<p>In spite of the tremendous body of cancer research, cancer remains a significant health issue requiring development of better therapeutics. The elucidation of the relationship between cancer and the immune system and the identification of tumour associated antigens together suggest that novel therapeutics using the immune system to target cancer is a promising avenue of research. Since immunological tolerance is a barrier to generating immune responses to self antigen, strategies to circumvent tolerance need to be investigated to target given antigens.</p> <p>Plac1 is a novel tumour associated antigen with expression restricted to placenta, testis and many tumour cells. Initial reports concerning the expression, immunogenicity and potential tumourigenic function of Plac1 suggest that it would be an ideal tumour antigen. Initial experiments in mice indicated that generating an immune response against the murine Plac1 would be difficult and the subsequent work sought to employ strategies to facilitate anti murine Plac1 immune responses and anti tumour efficacy in Plac1 expressing tumours.</p> <p>Another more studied tumour associated antigen is gp100. Unlike Plac1, immune responses against the murine gp100 can be generated through vaccination. These responses are unable to demonstrate any anti tumour activity in gp100 expressing cells. The bulk of the gp100 studies described here sought to modify the immune:tumour interaction such that the anti tumour activity of the anti gp100 responses could be improved.</p> <p>While the specific barriers to Plac1 vaccination and efficacy and gp100 vaccination and efficacy are different, they have in common that they represent likely issues in using therapeutic cancer vaccines clinically. In both cases investigating how these barriers can be overcome is important and relevant to the understanding of these barriers to success when they appear in the clinic.</p>

by Li Wen. / "April 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 200-236). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

by Tam Chi Hang, Frankie. / "August 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 162-174). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Clostridium sordellii infections cause gangrene and edema in humans and gastrointestinal infections in livestock. The two principle virulence factors, TcsH and TcsL, are highly homologous to C. difficile TcdA and TcdB, respectively. Experiments to compare the effects of TcsH and TcsL to TcdA and TcdB show that TcsH induces necrotic cell death similarly to TcdB while TcsL induces apoptotic cell death. Further work focuses on TcsL, which has two enzymatic domains, an N-terminal glucosyltransferase domain (GTD) and an autoprocessing domain responsible for release of the GTD within the cell. The GTD can then use its N-terminal membrane localization domain (MLD) for orientation on membranes and modification of GTPases. The use of conditionally immortalized murine pulmonary microvascular endothelial cells provides a model for the study of TcsL functional activities. Point mutations that disrupt the glucosyltransferase, autoprocessing, or membrane localization activities are introduced into a recombinant version of TcsL, and the activities of these mutants are compared to those of wild-type toxin. All mutants are defective or impaired in cytotoxicity but differ in their modification of Rac1 and Ras. The data suggest a model where differences in GTPase localization dictate cellular responses to intoxication and highlight the importance of autoprocessing in the function of TcsL.

Obesity is a serious health issue in the United States as well as worldwide and contributes to several other disorders such as cardiovascular diseases, type II diabetes and asthma. However, the impact of obesity on immune responses to infections is poorly understood. During the last decade, specifically after the 2009 H1N1 strain influenza pandemic, evidence has emerged that obesity increases the risk and worsens the outcome for infection by influenza A virus (IAV). Obese individuals were hospitalized at a higher rate compared to their lean counterparts, had longer hospitalization times, responded poorly to vaccination and had increased mortality. Host protection and clearance of respiratory pathogens like IAV require robust pulmonary immune responses. Since alveolar macrophages (AM) are the first line of defense against respiratory pathogens, we hypothesized that obesity-associated alterations in AM functions worsen IAV infection outcomes. To test this hypothesis I fed C57BL/6 mice with a low-fat or high-fat diet for different time periods and infected these animals with an H1N1 laboratory strain of IAV (PR/8). Mice on the high-fat diet (obese mice) showed increased morbidity and mortality upon infection as compared with mice on the low-fat diet (lean mice). I also found that obesity induces changes in overall lung cellularity, AM polarization and phagocytic ability, and alterations in the level of surface proteins such as Gal-3, MHC-II, Tim-3, and cytokines such as IL-6, TNF-?, IFN-? and IL-10 in the lung. These obesity-induced changes in AM may contribute to impaired immune responses during IAV infection, resulting in worsened outcomes.

Achieving transplant tolerance in the autoimmune environment will require targeting multiple immunologic dysregulations in T-B lymphocyte collaboration that drive the aggressive anti-graft response. At a biologic level, my findings reveal the necessity of overcoming B lymphocyte mediated restriction of CD4 Treg function, failed HSC mobilization, and enhanced T cell metabolism in achieving transplant tolerance in murine models of Type 1 Diabetes (T1D) and Systemic Lupus Erythematosus (SLE). At a cellular level, my dissertation demonstrates that specific failures in CD4 and CD8 Treg mediated suppression of the effector cell response in autoimmune T1D and SLE contributes to a generalized resistance to transplant tolerance observed in these strains. Overall, identification of and surmounting the key dysregulations in T-B cell collaboration that permit loss of tolerance in autoimmunity will advance the clinical potential of transplantation as a cure for autoimmune disease.

Seasonal influenza remains a worldwide health concern and recently, the novel avian influenza virus, H5N1, has infected and caused disease in humans, though the virus is not currently capable of human-to-human transmission. Since 2003, 850 human cases of the novel influenza virus H5N1 have been reported with a 50% mortality rate. Recently two labs have shown, very few mutations may be necessary for efficient transmission between humans. In order to examine the immune response to H5N1, a panel of antibodies from subjects in a phase I clinical trial of an experimental H5N1 vaccine were isolated and characterized. We choose a potent and specific anti-H5N1 antibody, H5.3, for further studies in order to determine the molecular mechanism of neutralization used by H5.3 and how the antibody developed. The structure of the H5.3 Fab in complex with the H5 head domain showed H5.3 interacts with the highly conserved receptor binding site and polymorphic residues on the edges of the interface, indicating breadth and potency of the antibody conflict due to variability outside the receptor-binding site. As evidenced by the structures of the H5.3 Fab in complex with H5 respiratory droplet transmissible variants, the receptor preference of the virus may not be critically important for recognition by a receptor binding site directed antibody. The H5N1 vaccine elicited a primarily naïve antibody response, as the H5-specific antibodies had a lower number of somatic mutations than the broadly neutralizing influenza antibodies. The H5.3 somatic mutations do not stabilize the protein conformation, as it remains flexibility after affinity maturation, and do not have a large effect on increasing the affinity of H5.3 for H5. Overall, this research will contribute to influenza vaccine design.

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