response.

Coordinated signals between the maternal endometrium and conceptus during the peri-implantation period are essential for the establishment and maintenance of pregnancy. In pigs, this involves estrogen secretion from conceptuses as the signal for maternal recognition of pregnancy. Pig conceptuses also secrete interferons (IFN) delta (IFND) and IFN gamma (IFNG). The uterine effects of pig IFNs are not known, although ruminant conceptuses secrete IFN tau (IFNT) for pregnancy recognition, and this increases the expression of IFN-stimulated genes (ISGs) in the endometrium. Therefore, studies were conducted to identify and characterize ISGs in the pig endometrium during pregnancy and to evaluate their regulation by estrogen and conceptus secretory proteins (CSPs) that contain IFNs. In the first study, four classical ISGs, including interferon regulatory factor 1 (IRF1) and signal transducer and activator of transcription 2 (STAT2), were detected in the pig endometrium and increased after Day 12 of pregnancy, specifically in stroma. IRF2, a transcriptional repressor of ISGs, increased in luminal epithelium (LE) by Day 12 of pregnancy. The increase of IRF2 was due to estrogen while the stromal increase of IRF1 was due to IFN-containing CSP infusion. In the second study, the ISG STAT1 increased in LE after Day 12 of pregnancy and estrogen resulted in a similar increase. After Day 15 of pregnancy, STAT1 increased in stroma. Infusion of IFN-containing CSPs resulted in a similar stromal increase. In the third study, the ISGs swine leukocyte antigen (SLA) class I and beta-2microglobulin (B2M) increased in LE between Days 5 and 9 of the estrous cycle and pregnancy and decreased between Days 15 and 20 of pregnancy. By Day 15 of pregnancy, SLAs and B2M increased in stroma where they remained through Day 40. Progesterone increased SLA and B2M in LE, and a progesterone receptor antagonist ablated the upregulation while infusion of IFN-containing CSP increased SLA and B2M in stroma. Collectively, these studies identify ISGs expressed in the pig endometrium during pregnancy. These genes may be involved in protecting the fetal semiallograft from immune rejection, limiting conceptus invasion through the uterine wall, and/or establishing a vascular supply to the conceptus. The interactions of estrogen, progesterone and IFNs to regulate cell-type specific expression of ISGs highlight the complex interplay between endometrium and conceptus for pregnancy recognition and implantation.

