Previous studies of the ontogeny of the mucosal immune system have shown a significant increase in salivary Immunoglobulin A levels occurring at about five years of age. This study has monitored a group of 3 and 4 year old children during one year of attendance at Pre-School to examine whether such an increase could be linked to increased antigenic exposure associated with moving into a school like environment. Saliva samples were collected at regular intervals and analysed for immunoglobulin and total protein levels. Daily health records were maintained for each child, and a detailed social and medical history was collected for each child at the beginning of the study. The elevated mucosal immune response observed in previous studies involving children in day care centres and attending school was not seen in this study. No significant difference was observed between children who had previously attended Pre-School or child care centres and those who were attending for the first time. However, a marked seasonal increase in mean salivary IgA during the winter months was observed and this increase correlated with an increase in respiratory infections. Hence, in studies of developmental aspects of mucosal immune response it is essential that modifiers such as season and infection be recorded.

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

<p>It is believed that many of the mechanisms present in the biological immune system are well suited for adoption to the field of computer intrusion detection, in the form of artificial immune systems. In this report mechanisms in the biological immune system are introduced, their parallels in artificial immune systems are presented, and how they may be applied to intrusion detection in a computer environment is discussed. An artificial immune system is designed, implemented and applied to detect intrusive behavior in real network data in a simulated network environment. The effect of costimulation and clonal proliferation combined with somatic hypermutation to perform affinity maturation of detectors in the artificial immune system is explored through experiments. An exact expression for the probability of a match between two randomly chosen strings using the r-contiguous matching rule is developed. The use of affinity maturation makes it possible to perform anomaly detection by using smaller sets of detectors with a high level of specificity while maintaining a high level of cover and diversity, which increases the number of true positives, while keeping a low level of false negatives.</p>

It is believed that many of the mechanisms present in the biological immune system are well suited for adoption to the field of computer intrusion detection, in the form of artificial immune systems. In this report mechanisms in the biological immune system are introduced, their parallels in artificial immune systems are presented, and how they may be applied to intrusion detection in a computer environment is discussed. An artificial immune system is designed, implemented and applied to detect intrusive behavior in real network data in a simulated network environment. The effect of costimulation and clonal proliferation combined with somatic hypermutation to perform affinity maturation of detectors in the artificial immune system is explored through experiments. An exact expression for the probability of a match between two randomly chosen strings using the r-contiguous matching rule is developed. The use of affinity maturation makes it possible to perform anomaly detection by using smaller sets of detectors with a high level of specificity while maintaining a high level of cover and diversity, which increases the number of true positives, while keeping a low level of false negatives.

