Advertisement

Immunologic Research

, Volume 58, Issue 2–3, pp 268–276 | Cite as

The interplay between Epstein–Barr virus and B lymphocytes: implications for infection, immunity, and disease

  • Olivia L. Hatton
  • Aleishia Harris-Arnold
  • Steven Schaffert
  • Sheri M. Krams
  • Olivia M. Martinez
IMMUNOLOGY AT STANFORD UNIVERSITY

Abstract

Human B cells are the primary targets of Epstein–Barr virus (EBV) infection. In most cases, EBV infection is asymptomatic because of a highly effective host immune response, but some individuals develop self-limiting infectious mononucleosis, while others develop EBV-associated lymphoid or epithelial malignancies. The viral and immune factors that determine the outcome of infection are not understood. The EBV life cycle includes a lytic phase, culminating in the production of new viral particles, and a latent phase, during which the virus remains largely silent for the lifetime of the host in memory B cells. Thus, in healthy individuals, there is a tightly orchestrated interplay between EBV and the host that allows the virus to persist. To promote viral persistence, EBV has evolved a variety of strategies to modulate the host immune response including inhibition of immune cell function, blunting of apoptotic pathways, and interfering with antigen processing and presentation pathways. In this article, we focus on mechanisms by which dysregulation of the host B cell and immune modulation by the virus can contribute to development of EBV+ B cell lymphomas.

Keywords

B cells Epstein–Barr virus Latent membrane protein 1 microRNA Signal transduction 

Notes

Acknowledgments

This work was supported by NIH award RO1 AI41769 (OMM), a ROTRF award (OMM), and the Lucile Salter Packard Foundation. Dr. Olivia Hatton is supported by an NIH IRACDA Fellowship, Dr. Steven Schaffert is supported by a Transplant and Tissue Engineering Center of Excellence Fellowship, and Aleishia Harris–Arnold is supported by an NIH pre-doctoral training award.

