Abstract

In the reported period we further dissected the role of LT and TNF in the development of Peyer's patches (PP). Our conditional knockout models have been generated in collaboration with L. Tessarollo and C. Steart. Firstly, in collaboration with A. Chervonsky from the Jackson Lab and D. Kuprash from the Engelhardt Institute, Moscow, we have demonstrated that LT and TNF produced by B cells are required for development of lymphoid follicles in PP, but are dispensable for maintenance of the follicle-associated epithelium. Secondly, we generated novel neo-free TNF KO mice which completely lack PP. This allowed us, in collaboration with W. Murphy from University of Nevada and D. Kuprash from the Engelhardt Institute, Moscow, to readdress the role of PP in GVHD. Our study indicates that neither TNF, nor the presence of PP, are required for GVHD in protocols with extensive conditioning of the host. Finally, our experiments with the panel of cell-type specific LT and TNF knockouts have established organ-specific """"""""rules"""""""" for the role of these cytokines in organization of spleen, lymph nodes and Peyer's patches.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009371-13
Application #
7048957
Study Section
(LMI)
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2004
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Kuprash, Dmitry V; Tumanov, Alexei V; Liepinsh, Dmitry J et al. (2005) Novel tumor necrosis factor-knockout mice that lack Peyer's patches. Eur J Immunol 35:1592-600
Grivennikov, Sergei I; Tumanov, Alexei V; Liepinsh, Dmitry J et al. (2005) Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity 22:93-104
Shakhov, Alexander N; Rybtsov, Stanislav; Tumanov, Alexei V et al. (2004) SMUCKLER/TIM4 is a distinct member of TIM family expressed by stromal cells of secondary lymphoid tissues and associated with lymphotoxin signaling. Eur J Immunol 34:494-503
Tumanov, Alexei V; Kuprash, Dmitry V; Mach, Julie A et al. (2004) Lymphotoxin and TNF produced by B cells are dispensable for maintenance of the follicle-associated epithelium but are required for development of lymphoid follicles in the Peyer's patches. J Immunol 173:86-91
Tumanov, Alexei V; Grivennikov, Sergei I; Shakhov, Alexander N et al. (2003) Dissecting the role of lymphotoxin in lymphoid organs by conditional targeting. Immunol Rev 195:106-16
Abe, Koichiro; Yarovinsky, Felix O; Murakami, Takaya et al. (2003) Distinct contributions of TNF and LT cytokines to the development of dendritic cells in vitro and their recruitment in vivo. Blood 101:1477-83
Tumanov, Alexei V; Kuprash, Dmitry V; Nedospasov, Sergei A (2003) The role of lymphotoxin in development and maintenance of secondary lymphoid tissues. Cytokine Growth Factor Rev 14:275-88
Baer, M; Nedospasov, S; Johnson, P F (1999) Attenuation of tumor necrosis factor alpha gene transcription in macrophages by an autocrine factor. Cold Spring Harb Symp Quant Biol 64:437-44
Kuprash, D V; Udalova, I A; Turetskaya, R L et al. (1999) Similarities and differences between human and murine TNF promoters in their response to lipopolysaccharide. J Immunol 162:4045-52
Ito, D; Back, T C; Shakhov, A N et al. (1999) Mice with a targeted mutation in lymphotoxin-alpha exhibit enhanced tumor growth and metastasis: impaired NK cell development and recruitment. J Immunol 163:2809-15

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