Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1998 Jun;152(6):1681–1688.

Tuberculin-induced delayed-type hypersensitivity reaction in a model of hu-PBMC-SCID mice grafted with autologous skin.

A Tsicopoulos 1, J Pestel 1, O Fahy 1, H Vorng 1, F Vandenbusche 1, H Porte 1, L Eraldi 1, A Wurtz 1, H Akoum 1, Q Hamid 1, B Wallaert 1, A B Tonnel 1
PMCID: PMC1858436  PMID: 9626072

Abstract

We have developed an animal model to study human delayed-type hypersensitivity reactions. Previous studies in humans have shown after tuberculin injection the presence of a mononuclear cell infiltration, with almost no eosinophils, associated with a preferential Th-1-type cytokine profile. Human skin graft obtained from tuberculin-reactive donors was grafted onto the back of severe combined immunodeficient mice. After healing, mice were reconstituted intraperitoneally with peripheral mononuclear cells. Tuberculin and diluent were injected intradermally, and skin biopsies were performed 72 hours later. Skin grafts were divided into two parts, one for immunohistochemistry and one for in situ hybridization studies. Immunohistochemistry was performed on cryostat sections using the alkaline phosphatase anti-alkaline phosphatase technique. In the tuberculin-injected sites as compared with the diluent-injected sites, there were significant increases in the number of CD45+ pan leukocytes and CD4+, CD8+, CD45RO+ T cells but not in CD68+ monocytes/macrophages and EG2 or MBP+ eosinophils. The activation markers CD25 and HLA-DR were up-regulated in the tuberculin-injected sites. In situ hybridization was performed using 35S-labeled riboprobes for interleukin (IL)-2, interferon (IFN)-gamma, IL-4, and IL-5. After tuberculin injection, a preferential Th-1-type cytokine profile was observed with significant increases in the numbers of IL-2 and IFN-gamma mRNA-expressing cells. These results are similar to those reported after tuberculin-induced delayed-type hypersensitivity in humans, suggesting that this model might be useful to study cutaneous inflammatory reaction.