References

  1. 1.
    Shannon-Lowe C, Rowe M. Epstein-Barr virus infection of polarized epithelial cells via the basolateral surface by memory B cell-mediated transfer infection. PLoS Pathog. 2011;7(5):e1001338 (Epub 2011/05/17).PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Heath E, Begue-Pastor N, Chaganti S, Croom-Carter D, Shannon-Lowe C, Kube D, et al. Epstein-Barr virus infection of naive B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology. PLoS Pathog. 2012;8(5):e1002697 (Epub 2012/05/17).PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Kurth J, Spieker T, Wustrow J, Strickler GJ, Hansmann LM, Rajewsky K, et al. EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency. Immunity. 2000;13(4):485–95 (Epub 2000/11/09).CrossRefPubMedGoogle Scholar
  4. 4.
    Tracy SI, Kakalacheva K, Lunemann JD, Luzuriaga K, Middeldorp J, Thorley-Lawson DA. Persistence of Epstein-Barr virus in self-reactive memory B cells. J Virol. 2012;86(22):12330–40 (Epub 2012/09/07).PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Angelini DF, Serafini B, Piras E, Severa M, Coccia EM, Rosicarelli B, et al. Increased CD8 + T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog. 2013;9(4):e1003220 (Epub 2013/04/18).PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Hislop AD, Taylor GS, Sauce D, Rickinson AB. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol. 2007;25:587–617.CrossRefPubMedGoogle Scholar
  7. 7.
    Callan MF, Tan L, Annels N, Ogg GS, Wilson JD, O’Callaghan CA, et al. Direct visualization of antigen-specific CD8 + T cells during the primary immune response to Epstein-Barr virus In vivo. J Exp Med. 1998;187(9):1395–402.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Long HM, Chagoury OL, Leese AM, Ryan GB, James E, Morton LT, et al. MHC II tetramers visualize human CD4 + T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response. J Exp Med. 2013;210(5):933–49 (Epub 2013/04/10).PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Falco DA, Nepomuceno RR, Krams SM, Lee PP, Davis MM, Salvatierra O, et al. Identification of Epstein-Barr virus-specific CD8 + T lymphocytes in the circulation of pediatric transplant recipients. Transplantation. 2002;74(4):501–10 Epub 2002/09/28.CrossRefPubMedGoogle Scholar
  10. 10.
    Macedo C, Webber SA, Donnenberg AD, Popescu I, Hua Y, Green M, et al. EBV-specific CD8 + T cells from asymptomatic pediatric thoracic transplant patients carrying chronic high EBV loads display contrasting features: activated phenotype and exhausted function. J Immunol. 2011;186(10):5854–62 Epub 2011/04/05.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Williams H, McAulay K, Macsween KF, Gallacher NJ, Higgins CD, Harrison N, et al. The immune response to primary EBV infection: a role for natural killer cells. Br J Haematol. 2005;129(2):266–74 Epub 2005/04/09.CrossRefPubMedGoogle Scholar
  12. 12.
    Chijioke O, Muller A, Feederle R, Barros MH, Krieg C, Emmel V, et al. Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein–Barr virus infection. Cell Rep. 2013;5(6):1489–98 Epub 2013/12/24.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Lunemann A, Vanoaica LD, Azzi T, Nadal D, Munz C. A distinct subpopulation of human NK cells restricts B cell transformation by EBV. J Immunol. 2013;191(10):4989–95 Epub 2013/10/11.CrossRefPubMedGoogle Scholar
  14. 14.
    Chaigne-Delalande B, Li FY, O’Connor GM, Lukacs MJ, Jiang P, Zheng L, et al. Mg2 + regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science. 2013;341(6142):186–91 Epub 2013/07/13.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S, Franceschini R, et al. X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. J Exp Med. 2000;192(3):337–46 Epub 2000/08/10.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Eidenschenk C, Dunne J, Jouanguy E, Fourlinnie C, Gineau L, Bacq D, et al. A novel primary immunodeficiency with specific natural-killer cell deficiency maps to the centromeric region of chromosome 8. Am J Hum Genet. 2006;78(4):721–7 Epub 2006/03/15.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Shaw RK, Issekutz AC, Fraser R, Schmit P, Morash B, Monaco-Shawver L, et al. Bilateral adrenal EBV-associated smooth muscle tumors in a child with a natural killer cell deficiency. Blood. 2012;119(17):4009–12 Epub 2012/03/20.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Snow AL, Martinez OM. Epstein-Barr virus: evasive maneuvers in the development of PTLD. Am J Transpl. 2007;7(2):271–7.CrossRefGoogle Scholar
