Featured on CTV News, our very own, Matthew Miller talks about the progress in developing a universal vaccine!
Chronic cigarette smoke exposure is known to damage pulmonary lipids, resulting in innate inflammatory responses. Cigarette smoke is also known to activate the adaptive immune system, however, the role of these adaptive immune processes has yet to be fully understood. A study by Danya Thayaparan, a Masters student from Dr. Stampfli’s lab, reports a link between damaged lipids and the production of autoantibodies. Thayaparan et al. showed, using a mouse model, that chronic exposure to cigarette smoke led to the induction of antibodies against oxidized low-density lipoproteins (OxLDL). To examine the potential function of autoantibodies against OxLDL, they used a monoclonal antibody against oxidized phosphatidylcholine (OxPC), the most prevalent phospholipid in lung surfactant. Overall, they found that antibodies against OxPC do not exacerbate cigarette smoke-induced inflammation, and instead, promote lipid and particle uptake by pulmonary macrophages, even after smoking cessation. Altogether, this study suggests a protective function for autoantibodies induced by chronic cigarette smoke exposure. Read more here.
Although NK cells are known to play a critical role in protecting against the development of cancer, NK cells become dysfunction due to the tumor microenvironment. The mechanisms by which the local tumor environment inhibits NK cell function are not well described. A study by Dr. Ali Ashkar’s group examining the interactions between the tumor microenvironment and murine NK cells recently reported that both M2-polarized macrophages and tumor-associated macrophages (TAMs) inhibit NK cell expression and cytotoxicity in a contact-dependent manner. Furthermore, they showed that the suppressive effective of these macrophages was due to TGF-β. This study presents a novel method to describe macrophage-mediated regulation of NK cells in a tumor.
Pulmonary tuberculosis (TB) caused by Mycobacterium Tuberculosis, is one of the leading causes of global morbidity and mortality, and one of the primary reasons for the deathly nature of this infection is the absence of an effective vaccine. Although there are numerous candidate TB vaccines being tested, the ability of these vaccines to improve protection by inducing clinically relevant protective T cell responses is largely unknown until the completion of expensive efficacy trails. As such, not only is there an urgent need to develop effective vaccination strategies, there is also a pressing need to develop alternative approaches to evaluate the protective potential of vaccine candidates. This can save a lot of valuable time and money. Interestingly, Dr. Zhou Xing’s lab has developed a systematic immunological approach to investigate the protective potential of a novel TB vaccine. In the newly published study directed by Dr. Mathy Jeyanathan, PBMC’s cryopreserved from healthy adults who had been vaccinated intramuscularly with a novel TB vaccine in a previous phase I study were used to screen for likely dominant T cell epitopes following vaccination. Next, Jeyanthan et al. expanded antigen-specific memory T cell lines to identify CD4 and CD8 memory T cell epitopes, and found that immunization with the vaccine in question resulted in the generation of a memory T cell repertoire capable of recognizing multiple epitopes. Furthermore, the epitope-specific memory T cells were polyfunctional and cytotoxic, and able to suppress mycobacterial growth in infected cells. Based on this approach, the study recommended that the candidate TB vaccine in question should undergo further development. Most importantly, Jeyanthan et al. have created an approach that can be incorporated into future early TB vaccine trails and can be used to greatly assist in TB vaccine development. Read more here.
Humanized mouse models, where human tissues are housed in the background of a mouse, allow researchers to directly examine human cells in a biological system. Development of this model has enabled the study of human-specific pathogens, and has considerably expanded the ability to conduct mechanistic, basic science research. MIRC members are fortunate to have access to humanized mice, thanks to the work being done in Dr. Ali Ashkar’s lab. A recent paper from Dr. Ali Ashkar’s research group provides greater detail about their highly regarded humanized mouse model. They compared two different methods of human stem cell engraftment, were mice were engrafted with human cord blood intravenously as adults or intrahepatically as newborns. They found that mice engrafted as newborns initially had higher levels of human CD3+ T cells and lower levels of human B cells in the blood. However, levels of human CD45 cells were comparable long-term in both adult and newborn mice, suggesting there is very little difference in human immune cell reconstitution between the two methods. When looking at reconstitution in different immunological tissues, they found significant levels of human immune cell reconstitution in all sites, including mesenteric lymph nodes and the liver. This is an interesting finding, as not much has been shown about the reconstitution of lymph nodes and the liver. Furthermore, this study suggests that this humanized mouse model can be used as a relevant pre-clinical model to study the human immune system in the gastrointestinal tract.