Multiple sclerosis (MS) is the most common primary demyelinating disease of the central nervous system in humans. Type I interferons are most frequently used to treat MS. However, their main mechanism of action remains elusive. Various biomarkers have been investigated for their ability to assess treatment efficacy, but results are often confounding due to differences in experimental design and variation in individual physiology. In fact, not all MS patients respond to IFN therapy and a significant number suffer severe negative side effects and must cease treatment. Thus, alternative therapeutics that offer less cytotoxicity and greater efficacy are a major objective of research. This dissertation evaluated a novel type I interferon, interferon-tau (IFNT), and its ability to attenuate Theiler’s virus-induced-demyelinating disease (TVID), a mouse model of MS. In this model, viral infection with the BeAn strain of Theiler’s murine encephalomyelitis virus (TMEV) is the initiating factor leading to demyelination of the CNS. It was hypothesized that IFNT would: 1) provide therapeutic benefit as witnessed by a stabilization of clinical score, a decrease in CNS inflammation, and a decrease in CNS demyelination, and 2) shift the immune profile from a Th1 to a Th2 response. Once mice developed chronic disability, IFNT treatment began. This novel IFN was delivered in an innovative way: encapsulation (eIFNT) in an alginate polymer, which allowed for slow and sustained release. eIFNT was delivered by a 100 μl intraperitoneal injection (i.p.) containing 1.4M U of IFNT once every two weeks for 8 weeks. Mice were clinically scored weekly and BeAn-eIFNT mice demonstrated a decrease in clinical score. Bright field microscopy was used to evaluate CNS tissues where a decrease in demyelination and inflammation was noted in BeAn-eIFNT-treated mice. Ex vivo stimulation of virus-specific lymphocytes revealed an increase in both T helper 1 (Th1) and T helper 2 (Th2) cytokine production. Specifically, TNFA was produced at very high levels by splenocytes from BeAneIFNT mice in response to UV-inactivated BeAn alone and in the presence of IFNT when compared to BeAn-eMOPS mice under the same conditions. IFNG was produced at elevated levels from the splenocytes of BeAn-eIFNT mice versus BeAn-eMOPS mice when stimulated in vitro with UV-inactivated Bean and with BeAn in the presence of IFNT. IL-2 was produced at moderately elevated levels from the splenocytes of BeAn-eIFNT mice versus BeAn-eMOPS mice when stimulated in vitro with UV-inactivated Bean. Il-2 was elevated to a statistically significant level (p<0.05) from BeAn-eIFNT mouse splenocytes when stimulated with BeAn in the presence of IFNT when compared to BeAn-eMOPS mice and IL-10 was produced at elevated levels by splenocytes from BeAn-eIFNT mice versus that produced from BeAn-eMOPS mouse splenocytes in response to UV-inactivated BeAn alone and in the presence of IFNT. Quantification of T regulatory (Treg) cells in the spleen of eIFNT vs. eMOPS mice and blood of eIFNT vs. eMOPS mice revealed no difference between the two groups. There was no statistical difference in virus-specific serum antibodies at the pretreatment time point noted in the OD readings of eIFNT mice at a dilution of 1/200 compared to the eMOPS mice. A modest decrease in the OD values at the 1/200 dilution were noted in the eIFNT mice compared to the eMOPS mice, but this difference was not significant. Antibody secreting cells (ASCs) from eIFNT mice versus eMOPS mice were slightly lower in the spleen and brains whereas there was a slight increase in ASCs from the spinal cord of eIFNT mice when compared to those from eMOPS mice. Altogether, the results support efficacy of the eIFNT treatment in the mice with TVID. Actual mechanisms of disease attenuation remain elusive at this time as mice exhibited an increase in certain Th1 and Th2 cytokines rather than the hypothesized shift from a Th1 to a Th2 immune profile. Likewise, mice exhibited a modest decrease in virus specific antibodies as well as the number virus-specific ASCs which also refute the hypothesized increase in these values. A remarkable finding was the fact that immune cells derived from eIFNT treated mice appeared to be divided into two distinct types of biological responders although all of the mice responded to the in vivo treatment with a decrease in disease severity. It is hypothesized that this difference is a reflection of individual genetic variability in response to immune modulation which is surprising owing to the fact that the animals used for these studies are in-bred and considered to be as identical genetically as is feasible in a population of animals. Obviously, immune modulation can proceed through different mechanisms and still provide the desired result of a decrease in disease severity. However, this reality creates an added level of difficulty when one is trying to interpret biological data in order to determine whether a therapeutic regimen is efficacious within a patient population.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 93-125). Also available in print.

Mammals have complicated antiviral innate immunity to combat viral infection and this poses a strong selection pressure on the viruses. As a result, many viruses have evolved different strategies to disrupt the function of hosts’ antiviral innate immunity. Herpes simplex virus type 1 (HSV-1) is one of the examples. HSV-1 is a common and important human pathogen. HSV-1 infection induces type I interferons (IFNs) which restrict viral replication potently. To ensure persistent infection and successful replication, HSV-1 encodes several IFN-suppressing proteins. One example is Us11. Interaction between Us11 and various cellular proteins, such as PKR, RIG-I and PACT, were shown by other studies. However, exactly how Us11 suppresses IFN function remains to be elucidated. In this study, I discovered that Us11 specifically inhibits PACT induced activation of RIG-I. In HSV-1 infected cells, PACT and Us11 associate with each other tightly and this interaction prevents the interaction of PACT with RIG-I. It was also found that RNA binding domains on both PACT and Us11 are important for the association. In infection experiments, the increased production of IFN- during the infection of PACT-competent cells with Us11-deficient HSV-1 recombinant virus was not observed in infected PACT-compromised cells, suggesting the requirement of PACT for Us11 suppression of IFN production. To conclude, this study provides an explanation for Us11 antagonism of IFN production. My findings suggest that PACT is a novel target of HSV-1 IFN-antagonizing protein Us11. / published_or_final_version / Biochemistry / Master / Master of Philosophy

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