Statement of Research Interests
My research has focused on changes in the immune system during infectious diseases, particularly on the development of memory cells during parasitic infection. I am also interested in the development of tolerance as regulated by dendritic cells.
1.) During my doctoral research, I examined the role of costimulatory molecules during the development of memory immune responses. Using mice genetically deficient for the costimulatory molecules B7-1 and B7-2, CD28, or OX40 Ligand (OX40L) our studies suggested that development of memory CD4+ T cells could occur in the absence of B7-1 and B7-2, or CD28, while OX40L interactions played a preferential role in development of Interleukin (IL)-4-producing CD4+ T cells. These studies also suggested that a host-protective memory response could develop in the absence of a primary response, such as occurs in the absence of both B7-1 and B7-2. This suggested that blocking B7-1/B7-2 costimulation might be particularly effective in the treatment of chronic diseases (such as psoriasis) where continuous renewal of effector populations from naïve precursor T cells mediates pathogenesis (Ekkens MJ et al, 2002; Ekkens MJ et al, 2003).
2.) My post-doctoral studies focused on the role of CD4 help during the priming of CD8+ T cells. When I began these studies, there had been no careful examination of whether T helper (Th) 1 or Th2 polarized CD4+ T cells were equally as capable of providing help for priming of CD8+ T cell responses, although CD8+ T cells provide an indispensable arm of the immune system for fighting many types of intracellular infection. The data from these studies suggested that both Th1 and Th2 CD4+ T cells were able to provide help while priming CD8+ T cell primary and memory immune responses. Additionally, the help provided by CD4+ T cells was independent of attributes acquired as a response to polarization. By broadening our understanding of the factors required for the development of effective CD8+ T cell responses, these studies enhanced our ability to design vaccines against intracellular pathogens or tumors (Ekkens MJ et al, 2007).
3. My current research interests are focused on the roles of dendritic cells (DC) and costimulatory molecules during the development of memory T cells. I am particularly interested in how the immune system makes the decision between tolerance and immunity. Previous studies have suggested a role for different DC subsets in priming tolerance versus protection. However, other studies have suggested a role for costimulatory molecules, such as CD40/CD40L interactions, or T cell receptor signaling.
To address the question of how DC make the decision between tolerance versus immunity, I will utilize a model of tolerance induction, in which murine DC are used to prime for tolerance, and the immune response is then challenged in the footpad to allow examination of a local (popliteal lymph node), and systemic (splenic), immune response. Preliminary experiments in the laboratory of Ed Pearce at the University of Pennsylvania, suggested that priming with DC lacking the costimulatory molecule CD40, was sufficient to induce tolerance. However, further studies suggested that in fact CD40-deficient DC were failing to induce a primary immune response, rather than inducing tolerance. If CD40-deficient DC are not inducing tolerance, this would provide a model to examine the unresponsive state of immune cells. However, if CD40-deficient DC are able to induce tolerance, this would provide a flexible model to examine the induction of tolerance. Either result will contribute to the understanding of how DC make decisions during infectious diseases, as well as during diseases where peripheral tolerance has been broken.
Please note – references cited are cross-listed in the C.V.