The peritoneal cavity (PerC) envelops the lower digestive tract with its extensive prokaryotic composition and constant passage of antigens. These challenges to immunity, addressed within the digestive tract by the mucosal immune system, are likely to be dominant factors in determining the extravascular residents found in the PerC. Intestinal microflora and foreign antigens require constant vigilance, however over-reactivity, as reflected by inflammatory bowel disease (IBD), is deleterious to the host. How does the immune system maintain a balance between reactivity and over-reactivity in this anatomic location? In this proposal, we describe experiments designed to test the hypothesis that the leucocytes found naturally in the PerC have roles in damping immune reactivity. We hypothesize that this protective, immunoregulatory capacity of the PerC facilitates B-l B cell transformation later in life. There are three specific aims to this research plan:
Aim 1. Investigate the role of Tr cells in peritoneal immunoregulation. Our preliminary data show that, relative to conventional, organized lymphoid tissue (eg., SP, LN), the PerC, in a normal, healthy animal, has the greatest proportion of CD4+CD25+CD44hl cells. To determine if these cells are Tr cells we will purify them and test their ability to suppress immune function.
Aim 2. Assess the role of IL-10 and TGF-beta production by B-l B cells in PerC immunoregulation. Our preliminary data show that PerC B-l B cells are less effective as APCs for the DBA/2J superantigen (SAg) Mls-la than PerC B-2 B cells. We will assess SAg expression by PerC B cell subsets and determine if IL-10 and TGF-P production by B-l B cells is a factor in their reduced ability to present Mls and activate Thl cells.
Aim 3. Investigate the role of macrophages and dendritic cells in peritoneal immunoregulation. Our preliminary studies suggest that peritoneal macrophages and/or dendritic cells, suppress T cell activation via tryptophan catabolism. We propose to confirm and extend these studies by testing purified macrophages and dendritic cells and further define this novel mechanism of immune regulation. These studies will provide insight concerning the means whereby PerC leucocytes naturally control immunity and how perturbation of this balance might promote intestinal inflammation. This information could be useful in the design of protocols to promote or subvert immune suppression. These studies will also provide information regarding how constitutive suppression of Thl activation could facilitate the generation of B cell lymphoma from B-l B cells in the PerC.
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