Skip to main content
PMC home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 19;94(9):796–801. doi: 10.1111/j.1349-7006.2003.tb01521.x

Cyclosporine A effectively inhibits graft‐versus‐host disease during development of Epstein‐Barr virus‐infected human B cell lymphoma in SCID mouse

Runliang Gan 1,✉, Zhihua Yin 2, Tengfei Liu 2, Lijiang Wang 1, Yunlian Tang 1, Ying Song 1
PMCID: PMC11160143  PMID: 12967478

Abstract

We previously constructed human peripheral blood lymphocyte (hu‐PBL)/severe combined immunodeficiency mouse (SCID) chimeras and induced human B‐cell lymphomas associated with Epstein‐Barr virus (EBV) in SCID mice. However, a number of SCID mice died of graft‐versus‐host disease (GVHD) during the early experimental course. The aim of this study was to test the efficacy of cyclosporine A (CSA) for prevention of GVHD and to define how CSA inhibits the occurrence of GVHD and the production of soluble interleukin (IL) 2 receptor (sIL‐2R) in hu‐PBL/SCID mice. No mouse died in the active EBV infection group with CSA administration, while 17 mice in three groups without CSA administration died of GVHD. Mortalities in these three groups were 55.56% (5/9), 30.43% (7/23), and 27.78% (5/18), and the medium life span was 17 days. Over the first 33 days after hu‐PBL transplantation, serum level of human sIL‐2R in hu‐PBL/SCID chimeras was stable in the active EBV infection plus CSA group, while sIL‐2R concentration gradually increased in the sera of mice with active EBV infection without CSA administration and peaked at 22 days. Thirty‐two mice developed tumors among the 43 surviving SCID mice. There was no significant difference of tumor incidence between the active EBV infection groups with CSA and without CSA administration (P>0.05). From their morphological and immunohistochemical features, as well as detection of human Alu‐sequence and EBV in tumor cells, these EBV‐induced tumors were identified as human B‐cell lymphomas. Thus, CSA can strikingly inhibit GVHD in hu‐PBL/SCID chimeras, and should therefore be effective to establish a stable SCID mouse model of human lymphoma associated with EBV. Treatment with CSA had no effect on the tumor incidence in hu‐PBL/SCID chimeras after active EBV infection. Accordingly, serum level of sIL‐2R is a valuable indicator of GVHD occurrence in hu‐PBL/SCID chimeras.

