The long term objective of this work is to understand the pathogenesis of Type I diabetes mellitus with an emphasis on elucidating mechanisms of inflammation and determinant spreading. The hypothesis to be tested is that tertiary lymphoid organs at the local site, which are characteristic of many autoimmune diseases, are crucial for IDDM. Mice transgenic for lymphotoxin (LTalpha; TNFbeta) under the control of the insulin promoter (RIPLT mice) express the transgene in the pancreas and kidney and develop inflammation at those sites. The insulitis and nephritis have lymph node (LN) characteristics, including T, B cell compartmentalization, antigen presenting cells (FDC and DC), vessels with the morphologic and antigenic (MAdCAM-1 and PNAd) characteristics of high endothelial venules (HEV), and plasma cells secreting specific IgG after immunization. This process, termed lymphoid neo-organogenesis, requires TNFR1 and may be a model for LT's role in development since mice deficient in members of the LT/TNF family have profound defects in lymphoid organs. LTbetaR contributes to PNAd expression and influences the ratio of naive cells in the tertiary lymphoid organ. Chemokines (RANTES, MCP-1, and IP-10) are induced in RIPLT islets. When RIPLT mice are crossed to RIPB7 mice, diabetes occurs.
The specific aims are to: 1. Identify the role of chemokines in islet tertiary lymphoid organs by crossing RIPLT mice with mice deficient in chemokines induced in RIPLT islets (MCP-1) or identified to be involved in lymphoid organ development and mononuclear trafficking (BRL-1) and by in situ hybridization; 2. Characterize the kinetics of tertiary lymphoid organs with a beta cell specific LT tetracycline (Dox) inducible system; 3. Determine whether the islet infiltrate is a functional lymphoid organ capable of presenting endogenous (Y-Ae) and exogenous antigen; 4. Determine whether the islet infiltrate is a functional lymphoid organ capable of responding to antigen; 5. Discover whether determinant spreading occurs in LT-induced diabetes and if maintenance of a tertiary lymphoid organ is required for this process. These studies which will provide insight into how and where antigens are presented in inflammatory autoimmunity concentrate on identifying cellular, molecular, and anatomic requirements for this process. They also provide insight into the mechanism of cytokine induction of lymphoid organs in development. Understanding how islet tertiary lymphoid organs are established and function will allow identification of therapeutic targets for determinant spreading and tissue damage in IDDM.
| Drayton, Danielle L; Liao, Shan; Mounzer, Rawad H et al. (2006) Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7:344-53 |
| Drayton, Danielle L; Chan, Kee; Lesslauer, Werner et al. (2002) Lymphocyte traffic in lymphoid organ neogenesis: differential roles of Ltalpha and LTalphabeta. Adv Exp Med Biol 512:43-8 |
| Hemmerich, S; Bistrup, A; Singer, M S et al. (2001) Sulfation of L-selectin ligands by an HEV-restricted sulfotransferase regulates lymphocyte homing to lymph nodes. Immunity 15:237-47 |