Despite the development of novel target therapy drugs in recent years, metastatic cancer remains refractory to current cancer therapies and accounts for the majority of cancer mortalities worldwide. Metastasis consists of multiple steps including angiogenesis, extravasion, escape from immune surveillance, adhesion, and clonal expansion in different organs that a systemic therapy is required for effective control of metastasis. The pro-inflammatory nuclear factor kappa B (NF£eB) pathway plays an important role during each of these metastatic events and constitutes an excellent target for metastasis control. Stress hormone pro-opiomelanocortin (POMC) and its derived neuropeptides including corticotrophin (ACTH), £\-, £]-, and £^-melanocyte¡Vstimulating hormone (£\-, £]-, and £^-MSH), £]-endorphin are potent inhibitors of NF£eB pathway. Other than the central regulation of stress response and energy homeostasis, POMC also regulates the skin pigmentation, inflammatory processes, and immune reactions in the peripheral system. Since adenovirus¡Vmediated POMC gene delivery leads to hepatic POMC expression, it seems plausible that POMC gene therapy may elicit systemic production of anti-inflammatory POMC-derived peptides and hold promises for control of primary and metastatic cancers. In B16-F10 melanoma models, POMC gene delivery elevated the circulating ACTH levels for more than 8 weeks and suppressed the growth of established melanoma, thereby prolonging the life span of tumor-bearing mice. Moreover, combination of POMC therapy with cisplatin further enhances the survival outcome. Subsequent analysis reveals that POMC gene therapy inhibits the growth and metastasis of melanoma through apoptosis, angiogenesis inhibition, and modulation of epithelial-mesenchymal transition. Besides, £\-MSH/melanortin-1 receptor (MC-1R) pathway is involved in the POMC-mediated melanoma suppression. To investigate whether POMC therapy could be applied to other types of tumor, we evaluated the therapeutic efficacy of POMC gene therapy in Lewis lung carcinoma (LLC) cells which lack MC-1R. Interestingly, POMC gene delivery effectively inhibited the proliferation and colony formation of LLC cells in vitro and the growth of established LLC in mice. Histological analysis indicated that POMC gene delivery attenuated LLC through proliferation inhibition, apoptosis induction, and angiogenesis blockade. Moreover, POMC gene delivery perturbed £]-catenin signaling by reducing protein levels of £]-catenin and its downstream proto-oncogenes, including cyclin D1 and c-myc. These results support the existence of an MC-1R-independent pathway for POMC gene therapy and expand the therapeutic spectrum of POMC therapy for multiple types of cancer. To elucidate the role of host immunity in anti-neoplastic mechanism underlying POMC therapy, we compared the treatment efficacy of POMC gene therapy for B16-F10 melanoma between severe combined immune-deficient (SCID) and immune-competent C57BL/6 mice, and found similar extent of tumor suppression in both strains of mice. In addition, POMC gene therapy reduced the spleen weight and the number of circulating lymphocytes in B6 mice. These findings suggest that POMC therapy was not dependent on host immunity, yet instead induced immune suppression of animals through ACTH/cortisol production. To minimize such side effect of POMC therapy, we generated a series of adenovirus vectors encoding POMC with mutations in ACTH domain (ACTH-K15A/R17A), which fails to stimulate cortisol synthesis in vitro and in vivo. Gene delivery of ACTH (K15A/R17A) remained capable of suppressing the primary and metastatic melanoma, but had no effect on immune functions in mice. In conclusion, we have characterized the anti-neoplastic function and mechanism of POMC therapy for cancer. Furthermore, we have developed improved POMC gene vectors to minimize its adverse effect for future cancer therapy.

published_or_final_version / Industrial and Manufacturing Systems Engineering / Master / Master of Philosophy

Effective process scheduling is very important to the modern manufacturing production. This research addresses a classical scheduling problem — the job shop scheduling problem from the standpoint of both static and dynamic environment. In this study, the job shop scheduling problem (JSSP) is investigated in three aspects: (1) static JSSP that operates under a static scheduling environment with known information about the jobs and machines without unexpected events; (2) semi-dynamic JSSP which is developed based on static JSSP but violating the non-operation disruption assumption due to the presence of uncertainties occurring in the dynamic scheduling process; (3) dynamic online JSSP that operates under a dynamic operating environment in which jobs continuously arrive that are accompanied by unpredictable disruptions, such as machine failures. In the thesis, these three types of JSSP are solved by artificial immune systems (AIS) based algorithms. For static JSSP, a hybrid algorithm is proposed based on clonal selection theory and immune network theory of AIS, and particle swarm optimization (PSO). The clonal selection theory establishes the framework of the hybrid algorithm, while the immune network theory is applied to increase the diversity of antibody set which represents the solution candidates. The proposed framework involves the processes of selection, cloning, hypermutation, memory, and receptor editing. The PSO is designed to optimize the hypermutation process of the antibodies to accelerate the search procedure. This hybrid algorithm is tested with benchmark problems of different sizes and is compared with other methods. The results demonstrate the efficiency of the proposed algorithm, the effectiveness of PSO, and the contribution of long-lasting memory which is one of the key features of AIS. The semi-dynamic JSSP is handled by the rescheduling process. An extended deterministic dendritic cell algorithm (dDCA) is proposed to control the rescheduling process under considerations of the stability and efficiency of the scheduling system. The main role of the extended dDCA is to quantify the negative effect generated from the unexpected disturbances and to determine the best time to trigger the rescheduling process. This algorithm is tested on static benchmark problems with the existence of different kinds of disruptions. The experimental results demonstrate its capability of timely triggering the rescheduling process. The dynamic online JSSP is modeled as a multi-objective optimization problem. In this case, the immune network theory of AIS is hybridized with priority dispatching rules (PDRs) to establish the idiotypic network model for dispatching rules. This idiotypic network model drives the dispatching rule selection process under a dynamic scheduling environment. Based on the job shop situations represented by the antigens, the dispatching rules that perform best under specific conditions are selected as the antibodies of the idiotypic network model. Finally, the thesis proposes a generic framework of JSSP that combines the three different aspects studied in this research with corresponding scheduling strategies. The scheduling framework for a job shop system consists of four collaborating modules and is designed to solve various scheduling situations efficiently under a dynamic operating environment. / published_or_final_version / Industrial and Manufacturing Systems Engineering / Doctoral / Doctor of Philosophy

