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Screening for HLA specific antibodies is an important part of laboratory testing for transplantation. The conventional technique for screening is complement dependent lymphocytotoxicity. The development and increasing use of the sensitive flow cytometric crossmatch technique has meant that this conventional screening method is often less sensitive than the final crossmatch. The aim of this study was the development of a flow cytometric screening technique which would be as sensitive as the flow cytometric crossmatch and the investigation of the newly developed ELISA screening method PRA-STAT. These methods were used to investigate antibody production in patients with failed transplants. Flow cytometric analysis of antibody binding to pooled cells was found to be a reliable and sensitive method for the detection of HLA class I and class II specific antibodies. PRA-STAT also detects both class I and class II specific antibodies. Both flow cytometric and PRA-STAT screening methods were shown to be more sensitive than conventional cytotoxic screening. Screening of patients with failed transplants by these sensitive methods showed that the majority of patients produce both HLA class I and class II donor specific antibodies following failure of a primary transplant. Flow cytometric and PRA-STAT screening detected antibody production earlier than cytotoxic screening in some patients. HLA matching was shown to be related to both graft survival and to the levels of antibody produced following graft failure with poorly matched grafts resulting in higher levels of sensitisation than well matched grafts. Patients with detectable post graft failure antibodies had a lower chance of receiving a second transplant and had significantly worse regraft survival than patients with no antibody. The results of the study suggest that HLA class II specific antibodies and repeat class II mismatches may be detrimental in regrafts and this requires further study.

The long-term success of lung transplantation has been challenged by chronic graft dysfunction, which is manifested as obliterative bronchiolitis (OB). We demonstrated that allograft airway fibrosis is a dynamic process of tissue remodelling, in which cellular and matrix components dynamically change before or after complete obliteration of the airway lumen. This dynamic process was associated with changes in expression and activity of matrix metalloproteinases (MMPs). The early inflammatory phase was associated with MMP-dependent migration of blood-borne fibrocytes, which highly express MMP-9 and MMP-12. ‘Established’ fibrosis was associated with MMP-2 and MMP-14 expressed by myofibroblasts in both human OB lesions and their animal models. In established allograft airway fibrosis, general MMP inhibition resulted in apoptosis of myofibroblasts in vivo and in vitro, while low-doses of MMP-inhibitor treatment induced upregulation of MMP-2, increased collagenolytic activity, and significantly decreased myofibroblasts and collagen. The dynamic process of tissue remodelling in established allograft airway fibrosis was supported by underlying continuous alloimmune responses, in particular, direct T-cell-myofibroblast contact. iii Modulation of tissue remodelling using a low-dose MMP inhibitor in combination with cyclosporine induced partial regression of fibrosis after its establishment. We further demonstrated the mechanism of alloimmune responses unique to the lung. Human and animal studies demonstrated that bronchioles develop de novo lymphoid tissue characterized by formation of high endothelial venules and homing of effector memory T-cells. A following study demonstrated the important role of local immunological memory maintained by the intrapulmonary lymphoid tissue in exerting effector function in allograft rejection. Collectively, the present studies support the hypothesis that tissue remodelling is an important mechanism of allograft airway fibrosis. Regulation of tissue remodelling and underlying tissue injury is important not only to arrest aberrant remodelling of allograft airways but likely to reverse aberrant remodelling and to regenerate normal tissue architecture in airways after lung transplantation.

The long-term success of lung transplantation has been challenged by chronic graft dysfunction, which is manifested as obliterative bronchiolitis (OB). We demonstrated that allograft airway fibrosis is a dynamic process of tissue remodelling, in which cellular and matrix components dynamically change before or after complete obliteration of the airway lumen. This dynamic process was associated with changes in expression and activity of matrix metalloproteinases (MMPs). The early inflammatory phase was associated with MMP-dependent migration of blood-borne fibrocytes, which highly express MMP-9 and MMP-12. ‘Established’ fibrosis was associated with MMP-2 and MMP-14 expressed by myofibroblasts in both human OB lesions and their animal models. In established allograft airway fibrosis, general MMP inhibition resulted in apoptosis of myofibroblasts in vivo and in vitro, while low-doses of MMP-inhibitor treatment induced upregulation of MMP-2, increased collagenolytic activity, and significantly decreased myofibroblasts and collagen. The dynamic process of tissue remodelling in established allograft airway fibrosis was supported by underlying continuous alloimmune responses, in particular, direct T-cell-myofibroblast contact. iii Modulation of tissue remodelling using a low-dose MMP inhibitor in combination with cyclosporine induced partial regression of fibrosis after its establishment. We further demonstrated the mechanism of alloimmune responses unique to the lung. Human and animal studies demonstrated that bronchioles develop de novo lymphoid tissue characterized by formation of high endothelial venules and homing of effector memory T-cells. A following study demonstrated the important role of local immunological memory maintained by the intrapulmonary lymphoid tissue in exerting effector function in allograft rejection. Collectively, the present studies support the hypothesis that tissue remodelling is an important mechanism of allograft airway fibrosis. Regulation of tissue remodelling and underlying tissue injury is important not only to arrest aberrant remodelling of allograft airways but likely to reverse aberrant remodelling and to regenerate normal tissue architecture in airways after lung transplantation.

