In order to address the physiological functions of the TNF/LT subfamily of cytokines we used Cre-loxP technology and have generated, in collaboration with laboratories of K. Pfeffer and L. Rajewsky, a panel of knock-out mice with single (LT-beta) , double (LT-beta-TNF) and complete (triple) deficiency in this locus. This allowed us to reveal distinct and overlapping contributions of TNF and LT signalling into organogenesis and maintenance of lymphoid tissues. We have demonstrated that LT deficiency is associated with enhanced tumor growth and metastasis and with impairment in development and recruitment of NK cells. Cre-loxP technology was also used in collaboration with laboratories of L. Tessarollo and C. Stewart to generate mice with conditionally targeted TNF and LT genes, in particular in B lymphocytes. In order to identify genes responsible for mutant phenotype in distinct histological compartments and organs in mice with LT, TNF or combined deficiencies, we searched for genes whose expression is substantially altered in knock-out mice. In particular, by subtraction cloning and by comparative hybridizations to gene arrays we have identified a number of known and novel sequences which are expressed at much lower level in spleens of LT- deficient mice. These genes include novel phospholipase A2, chemokines of lymphoid organs ELC, SLC and BLC, macrophage scavenger receptor, myeloperoxidase and others. Causative role of these genes in development and maintenance of mutant phenotype will be addressed in transgenic studies. Our studies may also reveal relevance of these murine models for human disease, including AIDS.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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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
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
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
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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