Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Nov 1;178(5):1607–1616. doi: 10.1084/jem.178.5.1607

Transfer of the inflammatory disease of HLA-B27 transgenic rats by bone marrow engraftment

PMCID: PMC2191228  PMID: 8228809

Abstract

We have previously produced lines of rats transgenic for HLA-B27 and human beta 2-microglobulin (h beta 2m) that develop a progressive inflammatory disease sharing many clinical and histologic features with the B27-associated human spondyloarthropathies, including gut and male genital inflammation, arthritis, and psoriasiform skin lesions. Other transgenic lines that express lower levels of B27 and h beta 2m remain healthy. To investigate the cellular basis for the multisystem inflammatory disease in these rats, we transferred lymphoid cell populations from disease-prone transgenic lines to irradiated disease- resistant transgenic and nontransgenic recipients. In recipients of cells from two different disease-prone lines, successful transfer required engraftment of bone marrow cells. Transfer of disease with fetal liver cells suggested that neither mature effector cells nor active disease in the donors was necessary for induction of disease in the recipients. Remission of the spontaneous disease in irradiated transgenic rats was induced by engraftment of nontransgenic bone marrow. These results suggest that the expression of HLA-B27 in bone marrow-derived cells alone is sufficient for the development of B27- associated disease, and that disease transfer requires engraftment of a bone marrow precursor cell for which mature cells in spleen or in lymph node cannot substitute.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

