The Journal of Immunology, Vol 151, Issue 4 1894-1906, Copyright © 1993 by American Association of Immunologists

ARTICLES

Wasting, ischemia, and lymphoid abnormalities in mice expressing T cell- targeted human tumor necrosis factor transgenes

L Probert, J Keffer, P Corbella, H Cazlaris, E Patsavoudi, S Stephens, E Kaslaris, D Kioussis and G Kollias
Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.

To evaluate the biologic potential of T cell-specific TNF production in vivo, we have generated transgenic mice constitutively expressing TNF in their T cell compartment. This was achieved by placing a wild-type or a 3'-UTR modified fragment of the human TNF gene under the influence of the T cell-specific, locus control region of the human CD2 gene. Transgenic mice that express human TNF mRNA in T cells develop marked histologic and cellular changes locally in their lymphoid organs and a lethal wasting syndrome associated with widespread vascular thrombosis and tissue necrosis. The extent of pathologic changes and their time of onset appear to reflect levels of transgene expression. Thus, transgenic lines that express the transgene at high levels show both lymphoid organ and systemic abnormalities with wasting. In one transgenic line, mice express lower levels of the transgene and develop normally despite pronounced local lymphoid organ defects, confirming in vivo, the differential potential of localized and systemic TNF action. All pathologic changes could be neutralized by the administration of mAb specific for human TNF. These results demonstrate the important role of T cell-specific TNF production in the development of specific pathology and provide a means by which to evaluate the role of TNF in thymocyte development. Transgenic mice that express TNF constitutively in the T cell compartment offer a unique in vivo system by which to analyze the molecular character of systemic vs contact-dependent and paracrine modes of TNF action. Furthermore, given the species-specific nature of the mouse p75 TNF receptor, it is assumed that the pathology induced by human TNF in these transgenic mice is associated exclusively with p55 TNF receptor signaling. Conceivably, the differential contribution of each of the two TNF receptors in thymus development and TNF-mediated disease can be assessed by comparison of the biologic potential of human vs mouse TNF in the transgenic system developed.

This article has been cited by other articles:

				K. J. Szretter, S. Gangappa, X. Lu, C. Smith, W.-J. Shieh, S. R. Zaki, S. Sambhara, T. M. Tumpey, and J. M. Katz Role of Host Cytokine Responses in the Pathogenesis of Avian H5N1 Influenza Viruses in Mice J. Virol., March 15, 2007; 81(6): 2736 - 2744. [Abstract] [Full Text] [PDF]

				S. Porcellini, E. Traggiai, U. Schenk, D. Ferrera, M. Matteoli, A. Lanzavecchia, M. Michalak, and F. Grassi Regulation of peripheral T cell activation by calreticulin. J. Exp. Med., February 20, 2006; 203(2): 461 - 471. [Abstract] [Full Text] [PDF]

				J. Mucci, E. Mocetti, M. S. Leguizamon, and O. Campetella A Sexual Dimorphism in Intrathymic Sialylation Survey Is Revealed by the trans-Sialidase from Trypanosoma cruzi J. Immunol., April 15, 2005; 174(8): 4545 - 4550. [Abstract] [Full Text] [PDF]

				H. Takada, N.-J. Chen, C. Mirtsos, S. Suzuki, N. Suzuki, A. Wakeham, T. W. Mak, and W.-C. Yeh Role of SODD in Regulation of Tumor Necrosis Factor Responses Mol. Cell. Biol., June 1, 2003; 23(11): 4026 - 4033. [Abstract] [Full Text] [PDF]

				R. B. Shaikh, S. Santee, S. W. Granger, K. Butrovich, T. Cheung, M. Kronenberg, H. Cheroutre, and C. F. Ware Constitutive Expression of LIGHT on T Cells Leads to Lymphocyte Activation, Inflammation, and Tissue Destruction J. Immunol., December 1, 2001; 167(11): 6330 - 6337. [Abstract] [Full Text] [PDF]

				L. Jin, D. P. Raymond, T. D. Crabtree, S. J. Pelletier, C. W. Houlgrave, T. L. Pruett, and R. G. Sawyer Enhanced Murine Macrophage TNF Receptor Shedding by Cytosine-Guanine Sequences in Oligodeoxynucleotides J. Immunol., November 1, 2000; 165(9): 5153 - 5160. [Abstract] [Full Text] [PDF]

				M. Fujimoto, T. Naka, R. Nakagawa, Y. Kawazoe, Y. Morita, A. Tateishi, K. Okumura, M. Narazaki, and T. Kishimoto Defective Thymocyte Development and Perturbed Homeostasis of T cells in STAT-Induced STAT Inhibitor-1/Suppressors of Cytokine Signaling-1 Transgenic Mice J. Immunol., August 15, 2000; 165(4): 1799 - 1806. [Abstract] [Full Text] [PDF]

				E. Douni and G. Kollias A Critical Role of the p75 Tumor Necrosis Factor Receptor (p75TNF-R) in Organ Inflammation Independent of  TNF, Lymphotoxin alpha , or the p55TNF-R J. Exp. Med., October 5, 1998; 188(7): 1343 - 1352. [Abstract] [Full Text] [PDF]

				E C Ebert Tumour necrosis factor-alpha enhances intraepithelial lymphocyte proliferation and migration Gut, May 1, 1998; 42(5): 650 - 655. [Abstract] [Full Text] [PDF]

				D. M. Page, E. M. Roberts, J. J. Peschon, and S. M. Hedrick TNF Receptor-Deficient Mice Reveal Striking Differences Between Several Models of Thymocyte Negative Selection J. Immunol., January 1, 1998; 160(1): 120 - 133. [Abstract] [Full Text] [PDF]

				M. A. O'Connell, R. Cleere, A. Long, and D. Kelleher Cellular Proliferation and Activation of NFkappaB Are Induced by Autocrine Production of Tumor Necrosis Factor alpha in the Human T Lymphoma Line HuT 78 J. Biol. Chem., March 31, 1995; 270(13): 7399 - 7404. [Abstract] [Full Text] [PDF]

				S. Iyer, D. Kontoyiannis, D. Chevrier, J. Woo, N. Mori, M. Cornejo, G. Kollias, and R. Buelow Inhibition of Tumor Necrosis Factor mRNA Translation by a Rationally Designed Immunomodulatory Peptide J. Biol. Chem., May 26, 2000; 275(22): 17051 - 17057. [Abstract] [Full Text] [PDF]

				Y. Morita, T. Naka, Y. Kawazoe, M. Fujimoto, M. Narazaki, R. Nakagawa, H. Fukuyama, S. Nagata, and T. Kishimoto Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor alpha -induced cell death in fibroblasts PNAS, May 9, 2000; 97(10): 5405 - 5410. [Abstract] [Full Text] [PDF]