Fluorescence enhanced optical imaging and tomography studies involve the detection of weak fluorescent signals emanating from nano- to picomolar concentrations of exogenous or endogenously produced fluorophore concurrent with the rejection of an overwhelmingly large component of backscattered excitation light. The elimination of the back-reflected excitation light of the collected signal remains a major and often unrecognized challenge for further reducing the noise floor and increasing sensitivity of small animal fluorescence imaging. In this dissertation, we adapted collimating and gradient index (GRIN) lenses in an existing frequency-domain system to improve excitation light rejection and enhance planar and tomographic imaging. To achieve this goal, we developed planar and tomographic imaging systems based upon ray tracing calculations for improved rejection of excitation light. The “out-of-band (S (λx))” to “in-band (S (λm) - S (λx))” signal ratio assessing excitation leakage was acquired with and without collimating optics. The addition of collimating optics resulted in a 51 to 75% reduction in the transmission ratio of (S (λx))/ (S (λm) - S (λx)) for the phantom studies and an increase of target to background ratio (TBR) from 11% to 31% in animal studies. Additionally, we presented results demonstrating the improvement of model match between experiments and forward simulation models by adaptation of GRIN lens optics to a breast phantom study. In particular, 128 GRIN lenses on the fiber bundle face were employed to align the collected excitation and emission light normal to the filter surface in an existing frequency-domain system. As a result of GRIN lens collimation, we reduced the transmission ratio between 10 and 86 % and improved the model match for tomographic reconstruction of one (1 cm3) and two (0.1 cm3) targets in a 1087 cm3 of breast phantom. Ultimately, this work improves the sensitivity of NIR fluorescence imaging by enhancing the rejection of excitation light and shows that the current sensitivity challenges for translating fluorescence-enhanced optical imaging into the clinic can be overcome.

The purpose of this research program was to examine how attachment anxiety and rejection interact to influence intentions and attitudes toward having unprotected sexual intercourse. I hypothesized that women who were high in attachment anxiety would hold weaker intentions to use a condom and would have more negative attitudes toward condoms than would women who were low in attachment anxiety. Moreover, I predicted that these expected main effects of anxiety on intentions and attitudes would interact with rejection, such that the association between high anxiety and both weak intentions and negative attitudes would be exacerbated among women that were exposed to a rejection-salient condition. I explored the interaction of interest in the context of specific romantic partner rejection (Study One) as well as general social rejection from peers (Study Two). In Study One, I manipulated potential partner rejection and found that attachment anxiety and rejection condition interacted to influence intentions to engage in unprotected sex. In the rejection condition, attachment anxiety was marginally positively related to intentions whereas in the non-rejection condition, attachment anxiety was marginally negatively related to intentions. Upon further investigation of this same interaction, I found that among women who were high in attachment anxiety, rejection condition did not significantly impact intention ratings. However, among women who were low in attachment anxiety, those who were rejected reported significantly weaker intentions to engage in unprotected sex than those who were not rejected. Attitudes toward condoms were not influenced by the interaction between attachment anxiety and rejection condition. In Study Two, I manipulated general social rejection and found that the intentions results from Study One were not replicated, as general social rejection and attachment anxiety did not interact to influence intentions to engage in unprotected sex. Once again, attitudes toward condoms were not influenced by this interaction. Explanations for the findings of Study One and Study Two are explored and implications of both studies’ findings for the literature on condom use and for sexual health promotion are discussed. / Thesis (Master, Psychology) -- Queen's University, 2009-08-18 11:55:36.243

Self-esteem involves a variety of cognitive processes that help people perceive, interpret, and process social information. A central component of people's self-esteem is their sense of belonging and feelings of acceptance. It follows that people react strongly to social rejection and that being attuned to signs of real or potential social rejection can serve a self-protection function. However, being overly attuned and sensitive to social rejection can have a paradoxical effect, whereby aberrant attentional processes can contribute to the perpetuation of the vicious cycle of low self-esteem. The goal of the research presented in this dissertation was twofold: to investigate whether people with low self-esteem are more vigilant for rejection information, and to investigate whether a rejection-inhibiting attentional training task that reduces their vigilance for rejection can help buffer against social and performance threats. I hypothesized that people with low self-esteem are more vigilant for rejection information than for acceptance information. I also hypothesized that training people, particularly those with low self-esteem, to inhibit and disengage from rejection promotes effective regulation of emotions and has positive psychological, behavioural, and physiological effects. Results from the first study show that people with low self-esteem have a greater attentional bias for rejection than for acceptance information. Across 7 other studies, participants with low self-esteem trained to inhibit rejection with a specially designed attentional training task showed a lower rejection bias for rejection information, less feelings of rejection after overt rejection, and less ineffective persistence. Regardless of level of self-esteem, participants trained to inhibit rejection showed less interfering thoughts about rejection while working on a task, higher state self-esteem after having been rejected and experiencing failure, less stress about their final exam, increases in self-esteem and decreases in perceived stress after a stressful work week, lower levels of cortisol, and increases in sales performance. Following a vicious cycle framework of low self-esteem and social stress, these results show that attentional bias training can circumvent the experience of social stress and possibly break the vicious cycle of low self-esteem.