The long range goal of this study is to improve treatment of allergic asthma by developing new methods of tolerizing the immune response toward allergens. Environmental exposure to allergens is ubiquitous, yet most individuals do not develop clinical asthma. Many studies have shown that the most important cell population in the pathogenesis of asthma are the CD4+ T helper (Th) lymphocytes, which play a central role in immune activation. The Th cell-driven development of asthma in an individual suggests that the mechanisms that normally control immune responses against allergens have been overwhelmed. Several lines of evidence from mouse models and epidemiological studies suggest that enhancing immune regulation of Th cells has therapeutic effects in asthma. A significant challenge remains in developing the means to translate these findings into clinical use. The goals of the current project will be to assess the therapeutic capacity of a naturally occurring subset of B lymphocytes. These killer/regulatory B cells may induce cell death of Th cells through direct cell-cell contact or through release of exosomes. The study will measure the effects of exosome transfer on Th cell death and allergen tolerance, and will test a novel method of targeting antigens specifically to the killer/regulatory B cell subset. We hypothesize that enhancing immune regulation through manipulation of killer/regulatory B cells will lead to reduction or elimination of effector Th cells and long-term suppression of allergic asthma. The following specific aims are proposed:
Aim 1 : Test the therapeutic capacity of B cell-derived, FasL+ killer exosomes in a TH cell- mediated asthma model.
Aim 2 : Engineer and test the efficacy of interbilayer-crosslinked multilamellar vesicles to deliver antigen and immune response modifiers to lung CD5+/FasL+ killer/regulatory B lymphocytes. This project leverages the specific expertise of the study team members in the understanding of killer/regulatory B cell activation and function, and improved methods of targeting specific cell types using nanotechnology. The knowledge gained from these studies will have direct application to the design and testing of novel therapeutics for patients with allergic asthma.
Poor immune suppression is thought to be a major contributor to the development and severity of allergic asthma. A subset of cells in the immune system known as killer/regulatory B cells has only recently been discovered to suppress immune responses. Killer/regulatory B cells have the ability to induce death of specific subsets of target cells known as T helper cells, which are responsible for directing inflammation in asthma. Mice with a genetic mutation that caused a deficiency of killer/regulatory B cells in the lung showed decreased death of lung T helper lymphocytes and increased severity of many aspects of allergic asthma. The goals of the current proposal are to manipulate the normal activities of killer/regulatory B cells in order to prevent or suppress asthma in the mouse model. These studies are expected to yield new information about the potential for killer/regulatory B cells to treat asthma and to test novel methods of safely targeting treatments toward these cells in humans.
| Wu, Qi; Wang, Qin; Mao, Guangmei et al. (2017) Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients. J Immunol 198:3069-3080 |