Full text

PDF
1681

Images in this article

1686Figure 4
on p.1686

Selected References

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

  1. Abbas A. K., Murphy K. M., Sher A. Functional diversity of helper T lymphocytes. Nature. 1996 Oct 31;383(6603):787–793. doi: 10.1038/383787a0. [DOI] [PubMed] [Google Scholar]
  2. Alegre M. L., Peterson L. J., Jeyarajah D. R., Weiser M., Bluestone J. A., Thistlethwaite J. R. Severe combined immunodeficient mice engrafted with human splenocytes have functional human T cells and reject human allografts. J Immunol. 1994 Sep 15;153(6):2738–2749. [PubMed] [Google Scholar]
  3. Boehncke W. H., Zollner T. M., Dressel D., Kaufmann R. Induction of psoriasiform inflammation by a bacterial superantigen in the SCID-hu xenogeneic transplantation model. J Cutan Pathol. 1997 Jan;24(1):1–7. doi: 10.1111/j.1600-0560.1997.tb00778.x. [DOI] [PubMed] [Google Scholar]
  4. Charley M. R., Tharp M., Locker J., Deng J. S., Goslen J. B., Mauro T., McCoy P., Abell E., Jegasothy B. Establishment of a human cutaneous T-cell lymphoma in C.B-17 SCID mice. J Invest Dermatol. 1990 Mar;94(3):381–384. doi: 10.1111/1523-1747.ep12874500. [DOI] [PubMed] [Google Scholar]
  5. Cher D. J., Mosmann T. R. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol. 1987 Jun 1;138(11):3688–3694. [PubMed] [Google Scholar]
  6. Christofidou-Solomidou M., Albelda S. M., Bennett F. C., Murphy G. F. Experimental production and modulation of human cytotoxic dermatitis in human-murine chimeras. Am J Pathol. 1997 Feb;150(2):631–639. [PMC free article] [PubMed] [Google Scholar]
  7. Christofidou-Solomidou M., Murphy G. F., Albelda S. M. Induction of E-selectin-dependent leukocyte recruitment by mast cell degranulation in human skin grafts transplanted on SCID mice. Am J Pathol. 1996 Jan;148(1):177–188. [PMC free article] [PubMed] [Google Scholar]
  8. Del Prete G. F., De Carli M., Mastromauro C., Biagiotti R., Macchia D., Falagiani P., Ricci M., Romagnani S. Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest. 1991 Jul;88(1):346–350. doi: 10.1172/JCI115300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Duez C., Tsicopoulos A., Janin A., Tillie-Leblond I., Thyphronitis G., Marquillies P., Hamid Q., Wallaert B., Tonnel A. B., Pestel J. An in vivo model of allergic inflammation: pulmonary human cell infiltrate in allergen-challenged allergic Hu-SCID mice. Eur J Immunol. 1996 May;26(5):1088–1093. doi: 10.1002/eji.1830260520. [DOI] [PubMed] [Google Scholar]
  10. Gaga M., Frew A. J., Varney V. A., Kay A. B. Eosinophil activation and T lymphocyte infiltration in allergen-induced late phase skin reactions and classical delayed-type hypersensitivity. J Immunol. 1991 Aug 1;147(3):816–822. [PubMed] [Google Scholar]
  11. Gilhar A., David M., Ullmann Y., Berkutski T., Kalish R. S. T-lymphocyte dependence of psoriatic pathology in human psoriatic skin grafted to SCID mice. J Invest Dermatol. 1997 Sep;109(3):283–288. doi: 10.1111/1523-1747.ep12335758. [DOI] [PubMed] [Google Scholar]
  12. Hamid Q., Wharton J., Terenghi G., Hassall C. J., Aimi J., Taylor K. M., Nakazato H., Dixon J. E., Burnstock G., Polak J. M. Localization of atrial natriuretic peptide mRNA and immunoreactivity in the rat heart and human atrial appendage. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6760–6764. doi: 10.1073/pnas.84.19.6760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Juhasz I., Lazarus G. S., Murphy G. F., Shih I. M., Herlyn M. Development of pemphigus vulgaris-like lesions in severe combined immunodeficiency disease mice reconstituted with lymphocytes from patients. J Clin Invest. 1993 Nov;92(5):2401–2407. doi: 10.1172/JCI116846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kawamura T., Niguma T., Fechner J. H., Jr, Wolber R., Beeskau M. A., Hullett D. A., Sollinger H. W., Burlingham W. J. Chronic human skin graft rejection in severe combined immunodeficient mice engrafted with human PBL from an HLA-presensitized donor. Transplantation. 1992 Mar;53(3):659–665. doi: 10.1097/00007890-199203000-00032. [DOI] [PubMed] [Google Scholar]
  15. Kim Y. H., Woodley D. T., Wynn K. C., Giomi W., Bauer E. A. Recessive dystrophic epidermolysis bullosa phenotype is preserved in xenografts using SCID mice: development of an experimental in vivo model. J Invest Dermatol. 1992 Feb;98(2):191–197. doi: 10.1111/1523-1747.ep12555849. [DOI] [PubMed] [Google Scholar]
  16. Kunstfeld R., Lechleitner S., Gröger M., Wolff K., Petzelbauer P. HECA-452+ T cells migrate through superficial vascular plexus but not through deep vascular plexus endothelium. J Invest Dermatol. 1997 Mar;108(3):343–348. doi: 10.1111/1523-1747.ep12286483. [DOI] [PubMed] [Google Scholar]
  17. Marchal G., Seman M., Milon G., Truffa-Bachi P., Zilberfarb V. Local adoptive transfer of skin delayed-type hypersensitivity initiated by a single T lymphocyte. J Immunol. 1982 Sep;129(3):954–958. [PubMed] [Google Scholar]
  18. Mazingue C., Cottrez F., Auriault C., Cesbron J. Y., Capron A. Obtention of a human primary humoral response against schistosome protective antigens in severe combined immunodeficiency mice after the transfer of human peripheral blood mononuclear cells. Eur J Immunol. 1991 Jul;21(7):1763–1766. doi: 10.1002/eji.1830210728. [DOI] [PubMed] [Google Scholar]
  19. Miossec P., Ziff M. Immune interferon enhances the production of interleukin 1 by human endothelial cells stimulated with lipopolysaccharide. J Immunol. 1986 Nov 1;137(9):2848–2852. [PubMed] [Google Scholar]
  20. Murphy W. J., Taub D. D., Anver M., Conlon K., Oppenheim J. J., Kelvin D. J., Longo D. L. Human RANTES induces the migration of human T lymphocytes into the peripheral tissues of mice with severe combined immune deficiency. Eur J Immunol. 1994 Aug;24(8):1823–1827. doi: 10.1002/eji.1830240815. [DOI] [PubMed] [Google Scholar]
  21. Murphy W. J., Tian Z. G., Asai O., Funakoshi S., Rotter P., Henry M., Strieter R. M., Kunkel S. L., Longo D. L., Taub D. D. Chemokines and T lymphocyte activation: II. Facilitation of human T cell trafficking in severe combined immunodeficiency mice. J Immunol. 1996 Mar 15;156(6):2104–2111. [PubMed] [Google Scholar]
  22. Murray A. G., Petzelbauer P., Hughes C. C., Costa J., Askenase P., Pober J. S. Human T-cell-mediated destruction of allogeneic dermal microvessels in a severe combined immunodeficient mouse. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):9146–9150. doi: 10.1073/pnas.91.19.9146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mårtensson C., Kristensson K., Kalliomäki S., Borrebaeck C. A., Carlsson R. Antigen-specific human immunoglobulin production in SCID mice transplanted with human peripheral lymphocytes is dependent on CD4+ CD45RO+ T cells. Immunology. 1994 Oct;83(2):171–179. [PMC free article] [PubMed] [Google Scholar]
  24. Nickoloff B. J., Kunkel S. L., Burdick M., Strieter R. M. Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model. Am J Pathol. 1995 Mar;146(3):580–588. [PMC free article] [PubMed] [Google Scholar]
  25. Nonoyama S., Smith F. O., Ochs H. D. Specific antibody production to a recall or a neoantigen by SCID mice reconstituted with human peripheral blood lymphocytes. J Immunol. 1993 Oct 1;151(7):3894–3901. [PubMed] [Google Scholar]
  26. Pestel J., Jeannin P., Delneste Y., Dessaint J. P., Cesbron J. Y., Capron A., Tsicopoulos A., Tonnel A. B. Human IgE in SCID mice reconstituted with peripheral blood mononuclear cells from Dermatophagoides pteronyssinus-sensitive patients. J Immunol. 1994 Oct 15;153(8):3804–3810. [PubMed] [Google Scholar]
  27. Petzelbauer P., Gröger M., Kunstfeld R., Petzelbauer E., Wolff K. Human delayed-type hypersensitivity reaction in a SCID mouse engrafted with human T cells and autologous skin. J Invest Dermatol. 1996 Oct;107(4):576–581. doi: 10.1111/1523-1747.ep12582823. [DOI] [PubMed] [Google Scholar]