  19. 19.
    Ning S. Innate immune modulation in EBV infection. Herpesviridae. 2011;2(1):1 (Epub 2011/03/25).PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Ressing ME, Horst D, Griffin BD, Tellam J, Zuo J, Khanna R, et al. Epstein–Barr virus evasion of CD8(+) and CD4(+) T cell immunity via concerted actions of multiple gene products. Semin Cancer Biol. 2008;18(6):397–408 Epub 2008/11/04.CrossRefPubMedGoogle Scholar
  21. 21.
    Jochum S, Moosmann A, Lang S, Hammerschmidt W, Zeidler R. The EBV immunoevasins vIL-10 and BNLF2a protect newly infected B cells from immune recognition and elimination. PLoS Pathog. 2012;8(5):e1002704 (Epub 2012/05/23).PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Cohen JI, Lekstrom K. Epstein–Barr virus BARF1 protein is dispensable for B-cell transformation and inhibits alpha interferon secretion from mononuclear cells. J Virol. 1999;73(9):7627–32 (Epub 1999/08/10).PubMedCentralPubMedGoogle Scholar
  23. 23.
    Tellam J, Connolly G, Green KJ, Miles JJ, Moss DJ, Burrows SR, et al. Endogenous presentation of CD8 + T cell epitopes from Epstein-Barr virus-encoded nuclear antigen 1. J Exp Med. 2004;199(10):1421–31 (Epub 2004/05/19).PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Voo KS, Fu T, Wang HY, Tellam J, Heslop HE, Brenner MK, et al. Evidence for the presentation of major histocompatibility complex class I-restricted Epstein–Barr virus nuclear antigen 1 peptides to CD8 + T lymphocytes. J Exp Med. 2004;199(4):459–70 (Epub 2004/02/11).PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Hislop AD, Ressing ME, van Leeuwen D, Pudney VA, Horst D, Koppers-Lalic D, et al. A CD8 + T cell immune evasion protein specific to Epstein–Barr virus and its close relatives in old world primates. J Exp Med. 2007;204(8):1863–73 (Epub 2007/07/11).PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Zuo J, Thomas W, van Leeuwen D, Middeldorp JM, Wiertz EJ, Ressing ME, et al. The DNase of gammaherpesviruses impairs recognition by virus-specific CD8 + T cells through an additional host shutoff function. J Virol. 2008;82(5):2385–93.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Zuo J, Currin A, Griffin BD, Shannon-Lowe C, Thomas WA, Ressing ME, et al. The Epstein-Barr virus G-protein-coupled receptor contributes to immune evasion by targeting MHC class I molecules for degradation. PLoS Pathog. 2009;5(1):e1000255 (Epub 2009/01/03).PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Desbien AL, Kappler JW, Marrack P. The Epstein–Barr virus Bcl-2 homolog, BHRF1, blocks apoptosis by binding to a limited amount of Bim. Proc Natl Acad Sci U S A. 2009;106(14):5663–8 Epub 2009/03/19.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Snow AL, Chen LJ, Nepomuceno RR, Krams SM, Esquivel CO, Martinez OM. Resistance to Fas-mediated apoptosis in EBV-infected B cell lymphomas is due to defects in the proximal Fas signaling pathway. J Immunol. 2001;167(9):5404–11 Epub 2001/10/24.CrossRefPubMedGoogle Scholar
  30. 30.
    Snow AL, Lambert SL, Natkunam Y, Esquivel CO, Krams SM, Martinez OM. EBV can protect latently infected B cell lymphomas from death receptor-induced apoptosis. J Immunol. 2006;177(5):3283–93 Epub 2006/08/22.CrossRefPubMedGoogle Scholar
  31. 31.
    Laherty CD, Hu HM, Opipari AW, Wang F, Dixit VM. The Epstein–Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor kappa B. J Biol Chem. 1992;267(34):24157–60.PubMedGoogle Scholar
  32. 32.
    Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, et al. Induction of bcl-2 expression by Epstein–Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell. 1991;65(7):1107–15.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang S, Rowe M, Lundgren E. Expression of the Epstein Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines. Cancer Res. 1996;56(20):4610–3.PubMedGoogle Scholar
  34. 34.
