Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1992 Dec 1;176(6):1763–1767. doi: 10.1084/jem.176.6.1763

Lymphoproliferative disease in human peripheral blood mononuclear cell- injected SCID mice. I. T lymphocyte requirement for B cell tumor generation

PMCID: PMC2119452  PMID: 1460431

Abstract

Mechanisms of tumor development were studied in SCID mice injected with human lymphoid cells from Epstein-Barr virus-positive (EBV+) donors. About 80% of peripheral blood mononuclear cell (PBMC)-injected animals developed a lymphoproliferative disease associated with oligoclonal EBV+ tumors of human B cell origin. No change in tumor development rate occurred when monocyte-depleted PBMC were inoculated. No tumors developed when purified B cells were injected. B cell lymphoproliferative disease was also prevented in most cases when PBMC- injected animals were treated with agents that prevent T cell activation, such as cyclosporin A. Both CD4+ and CD8+ T cell subpopulations were able to provide putative factor(s) necessary for EBV+ B cell expansion and progression to tumors. These data suggest that the transfer alone of potentially tumorigenic human cells into an immunodeficient environment, such as the SCID mouse, might not be sufficient for cell progression to tumor, and raise the possibility that chronic activation events could play a major role in the pathogenesis of some EBV+ lymphomas in the immunocompromised host.

Full Text

The Full Text of this article is available as a PDF (506.6 KB).

