Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1995 Jan;146(1):264–275.

Transforming growth factor-beta 1 null mice. An animal model for inflammatory disorders.

A B Kulkarni 1, J M Ward 1, L Yaswen 1, C L Mackall 1, S R Bauer 1, C G Huh 1, R E Gress 1, S Karlsson 1
PMCID: PMC1870760  PMID: 7856732

Abstract

Approximately 40% of transforming growth factor-beta 1 null (knockout) mice generated in our laboratory develop normally to term, but 60% die in utero. The animals appear normal during the first 2 weeks of life but develop a rapid wasting syndrome and die by 3 to 4 weeks of age. All of the knockout mice have a multifocal inflammatory disease in many tissues. The heart and lungs are most severely affected. Increased adhesion of leukocytes to the endothelium of pulmonary veins is the initial lesion seen at day 8 postnatally and is soon followed by perivascular cuffing as well as inflammatory infiltrates in lung parenchyma. The lesions in the heart begin as endocarditis and then progress to myocarditis and pericarditis. Within the lung, chronic inflammatory infiltrates consist of T and B lymphocytes, including plasma cells, whereas macrophages are the primary inflammatory cell type in the heart. Increased expression of major histocompatibility complex class I and II proteins is seen in pulmonary vascular endothelium as early as day 8. An immunoblastic response in mediastinal and mandibular lymph nodes and spleen is also seen. In the absence of any pathogens, this massive inflammatory disease, together with overexpression of major histocompatibility complex class I and II proteins and overproduction of immunoglobulins by lymphocytes, offers circumstantial evidence for an autoimmune etiology.

Full text

PDF
264

Images in this article

268Figure 2
on p.268
269Figure 3
on p.269
271Figure 4
on p.271
273Figure 5
on p.273