IL-33, known to play a role in both innate and adaptive immune responses, has been suggested to be involved in inflammatory lung disease, as IL-33 influences Th2-skewed immune functions in allergic responses. Evidently, elevated levels of IL-33 are found in mouse models of allergic airway disease and in chronic human lung conditions such as severe asthma. Similarly, the gp130 cytokine Oncostatin M (OSM) is also known to be elevated in cases of severe asthma. However, the link between OSM and IL-33 remained largely unknown until a recent study out of Dr. Carl Richard’s lab suggesting a novel OSM-IL-33 axis in lung tissue cells. Led by Dr. Fernando Botelho, the study provides evidence for a novel method of IL-33 regulation in murine lung epithelial cells mediated by OSM. Using an in vivo mouse model and cell-culture techniques, they found that transient overexpression of OSM resulted in significantly increased induction of IL-33 in the lung, specifically in alveolar epithelial cells. In addition, IL-33 induction was associated with the activation of STAT3 and inhibition of STAT3 reduced IL-33 levels, suggesting a role for STAT3 activation in OSM-mediated regulation of IL-33. This study demonstrates a new role for OSM as a potent inducer of IL-33 in mouse lung epithelial cells, suggesting an additional mechanism for IL-33 regulation in innate immunity and pulmonary pathology. Read more here.
Culture systems that model host-pathogen interactions in the vaginal mucosal epithelium have certain limitations in accurately mimicking in vivo conditions. Yung Lee, an undergraduate student in Dr. Charu Kaushic’s lab, recently published his first paper where he used an improved model to study the effects of female sex hormones on susceptibility to HSV-2 infection. Typically, a liquid-liquid interface (LLI) cell culture model, where both the apical and basolateral surfaces are submerged in growth medium, is used, however, this model is limited in its capacity to simulate physiological conditions. In the current study, immortalized vaginal cells were grown in an air-liquid interface (ALI), more closely simulating the in vivo conditions of the female reproductive tract. The vaginal cells grown in both LLI and ALI models were compared in regards to their growth, differentiation and susceptibility to HSV-2. Additionally, the effects of female sex hormones progesterone (P4) and estrogen (E2) were also examined. Lee et al. found that in comparison to LLI conditions, the ALI model induced cells to grow into multi-layers, which better resembles vaginal cells in vivo. They then used the ALI model to assess the effect of hormones and found that in the presence of P4, cells were more susceptible to HSV-2 infection. This is consistent with many studies showing that P4 can increase susceptibility to sexually transmitted infections. Overall, these results suggest an alternative model for studying host-pathogen interactions that is more physiological relevant to in vivo conditions of the female reproductive tract. Read more here.
Join us today to watch our very own, Dr. Dawn Bowdish, as she gives a presentation on inflammation, infections and the immune system on September 10th starting at 8 pm in EAC. The presentation is sponsored by Hamilton Association for the Advancement of Literature, Science and Art.
Recently, Matthew Miller's group in collaboration with Dr. Caitlin Mullarkey and a PhD candidate, Wengqian He have looked at the critical role of epitope specificity in regulating cell mediated cytotoxicity against influenza A virus. In addition to neutralizing antigens, antibodies are also capable of stimulating cellular responses through Fc–Fc receptor interactions. The type of response stimulated by these interactions is influenced by both the Fc receptor type expressed on the effector cell and the isotype of antibody to which it is bound. However, how antibody specificity influences Fc receptor functions, and how antibodies of different specificities interact to modulate these functions, remain unknown. Using influenza A virus as a model, we demonstrate that antibody specificity profoundly influences the induction of antibody-dependent cell-mediated cytotoxicity by effector cells. In addition, we show that interactions among antibodies that bind to discrete epitopes on the same antigen can influence the induction of Fc-dependent effector functions. Read more here.
Congratulations to Matthew Miller for being awarded the 2015 - 2016 CIHR New Investigator Award!