References

  • 1. Papesch M, Watkins R. Epstein‐Barr virus infectious mononucleosis. Clin Otolaryngol 2001; 26: 3–8. [DOI] [PubMed] [Google Scholar]
  • 2. Chan KC, Zhang J, Chan AT, Lei KI, Leung SF, Chan LY, Chow KC, Lo YM. Molecular characterization of circulating EBV DNA in the plasma of nasopharyngeal carcinoma and lymphoma patients. Cancer Res 2003; 63: 2028–32. [PubMed] [Google Scholar]
  • 3. Westphal EM, Mauser A, Swenson J, Davis MG, Talarico CL, Kenney SC. Induction of lytic Epstein‐Barr virus (EBV) infection in EBV‐associated malignancies. Cancer Res 1999; 59: 1485–91. [PubMed] [Google Scholar]
  • 4. Henry S, Sacaze C, Berrajah L, Karray H, Drira M, Hammami A, Icart J, Mariame B. In nasopharyngeal carcinoma‐bearing patients, tumors and lymphocytes are infected by different Epstein‐Barr virus strains. Int J Cancer 2001; 91: 698–704. [DOI] [PubMed] [Google Scholar]
  • 5. Baran‐Marszak F, Fagard R, Girard B, Camilleri‐Broet S, Zeng F, Lenoir GM, Raphael M, Feuillard J. Gene array identification of Epstein Barr virusregulated cellular genes in EBV‐converted Burkitt lymphoma cell lines. Lab Invest 2002; 82: 1463–79. [DOI] [PubMed] [Google Scholar]
  • 6. Gan R, Lan K, Yin Z, Wang L, Xiu L, Yao K. Development of human B‐cell lymphomas induced by Epstein‐Barr virus in SCID mouse. Chin J Clin Oncol 2002; 29: 733–8. [Google Scholar]
  • 7. Funakoshi S, Beckwith M, Fanslow W, Longo DL, Murphy WJ. EpsteinBarr virus‐induced human B‐cell lymphoma arising in Hu‐PBL/SCID chimeric mice: characterization and the role of CD40 stimulation in their treatment and prevention. Pathobiology 1995; 63: 133–42. [DOI] [PubMed] [Google Scholar]
  • 8. Fuzzati‐Armentero MT, Duchosal MA. Hu‐PBL‐SCID mice: an in vivo model of Epstein‐Barr virus‐dependent lymphoproliferative disease. Histol Histopathol 1998; 13: 155–68. [DOI] [PubMed] [Google Scholar]
  • 9. Strauss G, Osen W, Debatin KM. Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs. Clin Exp Immunol 2002; 128: 255–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Asano M, Gundry SR, Izutani H, Cannarella SN, Fagoaga O, Bailey LL. Baboons undergoing orthotopic concordant cardiac xenotransplantation surviving more than 300 days: effect of immunosuppressive regimen. J Thorac Cardiovasc Surg 2003; 125: 60–9. [DOI] [PubMed] [Google Scholar]
  • 11. Saunders RN, Bicknell GR, Nicholson ML. The impact of cyclosporine dose reduction with or without the addition of rapamycin on functional, molecular, and histological markers of chronic allograft nephropathy. Transplantation 2003; 75: 772–80. [DOI] [PubMed] [Google Scholar]
  • 12. Sokol DK, Molleston JP, Filo RS, Van Valer J, Edwards‐Brown M. Tacrolimus (FK506)‐induced mutism after liver transplant. Pediatr Neurol 2003; 28: 156–8. [DOI] [PubMed] [Google Scholar]
  • 13. Arranz R, Conde E, Rodriguez‐Salvanes F, Pajuelo FJ, Cabrera R, Sanz MA, Petit J, Bueno J, Maldonado J, Odriozola J, Conde JG, Brunet S, Carreras E, Iriondo A, Fernandez‐Ranada JM, Marin P. CSA‐based post‐graft immuno‐suppression: the main factor for improving outcome of allograft patients with acquired aplastic anemia. Bone Marrow Transplant 2002; 29: 205–11. [DOI] [PubMed] [Google Scholar]
  • 14. Gonwa TA, Hricik DE, Brinker K, Grinyo JM, Schena FP. Improved renal function in sirolimus‐treated renal transplant patients after early cyclosporine elimination. Transplantation 2002; 74: 1560–7. [DOI] [PubMed] [Google Scholar]
  • 15. Osorio LM, Rottenberg M, Jondal M, Chow SC. Simultaneous cross‐linking of CD6 and CD28 induced cell proliferation in resting T cells. Immunology 1998; 93: 358–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Morris JC, Waldmann TA. Advances in interleukin 2 receptor targeted treatment. Ann Rheum Dis 2000; 59 Suppl 1: i109–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Casiraghi F, Ruggenenti P, Noris M, Locatelli G, Perico N, Perna A, Remuzzi G. Sequential monitoring of urine‐soluble interleukin 2 receptor and interleukin 6 predicts acute rejection of human renal allografts before clinical or laboratory signs of renal dysfunction. Transplantation 1997; 63: 1508–14. [DOI] [PubMed] [Google Scholar]