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akhurst R. J., Fitzpatrick D. R., Fowlis D. J., Gatherer D., Millan F. A., Slager H. The role of TGF-beta s in mammalian development and neoplasia. Mol Reprod Dev. 1992 Jun;32(2):127–135. doi: 10.1002/mrd.1080320208. [DOI] [PubMed] [Google Scholar]
  2. Bhattacharya A., Dorf M. E., Springer T. A. A shared alloantigenic determinant on Ia antigens encoded by the I-A and I-E subregions: evidence for I region gene duplication. J Immunol. 1981 Dec;127(6):2488–2495. [PubMed] [Google Scholar]
  3. Bruce J., Symington F. W., McKearn T. J., Sprent J. A monoclonal antibody discriminating between subsets of T and B cells. J Immunol. 1981 Dec;127(6):2496–2501. [PubMed] [Google Scholar]
  4. Christ M., McCartney-Francis N. L., Kulkarni A. B., Ward J. M., Mizel D. E., Mackall C. L., Gress R. E., Hines K. L., Tian H., Karlsson S. Immune dysregulation in TGF-beta 1-deficient mice. J Immunol. 1994 Sep 1;153(5):1936–1946. [PubMed] [Google Scholar]
  5. Coffman R. L., Weissman I. L. B220: a B cell-specific member of th T200 glycoprotein family. Nature. 1981 Feb 19;289(5799):681–683. doi: 10.1038/289681a0. [DOI] [PubMed] [Google Scholar]
  6. Geiser A. G., Letterio J. J., Kulkarni A. B., Karlsson S., Roberts A. B., Sporn M. B. Transforming growth factor beta 1 (TGF-beta 1) controls expression of major histocompatibility genes in the postnatal mouse: aberrant histocompatibility antigen expression in the pathogenesis of the TGF-beta 1 null mouse phenotype. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9944–9948. doi: 10.1073/pnas.90.21.9944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Glick A. B., Kulkarni A. B., Tennenbaum T., Hennings H., Flanders K. C., O'Reilly M., Sporn M. B., Karlsson S., Yuspa S. H. Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6076–6080. doi: 10.1073/pnas.90.13.6076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hines K. L., Kulkarni A. B., McCarthy J. B., Tian H., Ward J. M., Christ M., McCartney-Francis N. L., Furcht L. T., Karlsson S., Wahl S. M. Synthetic fibronectin peptides interrupt inflammatory cell infiltration in transforming growth factor beta 1 knockout mice. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5187–5191. doi: 10.1073/pnas.91.11.5187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Janeway C. A., Jr, Conrad P. J., Lerner E. A., Babich J., Wettstein P., Murphy D. B. Monoclonal antibodies specific for Ia glycoproteins raised by immunization with activated T cells: possible role of T cellbound Ia antigens as targets of immunoregulatory T cells. J Immunol. 1984 Feb;132(2):662–667. [PubMed] [Google Scholar]
  10. Jhappan C., Geiser A. G., Kordon E. C., Bagheri D., Hennighausen L., Roberts A. B., Smith G. H., Merlino G. Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. EMBO J. 1993 May;12(5):1835–1845. doi: 10.1002/j.1460-2075.1993.tb05832.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Johns L. D., Flanders K. C., Ranges G. E., Sriram S. Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-beta 1. J Immunol. 1991 Sep 15;147(6):1792–1796. [PubMed] [Google Scholar]
  12. Kulkarni A. B., Huh C. G., Becker D., Geiser A., Lyght M., Flanders K. C., Roberts A. B., Sporn M. B., Ward J. M., Karlsson S. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770–774. doi: 10.1073/pnas.90.2.770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kulkarni A. B., Karlsson S. Transforming growth factor-beta 1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatory disease. Am J Pathol. 1993 Jul;143(1):3–9. [PMC free article] [PubMed] [Google Scholar]
  14. Kuruvilla A. P., Shah R., Hochwald G. M., Liggitt H. D., Palladino M. A., Thorbecke G. J. Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2918–2921. doi: 10.1073/pnas.88.7.2918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kühn R., Löhler J., Rennick D., Rajewsky K., Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
  16. Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Letterio J. J., Geiser A. G., Kulkarni A. B., Roche N. S., Sporn M. B., Roberts A. B. Maternal rescue of transforming growth factor-beta 1 null mice. Science. 1994 Jun 24;264(5167):1936–1938. doi: 10.1126/science.8009224. [DOI] [PubMed] [Google Scholar]
  18. Mackall C. L., Granger L., Sheard M. A., Cepeda R., Gress R. E. T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny. Blood. 1993 Oct 15;82(8):2585–2594. [PubMed] [Google Scholar]
  19. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. doi: 10.1146/annurev.cb.06.110190.003121. [DOI] [PubMed] [Google Scholar]
  20. McCartney-Francis N. L., Wahl S. M. Transforming growth factor beta: a matter of life and death. J Leukoc Biol. 1994 Mar;55(3):401–409. doi: 10.1002/jlb.55.3.401. [DOI] [PubMed] [Google Scholar]
  21. Mountz J. D., Edwards C. K., 3rd Murine models of autoimmune disease. Curr Opin Rheumatol. 1992 Oct;4(5):621–629. [PubMed] [Google Scholar]
  22. Mountz J. D., Gause W. C. Murine models of autoimmune disease and Sjögren's syndrome. Curr Opin Rheumatol. 1993 Sep;5(5):557–569. doi: 10.1097/00002281-199305050-00003. [DOI] [PubMed] [Google Scholar]
  23. Ozato K., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. III. Hybridoma antibodies reacting to antigens of the H-2b haplotype reveal genetic control of isotype expression. J Immunol. 1981 Jan;126(1):317–321. [PubMed] [Google Scholar]
  24. Racke M. K., Dhib-Jalbut S., Cannella B., Albert P. S., Raine C. S., McFarlin D. E. Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. J Immunol. 1991 May 1;146(9):3012–3017. [PubMed] [Google Scholar]
  25. Roberts A. B., Sporn M. B. Physiological actions and clinical applications of transforming growth factor-beta (TGF-beta). Growth Factors. 1993;8(1):1–9. doi: 10.3109/08977199309029129. [DOI] [PubMed] [Google Scholar]
  26. Rose N. R., Bona C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited) Immunol Today. 1993 Sep;14(9):426–430. doi: 10.1016/0167-5699(93)90244-F. [DOI] [PubMed] [Google Scholar]
  27. Sadlack B., Merz H., Schorle H., Schimpl A., Feller A. C., Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993 Oct 22;75(2):253–261. doi: 10.1016/0092-8674(93)80067-o. [DOI] [PubMed] [Google Scholar]
  28. Sellheyer K., Bickenbach J. R., Rothnagel J. A., Bundman D., Longley M. A., Krieg T., Roche N. S., Roberts A. B., Roop D. R. Inhibition of skin development by overexpression of transforming growth factor beta 1 in the epidermis of transgenic mice. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5237–5241. doi: 10.1073/pnas.90.11.5237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shull M. M., Ormsby I., Kier A. B., Pawlowski S., Diebold R. J., Yin M., Allen R., Sidman C., Proetzel G., Calvin D. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992 Oct 22;359(6397):693–699. doi: 10.1038/359693a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Springer T., Galfrè G., Secher D. S., Milstein C. Monoclonal xenogeneic antibodies to murine cell surface antigens: identification of novel leukocyte differentiation antigens. Eur J Immunol. 1978 Aug;8(8):539–551. doi: 10.1002/eji.1830080802. [DOI] [PubMed] [Google Scholar]
  31. Wahl S. M. Transforming growth factor beta (TGF-beta) in inflammation: a cause and a cure. J Clin Immunol. 1992 Mar;12(2):61–74. doi: 10.1007/BF00918135. [DOI] [PubMed] [Google Scholar]
  32. Zubler R. H., Lowenthal J. W., Erard F., Hashimoto N., Devos R., MacDonald H. R. Activated B cells express receptors for, and proliferate in response to, pure interleukin 2. J Exp Med. 1984 Oct 1;160(4):1170–1183. doi: 10.1084/jem.160.4.1170. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES