Project 1 - Targeting tissue tropic effector T cells
The efficient localization of effector T cells to sites of infection and tumor growth is critical to the development of a protective adaptive immune response. However dysregulated accumulation of T cells at sites of inflammation is thought, at least in part, to underlie the induction and maintenance of chronic inflammatory disorders such as Inflammatory Bowel Disease, rheumatoid arthritis and psoriasis. Effector T cell subsets display tropism for different tissues, a process that is regulated by their selective expression of cell adhesion molecules and chemokine receptors. The objective of the current proposal is to define the mechanisms regulating the generation of tissue tropic effector T cell subsets and to identify candidate targets for modulating this process. Key Aims include:(1) To identify dendritic cell (DC) derived molecules responsible for the generation of tissue tropic effector T cell subsets; (2) To identify the environmental factors that imprint DCs with the ability to generate tissue tropic effector T cell subsets; (3) To identify and characterize novel homing molecules required for effector T cell tropism to intestinal and non-intestinal effector sites. By providing insights into the generation of tissue specific immunity, the program aims to identify novel therapeutic opportunities for the treatment of chronic inflammatory disease, and for enhancing the efficacy of vaccination regimes and anti-tumor therapies.
(Image 1) CD103+ Dendritic cells (DCs) in the mesenteric lymph nodes. Blue (DAPI), cell nuclei: Green, CD103: Red, CD11c: Yellow, CD103+CD11c+ DCs
(Image 2) CD103+ Dendritic cells (DCs) in the small intestinal lamina propria. Blue(DAPI), cell nuclei: Green, CD103: Red, CD11c: Yellow, CD103+CD11c+ DCs
Project 2 - Bacterial:Epithelial cross-talk and the establishment of the mucosal immune system
The intestinal mucosa contains under basal conditions a large number of leukocytes including dendritic cells, macrophages, T and B lymphocytes as well as small populations of neutrophils, mast cells and eosinophils. Together these leukocyte populations play a critical role in mucosal innate and acquired immune defense and in maintaining intestinal barrier function. The intestinal microflora is thought to play a central role in the establishment of intestinal leukocyte populations but in addition is clearly involved in driving dysregulated leukocyte responses in experimental models of Inflammatory Bowel Disease. Thus, the normal microflora play a dual role in intestinal immunity: Firstly, in the establishment and maintenance of a protective intestinal immune compartment and secondly, in driving immune dysregulated responses leading ultimately to intestinal inflammation.
The aim of the current proposal is to examine the role of bacterial-epithelial cell interactions in the establishment and modulation of intestinal leukocyte populations important for mucosal immune defense. We will examine the responses of mucosal epithelial cells to bacteria in vivo and the importance of this interaction in leukocyte subset recruitment to the intestinal mucosa. Finally, we aim to determine the molecular mechanisms controlling leukocyte subset recruitment to the intestinal mucosa in response to bacterial colonization/infection. In this way we hope to identify novel targets for modulating intestinal immune responses and for the treatment of acute and chronic intestinal disease.
Project 3 - To determine the role of CCR9/CCL25 in lymphocyte development and function
The intestinal mucosa contains a large population of previously activated/memory T cells that are key players in the generation of effective mucosal immune responses. We have demonstrated an important role for the chemokine receptor/chemokine pair CCR9/CCL25 in T lymphocyte recruitment to the intestinal mucosa. The Aims of this project includes (1) To determine the conditions of CCR9 dependent/independent lymphocyte recruitment to the intestinal mucosa. (2) To determine the role of CCR9 in myeloid/lymphoid development. These studies will enhance our understanding of the role of CCR9 and its chemokine ligand CCL25 in vivo and determine the potential of these molecules as targets for regulating mucosal immune responses.
Project 4 - The role of chemokine/chemokine receptors in colon cancer
Chemokines and their receptors play a central role in regulating the selective trafficking of lymphocyte subsets to specific tissue locations. In addition, these molecules have recently been implicated in the formation of tumor metastasis by directing the localization of tumor cells from the primary tumor to secondary tissues.
The Key Aims of this project are (1) To determine the role of chemokine/chemokine receptors in mediating lymphocyte infiltration into colon tumors; (2) To determine the role of chemokine receptors in colon cancer metastasis. Selective chemokine receptors likely play an important role in mediating the influx of specific T lymphocyte populations into tumors and in tumor metastasis formation. The proposed studies will help identify which chemokine/chemokine receptors are involved in these processes and determine their potential as targets for promoting lymphocyte infiltration into tumours in lymphocyte based anti-tumour therapies and for preventing colon cancer metastasis.
SSF Microbes and Man and INGVAR II report
Frågor om innehållet: Anna Appelberg
Uppdaterad: 2011-02-21