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

  1. Bendelac A., Carnaud C., Boitard C., Bach J. F. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med. 1987 Oct 1;166(4):823–832. doi: 10.1084/jem.166.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benjamin R., Parham P. Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today. 1990 Apr;11(4):137–142. doi: 10.1016/0167-5699(90)90051-a. [DOI] [PubMed] [Google Scholar]
  3. Beschorner W. E., Tutschka P. J., Santos G. W. Chronic graft-versus-host disease in the rat radiation chimera. I. Clinical features, hematology, histology, and immunopathology in long-term chimeras. Transplantation. 1982 Apr;33(4):393–399. doi: 10.1097/00007890-198204000-00010. [DOI] [PubMed] [Google Scholar]
  4. Beschorner W. E., Tutschka P. J., Santos G. W. Sequential morphology of graft-versus-host disease in the rat radiation chimera. Clin Immunol Immunopathol. 1982 Feb;22(2):203–224. doi: 10.1016/0090-1229(82)90038-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bix M., Raulet D. Inefficient positive selection of T cells directed by haematopoietic cells. Nature. 1992 Sep 24;359(6393):330–333. doi: 10.1038/359330a0. [DOI] [PubMed] [Google Scholar]
  6. Chen B. P., Madrigal A., Parham P. Cytotoxic T cell recognition of an endogenous class I HLA peptide presented by a class II HLA molecule. J Exp Med. 1990 Sep 1;172(3):779–788. doi: 10.1084/jem.172.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chicz R. M., Urban R. G., Gorga J. C., Vignali D. A., Lane W. S., Strominger J. L. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J Exp Med. 1993 Jul 1;178(1):27–47. doi: 10.1084/jem.178.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dobber R., Hertogh-Huijbregts A., Rozing J., Bottomly K., Nagelkerken L. The involvement of the intestinal microflora in the expansion of CD4+ T cells with a naive phenotype in the periphery. Dev Immunol. 1992;2(2):141–150. doi: 10.1155/1992/57057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eedy D. J., Burrows D., Bridges J. M., Jones F. G. Clearance of severe psoriasis after allogenic bone marrow transplantation. BMJ. 1990 Apr 7;300(6729):908–908. doi: 10.1136/bmj.300.6729.908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Georgiou H. M., Lagarde A. C., Bellgrau D. T cell dysfunction in the diabetes-prone BB rat. A role for thymic migrants that are not T cell precursors. J Exp Med. 1988 Jan 1;167(1):132–148. doi: 10.1084/jem.167.1.132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Granfors K., Jalkanen S., von Essen R., Lahesmaa-Rantala R., Isomäki O., Pekkola-Heino K., Merilahti-Palo R., Saario R., Isomäki H., Toivanen A. Yersinia antigens in synovial-fluid cells from patients with reactive arthritis. N Engl J Med. 1989 Jan 26;320(4):216–221. doi: 10.1056/NEJM198901263200404. [DOI] [PubMed] [Google Scholar]
  12. Hammer R. E., Maika S. D., Richardson J. A., Tang J. P., Taurog J. D. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell. 1990 Nov 30;63(5):1099–1112. doi: 10.1016/0092-8674(90)90512-d. [DOI] [PubMed] [Google Scholar]
  13. Hermann E., Lohse A. W., Van der Zee R., Van Eden W., Mayet W. J., Probst P., Poralla T., Meyer zum Büschenfelde K. H., Fleischer B. Synovial fluid-derived Yersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells. Eur J Immunol. 1991 Sep;21(9):2139–2143. doi: 10.1002/eji.1830210923. [DOI] [PubMed] [Google Scholar]
  14. Howard J. C., Scott D. W. The role of recirculating lymphocytes in the immunological competence of rat bone marrow cells. Cell Immunol. 1972 Mar;3(3):421–429. doi: 10.1016/0008-8749(72)90247-x. [DOI] [PubMed] [Google Scholar]
  15. Hunt S. V., Fowler M. H. A repopulation assay for B and T lymphocyte stem cells employing radiation chimaeras. Cell Tissue Kinet. 1981 Jul;14(4):445–464. doi: 10.1111/j.1365-2184.1981.tb00551.x. [DOI] [PubMed] [Google Scholar]
  16. Ikehara S., Kawamura M., Takao F., Inaba M., Yasumizu R., Than S., Hisha H., Sugiura K., Koide Y., Yoshida T. O. Organ-specific and systemic autoimmune diseases originate from defects in hematopoietic stem cells. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8341–8344. doi: 10.1073/pnas.87.21.8341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kapasi K., Inman R. D. HLA-B27 expression modulates gram-negative bacterial invasion into transfected L cells. J Immunol. 1992 Jun 1;148(11):3554–3559. [PubMed] [Google Scholar]
  18. Kunz H. W., Gill T. J., 3rd Red blood cell alloantigenic systems in the rat. J Immunogenet. 1978 Dec;5(6):365–382. doi: 10.1111/j.1744-313x.1978.tb00666.x. [DOI] [PubMed] [Google Scholar]