    Hong SY, Yoon WH, Park JH, Kang SG, Ahn JH, Lee TH. Involvement of two NF-kappa B binding elements in tumor necrosis factor alpha-, CD40-, and Epstein–Barr virus latent membrane protein 1-mediated induction of the cellular inhibitor of apoptosis protein 2 gene. J Biol Chem. 2000;275(24):18022–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Kaye K, Izumi KM, Kieff E. Epstein Barr virus latent membrane protein 1 is essential for B lymphocyte growth transformation. Proc Natl Acad Sci U S A. 1993;90:9150–4.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985;43(3 Pt 2):831–40.CrossRefPubMedGoogle Scholar
  37. 37.
    Beatty PR, Krams SM, Martinez OM. Involvement of IL-10 in the autonomous growth of EBV-transformed B cell lines. J Immunol. 1997;158(9):4045–51 (Epub 1997/05/01).PubMedGoogle Scholar
  38. 38.
    Martinez OM, Villanueva JC, Lawrence-Miyasaki L, Quinn MB, Cox K, Krams SM. Viral and immunologic aspects of Epstein–Barr virus infection in pediatric liver transplant recipients. Transplantation. 1995;59(4):519–24 (Epub 1995/02/27).CrossRefPubMedGoogle Scholar
  39. 39.
    Nepomuceno RR, Balatoni CE, Natkunam Y, Snow AL, Krams SM, Martinez OM. Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res. 2003;63(15):4472–80 (Epub 2003/08/09).PubMedGoogle Scholar
  40. 40.
    Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221–41 (Epub 2012/01/10).CrossRefPubMedGoogle Scholar
  41. 41.
    Lambert SL, Martinez OM. Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. J Immunol. 2007;179(12):8225–34.CrossRefPubMedGoogle Scholar
  42. 42.
    Hatton O, Lambert SL, Krams SM, Martinez OM. Src kinase and Syk activation initiate PI3 K signaling by a chimeric latent membrane protein 1 in Epstein–Barr virus (EBV) + B cell lymphomas. PLoS ONE. 2012;7(8):e42610.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Hatton O, Phillips LK, Vaysberg M, Hurwich J, Krams SM, Martinez OM. Syk activation of phosphatidylinositol 3-kinase/Akt prevents HtrA2-dependent loss of X-linked inhibitor of apoptosis protein (XIAP) to promote survival of Epstein–Barr virus + (EBV +) B cell lymphomas. J Biol Chem. 2011;286(43):37368–78 (Epub 2011/09/13).PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Vaysberg M, Balatoni CE, Nepomuceno RR, Krams SM, Martinez OM. Rapamycin inhibits proliferation of Epstein–Barr virus-positive B-cell lymphomas through modulation of cell-cycle protein expression. Transplantation. 2007;83(8):1114–21.CrossRefPubMedGoogle Scholar
  45. 45.
    Furukawa S, Wei L, Krams SM, Esquivel CO, Martinez OM. PI3 K delta inhibition augments the efficacy of rapamycin in suppressing proliferation of Epstein-Barr virus (EBV) + B cell lymphomas. Am J Transpl. 2013;13(8):2035–43 (Epub 2013/07/12).CrossRefGoogle Scholar
  46. 46.
    Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ, Ju J, et al. Identification of virus-encoded microRNAs. Science. 2004;304(5671):734–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Kincaid RP, Sullivan CS. Virus-encoded microRNAs: an overview and a look to the future. PLoS Pathog. 2012;8(12):e1003018 (Epub 2013/01/12).PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Harris A, Krams SM, Martinez OM. MicroRNAs as immune regulators: implications for transplantation. Am J Transpl. 2010;10(4):713–9 (Epub 2010/03/05).CrossRefGoogle Scholar
  49. 49.
    Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316(5824):604–8 Epub 2007/04/28.CrossRefPubMedGoogle Scholar
  50. 50.
    Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF, et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A. 2005;102(10):3627–32 (Epub 2005/03/02).PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Kluiver J, Poppema S, de Jong D, Blokzijl T, Harms G, Jacobs S, et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol. 2005;207(2):243–9 Epub 2005/07/26.CrossRefPubMedGoogle Scholar
  52. 52.
    Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N, et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci U S A. 2006;103(18):7024–9 Epub 2006/04/28.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Thapa DR, Bhatia K, Bream JH, D’Souza G, Rinaldo CR, Wolinsky S, et al. B-cell activation induced microRNA-21 is elevated in circulating B cells preceding the diagnosis of AIDS-related non-Hodgkin lymphomas. AIDS. 2012;26(9):1177–80 Epub 2012/04/11.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, et al. PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res. 2004;64(21):7655–60 (Epub 2004/11/03).CrossRefPubMedGoogle Scholar
