Transgenic Mice Expressing Human Tumour Necrosis Factor: a Predictive Genetic Model of Arthritis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1991 Dec 1

PMID 1721867

Citations 558

Authors

J Keffer

L Probert

H Cazlaris

S Georgopoulos

E KASLARIS

D Kioussis

G Kollias

Affiliations

Soon will be listed here.

Abstract

We have generated transgenic mouse lines carrying and expressing wild-type and 3'-modified human tumour necrosis factor (hTNF-alpha, cachectin) transgenes. We show that correct, endotoxin-responsive and macrophage-specific hTNF gene expression can be established in transgenic mice and we present evidence that the 3'-region of the hTNF gene may be involved in macrophage-specific transcription. Transgenic mice carrying 3'-modified hTNF transgenes shows deregulated patterns of expression and interestingly develop chronic inflammatory polyarthritis. Treatment of these arthritic mice with a monoclonal antibody against human TNF completely prevents development of this disease. Our results indicate a direct involvement of TNF in the pathogenesis of arthritis. Transgenic mice which predictably develop arthritis represent a novel genetic model by which the pathogenesis and treatment of this disease in humans may be further investigated.

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References

Loetscher H, Pan Y, Lahm H, Gentz R, Brockhaus M, Tabuchi H . Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor. Cell. 1990; 61(2):351-9. DOI: 10.1016/0092-8674(90)90815-v. View

Hang L, Theofilopoulos A, Dixon F . A spontaneous rheumatoid arthritis-like disease in MRL/l mice. J Exp Med. 1982; 155(6):1690-701. PMC: 2186697. DOI: 10.1084/jem.155.6.1690. View

Harris Jr E . Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990; 322(18):1277-89. DOI: 10.1056/NEJM199005033221805. View

Gordon J, Galli S . Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature. 1990; 346(6281):274-6. DOI: 10.1038/346274a0. View

Kinkhabwala M, Sehajpal P, Skolnik E, Smith D, Sharma V, Vlassara H . A novel addition to the T cell repertory. Cell surface expression of tumor necrosis factor/cachectin by activated normal human T cells. J Exp Med. 1990; 171(3):941-6. PMC: 2187763. DOI: 10.1084/jem.171.3.941. View

Gowen M, Wood D, Ihrie E, McGuire M, Russell R . An interleukin 1 like factor stimulates bone resorption in vitro. Nature. 1983; 306(5941):378-80. DOI: 10.1038/306378a0. View

Houssiau F, Nagant de Deuxchaisnes C . Cytokines and inflammatory arthritides. Clin Exp Rheumatol. 1990; 8(6):531-3. View

Hammer R, Maika S, Richardson J, Tang J, Taurog J . Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell. 1990; 63(5):1099-112. DOI: 10.1016/0092-8674(90)90512-d. View

Yocum D, Esparza L, Dubry S, Benjamin J, Volz R, Scuderi P . Characteristics of tumor necrosis factor production in rheumatoid arthritis. Cell Immunol. 1989; 122(1):131-45. DOI: 10.1016/0008-8749(89)90154-8. View

10.

Kollias G, Wrighton N, Hurst J, Grosveld F . Regulated expression of human A gamma-, beta-, and hybrid gamma beta-globin genes in transgenic mice: manipulation of the developmental expression patterns. Cell. 1986; 46(1):89-94. DOI: 10.1016/0092-8674(86)90862-7. View

11.

Shaw G, Kamen R . A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986; 46(5):659-67. DOI: 10.1016/0092-8674(86)90341-7. View

12.

Kollias G, Hurst J, DEBOER E, Grosveld F . The human beta-globin gene contains a downstream developmental specific enhancer. Nucleic Acids Res. 1987; 15(14):5739-47. PMC: 306019. DOI: 10.1093/nar/15.14.5739. View

13.

Peters P, Ortaldo J, Shalaby M, Svedersky L, Nedwin G, Bringman T . Natural killer-sensitive targets stimulate production of TNF-alpha but not TNF-beta (lymphotoxin) by highly purified human peripheral blood large granular lymphocytes. J Immunol. 1986; 137(8):2592-8. View

14.

Ollivierre F, Gubler U, Towle C, Laurencin C, Treadwell B . Expression of IL-1 genes in human and bovine chondrocytes: a mechanism for autocrine control of cartilage matrix degradation. Biochem Biophys Res Commun. 1986; 141(3):904-11. DOI: 10.1016/s0006-291x(86)80128-0. View

15.

Dayer J, de Rochemonteix B, Burrus B, Demczuk S, Dinarello C . Human recombinant interleukin 1 stimulates collagenase and prostaglandin E2 production by human synovial cells. J Clin Invest. 1986; 77(2):645-8. PMC: 423407. DOI: 10.1172/JCI112350. View

16.

Dayer J, Beutler B, Cerami A . Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985; 162(6):2163-8. PMC: 2187983. DOI: 10.1084/jem.162.6.2163. View

17.

Kioussis D, Wilson F, Daniels C, Leveton C, Taverne J, Playfair J . Expression and rescuing of a cloned human tumour necrosis factor gene using an EBV-based shuttle cosmid vector. EMBO J. 1987; 6(2):355-61. PMC: 553403. DOI: 10.1002/j.1460-2075.1987.tb04762.x. View

18.

Saklatvala J, Sarsfield S, Townsend Y . Pig interleukin 1. Purification of two immunologically different leukocyte proteins that cause cartilage resorption, lymphocyte activation, and fever. J Exp Med. 1985; 162(4):1208-22. PMC: 2187869. DOI: 10.1084/jem.162.4.1208. View

19.

Nedwin G, Naylor S, Sakaguchi A, Smith D, Pennica D, Goeddel D . Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985; 13(17):6361-73. PMC: 321958. DOI: 10.1093/nar/13.17.6361. View

20.

Tiku M, Liu S, Weaver C, Teodorescu M, Skosey J . Class II histocompatibility antigen-mediated immunologic function of normal articular chondrocytes. J Immunol. 1985; 135(5):2923-8. View