  19. Lubaroff D. M., Waksman B. H. Bone marrow as source of cells in reactions of cellular hypersensitivity. II. Identification of allogeneic or hybrid cells by immunofluorescence in passively transferred tuberculin reactions. J Exp Med. 1968 Dec 1;128(6):1437–1447. doi: 10.1084/jem.128.6.1437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mowat A. M., Sprent J. Induction of intestinal graft-versus-host reactions across mutant major histocompatibility antigens by T lymphocyte subsets in mice. Transplantation. 1989 May;47(5):857–863. doi: 10.1097/00007890-198905000-00022. [DOI] [PubMed] [Google Scholar]
  21. Nakano K., Mordes J. P., Handler E. S., Greiner D. L., Rossini A. A. Role of host immune system in BB/Wor rat. Predisposition to diabetes resides in bone marrow. Diabetes. 1988 May;37(5):520–525. doi: 10.2337/diab.37.5.520. [DOI] [PubMed] [Google Scholar]
  22. Raybourne R. B., Williams K. M. Monoclonal antibodies against an HLA-B27-derived peptide react with an epitope present on bacterial proteins. J Immunol. 1990 Oct 15;145(8):2539–2544. [PubMed] [Google Scholar]
  23. Remmers E. F., Goldmuntz E. A., Cash J. M., Crofford L. J., Misiewicz-Poltorak B., Zha H., Wilder R. L. Genetic map of nine polymorphic loci comprising a single linkage group on rat chromosome 10: evidence for linkage conservation with human chromosome 17 and mouse chromosome 11. Genomics. 1992 Nov;14(3):618–623. doi: 10.1016/s0888-7543(05)80160-0. [DOI] [PubMed] [Google Scholar]
  24. Robinson A. P., White T. M., Mason D. W. Macrophage heterogeneity in the rat as delineated by two monoclonal antibodies MRC OX-41 and MRC OX-42, the latter recognizing complement receptor type 3. Immunology. 1986 Feb;57(2):239–247. [PMC free article] [PubMed] [Google Scholar]
  25. Rossini A. A., Mordes J. P., Greiner D. L. The pathogenesis of autoimmune diabetes mellitus. Curr Opin Immunol. 1989;2(4):598–603. doi: 10.1016/0952-7915(90)90017-b. [DOI] [PubMed] [Google Scholar]
  26. STASTNY P., STEMBRIDGE V. A., ZIFF M. HOMOLOGOUS DISEASE IN THE ADULT RAT, A MODEL FOR AUTOIMMUNE DISEASE. I. GENERAL FEATURES AND CUTANEOUS LESIONS. J Exp Med. 1963 Oct 1;118:635–648. doi: 10.1084/jem.118.4.635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schild H., Rötzschke O., Kalbacher H., Rammensee H. G. Limit of T cell tolerance to self proteins by peptide presentation. Science. 1990 Mar 30;247(4950):1587–1589. doi: 10.1126/science.2321019. [DOI] [PubMed] [Google Scholar]
  28. Serreze D. V., Leiter E. H., Worthen S. M., Shultz L. D. NOD marrow stem cells adoptively transfer diabetes to resistant (NOD x NON)F1 mice. Diabetes. 1988 Feb;37(2):252–255. doi: 10.2337/diab.37.2.252. [DOI] [PubMed] [Google Scholar]
  29. Simmons W. A., Taurog J. D., Hammer R. E., Breban M. Sharing of an HLA-B27-restricted H-Y antigen between rat and mouse. Immunogenetics. 1993;38(5):351–358. doi: 10.1007/BF00210477. [DOI] [PubMed] [Google Scholar]
  30. Stam N. J., Spits H., Ploegh H. L. Monoclonal antibodies raised against denatured HLA-B locus heavy chains permit biochemical characterization of certain HLA-C locus products. J Immunol. 1986 Oct 1;137(7):2299–2306. [PubMed] [Google Scholar]
  31. Stieglitz H., Fosmire S., Lipsky P. Identification of a 2-Md plasmid from Shigella flexneri associated with reactive arthritis. Arthritis Rheum. 1989 Aug;32(8):937–946. doi: 10.1002/anr.1780320802. [DOI] [PubMed] [Google Scholar]
  32. Taurog J. D., Maika S. D., Simmons W. A., Breban M., Hammer R. E. Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlates with the level of B27 expression. J Immunol. 1993 May 1;150(9):4168–4178. [PubMed] [Google Scholar]
  33. Taurog J. D., Sandberg G. P., Mahowald M. L. The cellular basis of adjuvant arthritis. I. Enhancement of cell-mediated passive transfer by concanavalin A and by immunosuppressive pretreatment of the recipient. Cell Immunol. 1983 Feb 1;75(2):271–282. doi: 10.1016/0008-8749(83)90325-8. [DOI] [PubMed] [Google Scholar]
  34. Wicker L. S., Miller B. J., Chai A., Terada M., Mullen Y. Expression of genetically determined diabetes and insulitis in the nonobese diabetic (NOD) mouse at the level of bone marrow-derived cells. Transfer of diabetes and insulitis to nondiabetic (NOD X B10) F1 mice with bone marrow cells from NOD mice. J Exp Med. 1988 Jun 1;167(6):1801–1810. doi: 10.1084/jem.167.6.1801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. van den Brink M. R., Hunt L. E., Hiserodt J. C. In vivo treatment with monoclonal antibody 3.2.3 selectively eliminates natural killer cells in rats. J Exp Med. 1990 Jan 1;171(1):197–210. doi: 10.1084/jem.171.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. von Boehmer H., Kisielow P. Self-nonself discrimination by T cells. Science. 1990 Jun 15;248(4961):1369–1373. doi: 10.1126/science.1972594. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES