This thesis embodies much of my work done over the past 25 years. The impetus for these studies was the need to provide the best tissue typing available for organ transplantation and to overcome the problems of defining HLA antigens in different ethnic groups. These goals were achieved by extensive international collaboration and participation in the International Histocompatibility Workshops. The discovery that the HLA antigens are associated with many diseases led to an epidemic of investigations in which over 500 diseases have been studied. In retrospect, it is not surprising that auto-immune diseases such as diabetes and rheumatoid arthritis showed such marked associations with HLA antigens. The studies in Part II of this thesis were aimed at finding out if the HLA associations reported in Caucasian populations were also present in the Black and Indian populations. These research interests led to my being invited by the National Science Council of the Republic of China in Taiwan to be a Visiting Professor at the National Taiwan University in Taipei for the 1989 academic year. I investigated the association between HLA and naso-pharyngeal carcinoma in Chinese during that year. I wish to express my appreciation to Dr Peter Brain who inspired the early investigations and continued to encourage and support my research. I am grateful to all my co-authors and the many colleagues, clinicians and laboratory staff who have contributed to the various research programmes. Studies of the relationship of the HLA system to cancer, diabetes, arthritis and other diseases have been supported in part by grants from the National Cancer Association and the Medical Research Council of South Africa. / Thesis (D.Sc.)-University of Natal, Durban, 1992.

The natural history for patients with de novo donor-specific antibodies (dnDSA) and the risk factors for its development have not been well defined. Furthermore, clinical and histologic correlation with serologic data is limited. We studied 315 consecutive renal transplants without pre-transplant donor-specific antibody (DSA), with a mean follow-up of 6.2 ± 2.9 years. Protocol (n = 215) and for cause (n = 163) biopsies were analyzed. Solid phase assays were used to screen for dnDSA post-transplant. A total of 47 out of 315 (15%) patients developed dnDSA at a mean of 4.6 ± 3.0 years post-transplant. Independent predictors of dnDSA were HLA-DRβ1 MM > 0 (OR 5.66, p < 0.006); and non-adherence (OR 8.75, p < 0.001); with a strong trend toward clinical rejection episodes preceding dnDSA (OR 1.57 per rejection episode, p=0.061). The median 10-year graft survival for those with dnDSA was lower than the No dnDSA group (57% vs. 96%, p < 0.0001). Pathology consistent with antibody-mediated injury occurred and progressed in patients with dnDSA in the absence of graft dysfunction. Furthermore, non-adherence and cellular rejection contributed to both dnDSA development and the risk of progression to graft loss. (Human leukocyte antigen) HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA-DR/DQ/DP conformational epitopes for a subset of 286 donor–recipient pairs in which samples were available for high-resolution HLA-typing. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus-specific epitope mismatches were more numerous in patients who developed HLA-DR dnDSA alone (21.4 vs. 13.2, p<0.02) or HLA-DQ dnDSA alone (27.5 vs. 17.3, p<0.001). An optimal threshold for epitope mismatch (10 for HLA-DR, 17 for HLA-DQ) was defined that was associated with minimal development of Class II dnDSA using a receiver operating characteristic analysis. Applying these thresholds, 0% and 2.7% of patients developed dnDSA against HLA-DR and HLA-DQ, respectively, after a median of 6.9 years follow-up. Epitope specificity analysis revealed that 3 HLA-DR and 3 HLA-DQ epitopes were independent multivariate predictors of Class II dnDSA when mismatched between the donor and recipient. HLA-DR and DQ epitope matching outperforms traditional low-resolution antigen-based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long-term graft outcome.

Host factors can have important consequences for HIV risk and disease progression. Two separate projects relevant to Aboriginal populations in Manitoba were undertaken. The Solvent Use Project investigated solvent use in Winnipeg through an interdisciplinary multi-phase approach that integrated community based research and basic science. From interviews with solvent users and key informants we learned that solvent users experience many health and social disparities. We demonstrated that there is support within the community to work with solvent users and study solvent use further. The HLA-B*35 Project aimed to identify the diversity of HLA-B*35 allele subtypes, in HIV+ patients that presented to care between 2007 and 2010 in Manitoba. We observed 11 distinct HLA-B*35 allele subtypes. Case studies reflected the overrepresentation of Aboriginal people infected with HIV in Manitoba, and the pressing issues of either late presentation to care or rapid disease progression within patients who are HLA B*35.

Tübingen, Univ., Diss., 2008.

Thesis (M. Phil.)--University of Hong Kong, 1997. / Includes bibliographical references (leaf 118-137).

Ulm, Univ. Diss., 2007.

Thesis (doctoral)--University of Uppsala, 1980. / Includes bibliographical references (p. 33-41).

Thesis (Ph. D.)--University of St Andrews, February 2009. / Restricted until 23rd February 2012.

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2006. / On t.p. "+" is superscript. Includes bibliographical references (leaves 107-131). Also available in electronic version.

In combating variable pathogens, mammalian immune systems have evolved diverse families of ligands and receptors. Epitomizing this strategy are the polymorphic major histocompatibility complex class I genes (termed HLA class I in humans) that encode ligands for highly variable natural killer (NK) cell receptors (in humans, the killer cell immunoglobulin-like receptors or KIR). Technological advances are poised to allow sequencing of these polymorphic genes, the most variable in the human genome, at the highest possible accuracy and resolution. However, studies that correlate immunogenetic polymorphisms with functional changes are in their infancy and often limited to those variants that combine high ligand avidity and high frequency in Caucasians. As a result, there is a paucity of information regarding the true scope of functional human immunogenetic diversity. This not only restricts our understanding of the evolution and function of the human immune system, but also underserves non-Caucasian populations with respect to disease association studies and therapeutic advances. The work presented in this thesis details original research and methodological advances that begin to address these functional shortfalls, the goal being to improve our understanding of the relationship between immunogenetic diversity, protein structure and immune function.