Chronic subclinical levels of disease occur frequently in intensive swine production and compromise nutrient utilization efficiency. Sulfur amino acids (methionine plus cysteine; M+C) have been implicated in improving the animal’s response to immune system stimulation (ISS). Research objectives were to determine the effects of ISS on the optimal dietary methionine to methionine plus cysteine ratio (M:M+C) and on the fractional synthesis rate (FSR) of albumin, fibrinogen and total protein in plasma, liver, and small intestine (SI) of growing pigs. A nitrogen balance study showed that the optimal M:M+C was increased during ISS and greater than 0.62. In a flooding dose infusion study it was determined that total plasma protein FSR was increased during ISS and tended to decrease with reduced M+C intake. Plasma albumin FSR decreased with reduced M+C intake. The data implicates M+C as important nutrients involved in the immune response and careful dietary supplementation during ISS is necessary. / Funding sponsored by Evonik Degussa, Ontario Pork, the Ontario Ministry of Agriculture, Food and Rural Affairs and the Natural Sciences and Engineering Research Council of Canada.

Human leukocyte antigen-G (HLA-G), a non-classical MHC I protein, plays an essential role in immune tolerance and is associated with a lower incidence of graft rejection and cardiac allograft vasculopathy (CAV). To examine the pattern of HLA-G expression post-transplantation we determined that HLA-G can be up-regulated in smooth muscle cells (SMCs) following exposure to everolimus. We also determined that HLA-G at 500 and 1000 ng/ml reduces SMC proliferation. In further studies, treatment with HLA-G inhibited TNFα-stimulated neutrophil adhesion to endothelial cells (ECs) at all concentrations tested (0.1-1 ng/ml), suggesting a role in inflammation. The expression of HLA-G is influenced by a polymorphism in the HLA-G gene. We sought to determine if the 14bp insertion/deletion polymorphism can predict the development of CAV. There was no association between this polymorphism and CAV; however, this study had a small number of patients; therefore further investigations are needed to confirm these findings.

Human leukocyte antigen-G (HLA-G), a non-classical MHC I protein, plays an essential role in immune tolerance and is associated with a lower incidence of graft rejection and cardiac allograft vasculopathy (CAV). To examine the pattern of HLA-G expression post-transplantation we determined that HLA-G can be up-regulated in smooth muscle cells (SMCs) following exposure to everolimus. We also determined that HLA-G at 500 and 1000 ng/ml reduces SMC proliferation. In further studies, treatment with HLA-G inhibited TNFα-stimulated neutrophil adhesion to endothelial cells (ECs) at all concentrations tested (0.1-1 ng/ml), suggesting a role in inflammation. The expression of HLA-G is influenced by a polymorphism in the HLA-G gene. We sought to determine if the 14bp insertion/deletion polymorphism can predict the development of CAV. There was no association between this polymorphism and CAV; however, this study had a small number of patients; therefore further investigations are needed to confirm these findings.