  28. Platt J. L., Grant B. W., Eddy A. A., Michael A. F. Immune cell populations in cutaneous delayed-type hypersensitivity. J Exp Med. 1983 Oct 1;158(4):1227–1242. doi: 10.1084/jem.158.4.1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Poulter L. W., Seymour G. J., Duke O., Janossy G., Panayi G. Immunohistological analysis of delayed-type hypersensitivity in man. Cell Immunol. 1982 Dec;74(2):358–369. doi: 10.1016/0008-8749(82)90036-3. [DOI] [PubMed] [Google Scholar]
  30. Scheynius A., Klareskog L., Forsum U. In situ identification of T lymphocyte subsets and HLA-DR expressing cells in the human skin tuberculin reaction. Clin Exp Immunol. 1982 Aug;49(2):325–330. [PMC free article] [PubMed] [Google Scholar]
  31. Spiegelberg H. L., Beck L., Kocher H. P., Fanslow W. C., Lucas A. H. Role of interleukin-4 in human immunoglobulin E formation in hu-PBL-SCID mice. J Clin Invest. 1994 Feb;93(2):711–717. doi: 10.1172/JCI117024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Street N. E., Mosmann T. R. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J. 1991 Feb;5(2):171–177. doi: 10.1096/fasebj.5.2.1825981. [DOI] [PubMed] [Google Scholar]
  33. Sultan P., Schechner J. S., McNiff J. M., Hochman P. S., Hughes C. C., Lorber M. I., Askenase P. W., Pober J. S. Blockade of CD2-LFA-3 interactions protects human skin allografts in immunodeficient mouse/human chimeras. Nat Biotechnol. 1997 Aug;15(8):759–762. doi: 10.1038/nbt0897-759. [DOI] [PubMed] [Google Scholar]
  34. Tary-Lehmann M., Lehmann P. V., Schols D., Roncarolo M. G., Saxon A. Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras. J Exp Med. 1994 Nov 1;180(5):1817–1827. doi: 10.1084/jem.180.5.1817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tary-Lehmann M., Saxon A. Human mature T cells that are anergic in vivo prevail in SCID mice reconstituted with human peripheral blood. J Exp Med. 1992 Feb 1;175(2):503–516. doi: 10.1084/jem.175.2.503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tsicopoulos A., Hamid Q., Haczku A., Jacobson M. R., Durham S. R., North J., Barkans J., Corrigan C. J., Meng Q., Moqbel R. Kinetics of cell infiltration and cytokine messenger RNA expression after intradermal challenge with allergen and tuberculin in the same atopic individuals. J Allergy Clin Immunol. 1994 Oct;94(4):764–772. doi: 10.1016/0091-6749(94)90185-6. [DOI] [PubMed] [Google Scholar]
  37. Tsicopoulos A., Hamid Q., Varney V., Ying S., Moqbel R., Durham S. R., Kay A. B. Preferential messenger RNA expression of Th1-type cells (IFN-gamma+, IL-2+) in classical delayed-type (tuberculin) hypersensitivity reactions in human skin. J Immunol. 1992 Apr 1;148(7):2058–2061. [PubMed] [Google Scholar]
  38. Vaporciyan A. A., DeLisser H. M., Yan H. C., Mendiguren I. I., Thom S. R., Jones M. L., Ward P. A., Albelda S. M. Involvement of platelet-endothelial cell adhesion molecule-1 in neutrophil recruitment in vivo. Science. 1993 Dec 3;262(5139):1580–1582. doi: 10.1126/science.8248808. [DOI] [PubMed] [Google Scholar]
  39. Walker W., Brewer J. M., Alexander J. Lipid vesicle-entrapped influenza A antigen modulates the influenza A-specific human antibody response in immune reconstituted SCID-human mice. Eur J Immunol. 1996 Jul;26(7):1664–1667. doi: 10.1002/eji.1830260740. [DOI] [PubMed] [Google Scholar]
  40. Wrone-Smith T., Nickoloff B. J. Dermal injection of immunocytes induces psoriasis. J Clin Invest. 1996 Oct 15;98(8):1878–1887. doi: 10.1172/JCI118989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Yan H. C., Delisser H. M., Pilewski J. M., Barone K. M., Szklut P. J., Chang X. J., Ahern T. J., Langer-Safer P., Albelda S. M. Leukocyte recruitment into human skin transplanted onto severe combined immunodeficient mice induced by TNF-alpha is dependent on E-selectin. J Immunol. 1994 Mar 15;152(6):3053–3063. [PubMed] [Google Scholar]
  42. Yan H. C., Juhasz I., Pilewski J., Murphy G. F., Herlyn M., Albelda S. M. Human/severe combined immunodeficient mouse chimeras. An experimental in vivo model system to study the regulation of human endothelial cell-leukocyte adhesion molecules. J Clin Invest. 1993 Mar;91(3):986–996. doi: 10.1172/JCI116320. [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