  • 18. Lun A, Cho MY, Muller C, Staffa G, Bechstein WO, Radke C, Neuhaus P, Renz H. Diagnostic value of peripheral blood T‐cell activation and soluble IL‐2 receptor for acute rejection in liver transplantation. Clin Chim Acta 2002; 320: 69–78. [DOI] [PubMed] [Google Scholar]
  • 19. Dejica D. Serum soluble IL‐2 receptor as a marker of lymphocyte activation in some autoimmune diseases. Roum Arch Microbiol Immunol 2001; 60: 183–201. [PubMed] [Google Scholar]
  • 20. Papadaki HA, Coulocheri S, Eliopoulos GD. Patients with chronic idiopathic neutropenia of adults have increased serum concentrations of inflammatory cytokines and chemokines. Am J Hematol 2000; 65: 271–7. [DOI] [PubMed] [Google Scholar]
  • 21. Porcel JM, Gazquez I, Vives M, Perez B, Rubio M, Rivas MC. Diagnosis of tuberculous pleuritis by the measurement of soluble interleukin 2 receptor in pleural fluid. Int J Tuberc Lung Dis 2000; 4: 975–9. [PubMed] [Google Scholar]
  • 22. Fukuchi Y, Miyakawa Y, Kizaki M, Umezawa A, Shimamura K, Kobayashi K, Kuramochi T, Hata J, Ikeda Y, Tamaoki N, Nomura T, Ueyama Y, Ito M. Human acute myelo‐blastic leukemia‐ascites model using the human GM‐CSF‐ and IL‐3‐releasing transgenic SCID mice. Ann Hematol 1999; 78: 223–31. [DOI] [PubMed] [Google Scholar]
  • 23. Fauser AA, Basara N, Blau IW, Kiehl MG. A comparative study of peripheral blood stem cell vs bone marrow transplantation from unrelated donors (MUD): a single center study. Bone Marrow Transplant 2000; 25 Suppl 2: S27–31. [DOI] [PubMed] [Google Scholar]
  • 24. Ji S, Chen H, Wang H, Ma J, Pan S, Xue M, Zhu L, Liu J, Xiao M, Zhou L. Low incidence of severe aGVHD and accelerating hemopoietic reconstitution in allo‐BMT using lenograstim stimulated BM cells. Chin Med J 2001; 114: 191–5. [PubMed] [Google Scholar]
  • 25. Kroger N, Einsele H, Wolff D, Casper J, Freund M, Derigs G, Wandt H, Schafer‐Eckart K, Wittkowsky G, Schmitz N, Kruger W, Zabelina T, Renges H, Ayuk F, Krull A, Zander A. Myeloablative intensified conditioning regimen with in vivo T‐cell depletion (ATG) followed by allografting in patients with advanced multiple myeloma: a phase I/II study of the German Studygroup Multiple Myeloma (DSMM). Bone Marrow Transplant 2003; 31: 973–9. [DOI] [PubMed] [Google Scholar]
  • 26. Van Dijk AM, Kessler FL, Stadhouders‐Keet SA, Verdonck LF, de Gast GC, Otten HG. Selective depletion of major and minor histocompatibility antigen reactive T cells: towards prevention of acute graft‐versus‐host disease. Br J Haematol 1999; 107: 169–75. [DOI] [PubMed] [Google Scholar]
  • 27. Simpson D. T‐cell depleting antibodies: new hope for induction of allograft tolerance in bone marrow transplantation. Bio Drugs 2003; 17: 147–54. [DOI] [PubMed] [Google Scholar]
  • 28. Shaw KT, Ho AM, Raghavan A, Kim J, Jain J, Park J, Sharma S, Rao A, Hogan PG. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci USA 1995; 92: 11205–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Krook H, Wennberg L, Hagberg A, Song Z, Groth CG, Korsgren O. Immunosuppressive drugs in islet xenotransplantation: a tool for gaining further insights in the mechanisms of the rejection process. Transplantation 2002; 74: 1084–9. [DOI] [PubMed] [Google Scholar]
  • 30. Miyamono T, Akashi K, Hayashi S, Gondo H, Murakawa M, Tanimoto K, Harada M, Niho Y. Serum concentration of the soluble interleukin‐2 receptor for monitoring acute graft‐versus‐host disease. Bone Marrow Transplant 1996; 17: 185–90. [PubMed] [Google Scholar]
  • 31. Economidou J, Barkis J, Demetriou Z, Avgerinou G, Psarra K, Degiannis D, Vareltzidis A, Katsambas A. Effects of cyclosporin A on immune activation markers in patients with active psoriasis. Dermatology 1999; 199: 144–8. [DOI] [PubMed] [Google Scholar]
  • 32. Mathias C, Mick R, Grupp S, Duffy K, Harris F, Laport G, Stadtmauer E, Luger S, Schuster S, Wasik MA, Porter DL. Soluble interleukin‐2 receptor concentration as a biochemical indicator for acute graft‐versus‐host disease after allogeneic bone marrow transplantation. J Hematother Stem Cell Res 2000; 9: 393–400. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES