The goal of these studies is to understand the mechanisms and relationships of lymphoid organ development and inflammation as mediated by LTalpha3 and LTalphaB. The hypothesis to be tested is that the processes are similar by which LT/TNF cytokines induce lymphoid organs in ontogeny (secondary lymphoid organs) (lymphoid organogenesis) and inflammation (tertiary lymphoid organs) (lymphoid neogenesis) and that these lymphoid organs have common functions, i.e. presentation and response to antigen. Mice transgenic for LTalpha under the control of the rat insulin promoter (RIPLT mouse) that expresses LTalpha constitutively in the islets of Langerhans, the kidney, and skin, exhibit inflammation at the sites of transgene expression that has many characteristics of lymphoid organs with regard to expression of adhesion molecules, chemokines, and cellular composition. Some (MAdCAM-1, SLC, and BLC) are mediated by LTalpha3, whereas others (PNAd; L-selectin hi cells) require LTalphabeta as well. These data and others from mice selectively deficient in cytokines or their receptors suggest that LTalpha induces mesenteric and peripheral LN and LTalphabeta induces peripheral LN. The RIPLT mouse is a unique reagent that provides an accessible system to study mechanisms, kinetics, and molecular requirements for lymphoid organogenesis which will be used to answer the following questions: 1. Does the simultaneous expression of LTalpha and LTalphabeta result in neogenesis with the characteristics of peripheral lymph nodes? The infiltrates of mice transgenic for RIPLTalpha and RIPLTbeta will be analyzed for expression of PNAd and L-selectin, chemokines, DC, and FDC. 2. How precisely does the LT-induced infiltrate resemble a functional lymphoid organ? The ability of the infiltrates to present and respond to endogenous (Y-Ae) and exogenous antigen will be evaluated. 3. What are the individual roles of LTalpha and LTbeta in the kinetics of lymphoid neogenesis? Does LT production need to be sustained to maintain a lymphoid organ? RIP specific and inducible systems that express LTalpha and/or LTbeta will be developed, turned on and off at will and evaluated for lymphoid neogenesis. 4. What is the role of LT-induced NFkappaB activation in lymphoid organogenesis? RIPLT mice will be crossed with mice expressing a superinhibitor Ikappabalpha and the effect on lymphoid neogenesis evaluated. These studies will provide information regarding the mechanisms of cytokine induced inflammation and identify targets for therapeutics in disease and provide insight into the process and importance of determinant spreading by elucidating the establishment of a new lymphoid organ at the local site in inflammatory autoimmune diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Immunobiology Study Section (IMB)
Program Officer
Akolkar, Beena
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Public Health & Prev Medicine
Schools of Medicine
New Haven
United States
Zip Code
Mionnet, Cyrille; Mondor, Isabelle; Jorquera, Audrey et al. (2013) Identification of a new stromal cell type involved in the regulation of inflamed B cell follicles. PLoS Biol 11:e1001672
Bentley, Kevin L; Stranford, Sharon; Liao, Shan et al. (2011) High endothelial venule reporter mice to probe regulation of lymph node vasculature. Adv Exp Med Biol 691:35-44
Liao, Shan; Cheng, Gang; Conner, David A et al. (2011) Impaired lymphatic contraction associated with immunosuppression. Proc Natl Acad Sci U S A 108:18784-9
Mounzer, Rawad H; Svendsen, Oyvind S; Baluk, Peter et al. (2010) Lymphotoxin-alpha contributes to lymphangiogenesis. Blood 116:2173-82
Ruddle, Nancy H; Akirav, Eitan M (2009) Secondary lymphoid organs: responding to genetic and environmental cues in ontogeny and the immune response. J Immunol 183:2205-12
Bistrup, Annette; Tsay, Durwin; Shenoy, Priti et al. (2004) Detection of a sulfotransferase (HEC-GlcNAc6ST) in high endothelial venules of lymph nodes and in high endothelial venule-like vessels within ectopic lymphoid aggregates: relationship to the MECA-79 epitope. Am J Pathol 164:1635-44
Drayton, Danielle L; Ying, Xiaoyan; Lee, Jason et al. (2003) Ectopic LT alpha beta directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. J Exp Med 197:1153-63