Selected References

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

  1. Amadori A., De Silvestro G., Zamarchi R., Veronese M. L., Mazza M. R., Schiavo G., Panozzo M., De Rossi A., Ometto L., Mous J. CD4 epitope masking by gp120/anti-gp120 antibody complexes. A potential mechanism for CD4+ cell function down-regulation in AIDS patients. J Immunol. 1992 May 1;148(9):2709–2716. [PubMed] [Google Scholar]
  2. Amadori A., De Silvestro G., Zamarchi R., Veronese M. L., Mazza M. R., Schiavo G., Panozzo M., De Rossi A., Ometto L., Mous J. CD4 epitope masking by gp120/anti-gp120 antibody complexes. A potential mechanism for CD4+ cell function down-regulation in AIDS patients. J Immunol. 1992 May 1;148(9):2709–2716. [PubMed] [Google Scholar]
  3. Amadori A., Zamarchi R., Ciminale V., Del Mistro A., Siervo S., Alberti A., Colombatti M., Chieco-Bianchi L. HIV-1-specific B cell activation. A major constituent of spontaneous B cell activation during HIV-1 infection. J Immunol. 1989 Oct 1;143(7):2146–2152. [PubMed] [Google Scholar]
  4. Amadori A., Zamarchi R., Veronese M. L., Panozzo M., Mazza M. R., Barelli A., Borri A., Chieco-Bianchi L. B-cell activation during HIV-1 infection. III. Down-regulating effect of mitogens. AIDS. 1991 Jul;5(7):821–828. doi: 10.1097/00002030-199107000-00005. [DOI] [PubMed] [Google Scholar]
  5. Amadori A., Zamarchi R., Veronese M. L., Panozzo M., Mazza M. R., Barelli A., Borri A., Chieco-Bianchi L. B-cell activation during HIV-1 infection. III. Down-regulating effect of mitogens. AIDS. 1991 Jul;5(7):821–828. doi: 10.1097/00002030-199107000-00005. [DOI] [PubMed] [Google Scholar]
  6. Borrebaeck C. A., Danielsson L., Möller S. A. Human monoclonal antibodies produced by primary in vitro immunization of peripheral blood lymphocytes. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3995–3999. doi: 10.1073/pnas.85.11.3995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bosma G. C., Custer R. P., Bosma M. J. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. doi: 10.1038/301527a0. [DOI] [PubMed] [Google Scholar]
  8. Brieva J. A., Targan S., Stevens R. H. NK and T cell subsets regulate antibody production by human in vivo antigen-induced lymphoblastoid B cells. J Immunol. 1984 Feb;132(2):611–615. [PubMed] [Google Scholar]
  9. Cannon M. J., Pisa P., Fox R. I., Cooper N. R. Epstein-Barr virus induces aggressive lymphoproliferative disorders of human B cell origin in SCID/hu chimeric mice. J Clin Invest. 1990 Apr;85(4):1333–1337. doi: 10.1172/JCI114573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Custer R. P., Bosma G. C., Bosma M. J. Severe combined immunodeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms. Am J Pathol. 1985 Sep;120(3):464–477. [PMC free article] [PubMed] [Google Scholar]
  11. Dorshkind K., Pollack S. B., Bosma M. J., Phillips R. A. Natural killer (NK) cells are present in mice with severe combined immunodeficiency (scid). J Immunol. 1985 Jun;134(6):3798–3801. [PubMed] [Google Scholar]
  12. Flanagan W. M., Corthésy B., Bram R. J., Crabtree G. R. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature. 1991 Aug 29;352(6338):803–807. doi: 10.1038/352803a0. [DOI] [PubMed] [Google Scholar]
  13. Gleichmann E., Gleichmann H., Schwartz R. S., Weinblatt A., Armstrong Y. K. Immunologic induction of malignant lymphoma: identification of donor and host tumors in the graft-versus-host model. J Natl Cancer Inst. 1975 Jan;54(1):107–116. doi: 10.1093/jnci/54.1.107. [DOI] [PubMed] [Google Scholar]
  14. Hudnall S. D. Cyclosporin A renders target cells resistant to immune cytolysis. Eur J Immunol. 1991 Jan;21(1):221–226. doi: 10.1002/eji.1830210133. [DOI] [PubMed] [Google Scholar]
  15. Ioachim H. L. The opportunistic tumors of immune deficiency. Adv Cancer Res. 1990;54:301–317. [PubMed] [Google Scholar]
  16. Kosugi A., Shearer G. M. Effect of cyclosporin A on lymphopoiesis. III. Augmentation of the generation of natural killer cells in bone marrow transplanted mice treated with cyclosporin A. J Immunol. 1991 Mar 1;146(5):1416–1421. [PubMed] [Google Scholar]
  17. McCune J. M., Namikawa R., Kaneshima H., Shultz L. D., Lieberman M., Weissman I. L. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988 Sep 23;241(4873):1632–1639. doi: 10.1126/science.241.4873.1632. [DOI] [PubMed] [Google Scholar]
  18. Mosier D. E., Gulizia R. J., Baird S. M., Wilson D. B. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988 Sep 15;335(6187):256–259. doi: 10.1038/335256a0. [DOI] [PubMed] [Google Scholar]
  19. Nadal D., Albini B., Schläpfer E., Bernstein J. M., Ogra P. L. Role of Epstein-Barr virus and interleukin 6 in the development of lymphomas of human origin in SCID mice engrafted with human tonsillar mononuclear cells. J Gen Virol. 1992 Jan;73(Pt 1):113–121. doi: 10.1099/0022-1317-73-1-113. [DOI] [PubMed] [Google Scholar]
  20. Pelicci P. G., Knowles D. M., 2nd, Arlin Z. A., Wieczorek R., Luciw P., Dina D., Basilico C., Dalla-Favera R. Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immune deficiency syndrome-related lymphoproliferative disorders. Implications for lymphomagenesis. J Exp Med. 1986 Dec 1;164(6):2049–2060. doi: 10.1084/jem.164.6.2049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Penn I. Tumors of the immunocompromised patient. Annu Rev Med. 1988;39:63–73. doi: 10.1146/annurev.me.39.020188.000431. [DOI] [PubMed] [Google Scholar]
  22. Pluda J. M., Yarchoan R., Jaffe E. S., Feuerstein I. M., Solomon D., Steinberg S. M., Wyvill K. M., Raubitschek A., Katz D., Broder S. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med. 1990 Aug 15;113(4):276–282. doi: 10.7326/0003-4819-113-4-276. [DOI] [PubMed] [Google Scholar]
  23. Purtilo D. T., Falk K., Pirruccello S. J., Nakamine H., Kleveland K., Davis J. R., Okano M., Taguchi Y., Sanger W. G., Beisel K. W. SCID mouse model of Epstein-Barr virus-induced lymphomagenesis of immunodeficient humans. Int J Cancer. 1991 Feb 20;47(4):510–517. doi: 10.1002/ijc.2910470407. [DOI] [PubMed] [Google Scholar]
  24. Rowe M., Young L. S., Crocker J., Stokes H., Henderson S., Rickinson A. B. Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man. J Exp Med. 1991 Jan 1;173(1):147–158. doi: 10.1084/jem.173.1.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11;254(5029):279–282. doi: 10.1126/science.254.5029.279. [DOI] [PubMed] [Google Scholar]
  26. Suciu-Foca N., Dumitrescu V., Lazar C., Nachtigal M. Host and tumor modifications associated with serial heterotransplantation of tumors through immunologically tolerant animals. Cancer Res. 1970 Jun;30(6):1681–1691. [PubMed] [Google Scholar]
  27. Swinnen L. J., Costanzo-Nordin M. R., Fisher S. G., O'Sullivan E. J., Johnson M. R., Heroux A. L., Dizikes G. J., Pifarre R., Fisher R. I. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med. 1990 Dec 20;323(25):1723–1728. doi: 10.1056/NEJM199012203232502. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Thiele D. L., Lipsky P. E. The immunosuppressive activity of L-leucyl-L-leucine methyl ester: selective ablation of cytotoxic lymphocytes and monocytes. J Immunol. 1986 Feb 1;136(3):1038–1048. [PubMed] [Google Scholar]
  30. Tosato G., Blaese R. M. Epstein-Barr virus infection and immunoregulation in man. Adv Immunol. 1985;37:99–149. doi: 10.1016/s0065-2776(08)60339-9. [DOI] [PubMed] [Google Scholar]

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

RESOURCES