Inflammatory bowel diseases (IBD) are chronic, relapsing and tissue destructive diseases. T helper type l (Thl) cells secreting TNF-alpha and IFN-gamma have been emphasized in ulcerative colitis, while Th2 cells may be more closely associated with Crohn's disease. However, either Thl or Th2 cells can induce colitis in several mouse models; hence the precise causes of these two forms of IBD are incompletely understood. It has recently been shown that the mechanisms of IBD involve antigen- dependent interactions between CD4+ T cells and antigen-presenting cells (APCs) as well as genetic factors. A major deficiency in understanding the steps responsible for IBD, is the lack of comprehension for the role innate and early acting factors play in mucosal immune responses. Chemokines are a family of proteins that are resistant to inactivation by pH or proteolysis as well as affect the chemotaxis and angiogenesis of leukocytes and endothelial cells. Therefore, chemokines no doubt play a pivotal role in the regulation (i.e., initiation, maintenance, and suppression) of mucosal inflammation and tissue destruction. In fact, human interleukin-8 (IL-8), IFN-gamma inducible protein - l0 (IP-l0), CXCR3 (the receptor for IP-10), RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted), and MCP-l/JE (monocyte chemotactic protein-1) have been shown to be unregulated at the sites of mucosal inflammation (IBD). The current proposal stems from our recent findings that RANTES, IP-10, IL- 8, lymphotactin (Lptn), but not MCP-l/JE, can enhance mucosal adaptive immune responses. Since these chemolcines act at several levels, four Specific Aims will be addressed to elucidate the precise role of these chemokines and their corresponding receptors in IBD. The first aim will define the regulatory role of chemokines that are secreted by CD45RBHI CD4+ T cells subsets, which cause experimental IBD after adoptive transfer. The second aim will assess the role of mIL-8Rh (murine IL- 8/GCP2 receptor), CCR5 (a RANTES receptor), CXCR3, and XCRl (Lptn receptor) interactions in the CD45RBHI CD4+ T cell transfer model of murine IBD. The third aim will evaluate the chemokines, cytokines, and corresponding receptors that are expressed by the IBD inducers (CD45RBHI) and IBD suppressors (CDRB45LO) CD4+ T cells subsets. The fourth aim will ascertain the angiogenic or angiostatic factors and cell signaling molecules that are expressed or activated, respectively, by chemokines that regulate IBD. These proposed studies will provide important and novel information regarding the cellular and molecular mechanisms that chemokines use to induce, maintain, and suppress mucosal inflammation and angiogenesis.

R03DK058967

2000-09-30

2004-08-31