  55. 55.
    Medina PP, Nolde M, Slack FJ. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature. 2010;467(7311):86–90 Epub 2010/08/10.CrossRefPubMedGoogle Scholar
  56. 56.
    Skalsky RL, Corcoran DL, Gottwein E, Frank CL, Kang D, Hafner M, et al. The viral and cellular microRNA targetome in lymphoblastoid cell lines. PLoS Pathog. 2012;8(1):e1002484 (Epub 2012/02/01).PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Vaysberg M, Hatton O, Lambert SL, Snow AL, Wong B, Krams SM, et al. Tumor-derived variants of Epstein–Barr virus latent membrane protein 1 induce sustained Erk activation and c-Fos. J Biol Chem. 2008;283(52):36573–85 Epub 2008/11/07.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Chen ML, Tsai CN, Liang CL, Shu CH, Huang CR, Sulitzeanu D, et al. Cloning and characterization of the latent membrane protein (LMP) of a specific Epstein–Barr virus variant derived from the nasopharyngeal carcinoma in the Taiwanese population. Oncogene. 1992;7(11):2131–40 Epub 1992/11/01.PubMedGoogle Scholar
  59. 59.
    Li SN, Chang YS, Liu ST. Effect of a 10-amino acid deletion on the oncogenic activity of latent membrane protein 1 of Epstein–Barr virus. Oncogene. 1996;12(10):2129–35 Epub 1996/05/16.PubMedGoogle Scholar
  60. 60.
    Johnson RJ, Stack M, Hazlewood SA, Jones M, Blackmore CG, Hu LF, et al. The 30-base-pair deletion in Chinese variants of the Epstein–Barr virus LMP1 gene is not the major effector of functional differences between variant LMP1 genes in human lymphocytes. J Virol. 1998;72(5):4038–48.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Chang CM, Yu KJ, Mbulaiteye SM, Hildesheim A, Bhatia K. The extent of genetic diversity of Epstein–Barr virus and its geographic and disease patterns: a need for reappraisal. Virus Res. 2009;143(2):209–21 (Epub 2009/07/15).PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    Mainou BA, Raab-Traub N. LMP1 strain variants: biological and molecular properties. J Virol. 2006;80(13):6458–68.PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Walling DM, Shebib N, Weaver SC, Nichols CM, Flaitz CM, Webster-Cyriaque J. The molecular epidemiology and evolution of Epstein–Barr virus: sequence variation and genetic recombination in the latent membrane protein-1 gene. J Infect Dis. 1999;179(4):763–74 Epub 1999/03/09.CrossRefPubMedGoogle Scholar
  64. 64.
    Sandvej K, Gratama JW, Munch M, Zhou XG, Bolhuis RL, Andresen BS, et al. Sequence analysis of the Epstein–Barr virus (EBV) latent membrane protein-1 gene and promoter region: identification of four variants among wild-type EBV isolates. Blood. 1997;90(1):323–30.PubMedGoogle Scholar
  65. 65.
    Walling DM, Brown AL, Etienne W, Keitel WA, Ling PD. Multiple Epstein–Barr virus infections in healthy individuals. J Virol. 2003;77(11):6546–50 Epub 2003/05/14.PubMedCentralCrossRefPubMedGoogle Scholar
  66. 66.
    Pai S, O’Sullivan B, Abdul-Jabbar I, Peng J, Connoly G, Khanna R, et al. Nasopharyngeal carcinoma-associated Epstein–Barr virus-encoded oncogene latent membrane protein 1 potentiates regulatory T-cell function. Immunol Cell Biol. 2007;85(5):370–7 (Epub 2007/03/21).CrossRefPubMedGoogle Scholar
  67. 67.
    Lin HJ, Cherng JM, Hung MS, Sayion Y, Lin JC. Functional assays of HLA A2-restricted epitope variant of latent membrane protein 1 (LMP-1) of Epstein–Barr virus in nasopharyngeal carcinoma of Southern China and Taiwan. J Biomed Sci. 2005;12(6):925–36 Epub 2005/11/25.CrossRefPubMedGoogle Scholar
  68. 68.
    Baer R, Bankier AT, Biggin MD, Deininger PL, Farrell PJ, Gibson TJ, et al. DNA sequence and expression of the B95-8 Epstein–Barr virus genome. Nature. 1984;310(5974):207–11 Epub 1984/07/19.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Olivia L. Hatton
    • 1
  • Aleishia Harris-Arnold
    • 1
  • Steven Schaffert
    • 1
  • Sheri M. Krams
    • 1
  • Olivia M. Martinez
    • 1
  1. 1.Program in Immunology and Department of Abdominal TransplantationStanford University School of MedicineStanfordUSA

Personalised recommendations