Our group has continued generation and characterization of a panel of mice with conditionally targeted TNF, LTa and LTb genes. We have documented the role of TNF or LT produced by B cells in the maintenance of the microarchitecture of lymphoid organs. Requirements in different lymphoid organs are distinct, and the role of LT versus TNF is different in spleen versus lymph nodes or Peyer's patches. We are in the process of characterization of inducible TNF and LT knockouts which may become valuable murine models for human subjects on TNF/LT blockers (such as RA patients). The distinct features in this panel of conditional knock-out are being correlated with the expression pattern of specific genes, including lymphoid tissue chemokines, adhesion molecules and several novel genes. Additionally, we have generated mice with combined p53.TNF/LT. p53.TNF and p53-LTa deficiencies and observed that the deletion of TNF/LT locus, but not of TNF, results in significant extension of the life span of p53-/- mice.

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