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Human plasma contains a soluble form of CD86 which is present at elevated levels in some leukaemia patients

Abstract

Cell surface expression of CD86 (mCD86) provides an important co-stimulatory signal which profoundly influences immune responses. In this report, we investigated the potential presence of a circulating soluble form of CD86 (sCD86) in normal individuals and patients with acute myeloid leukaemia (AML) or B cell chronic lymphocytic leukaemia (B-CLL). Circulating sCD86 was detected in the plasma of all normal individuals (1.04 ± 0.33 ng/ml, n = 51) and patients analysed. Plasma collected from AML patients in remission (n = 6) contained only low levels of sCD86 but significantly elevated levels (2.65 ng/ml, P < 0.0001) were detected in 10/24 AML patients analysed at the time of presentation or relapse. Significantly elevated levels of sCD86 were also detected in 2/17 B-CLL patients. There was no correlation between sCD86 levels and other clinical parameters. RT-PCR analysis demonstrated that normal monocytes and dendritic cells, as well as isolated AML (n = 2) and B-CLL (n = 4) cells, expressed an alternatively spliced transcript of CD86 which encoded a soluble form absent in normal T, B and NK cells. The finding that a proportion of leukaemia patients contain elevated levels of sCD86 and that at least some leukaemic cells express sCD86 transcript suggests a potential role for sCD86 in modulating mCD86 signalling during the malignant process.

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References

  1. Mueller DL, Jenkins MK, Schwartz RH . Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy Ann Rev Immunol 1989 7: 445–480

    Article  CAS  Google Scholar 

  2. Lenschow DJ, Walunas TL, Bluestone JA . CD28/B7 system of T cell costimulation Ann Rev Immunol 1996 14: 233–258

    Article  CAS  Google Scholar 

  3. Azuma M, Ito D, Yagita H, Okumura K, Phillips JH, Lanier LL, Somoza C . B70 antigen is a second ligand for CTLA-4 and CD28 Nature 1993 366: 76–79

    Article  CAS  PubMed  Google Scholar 

  4. Freeman GJ, Gribben JG, Boussiotis VA, Ng JW, Restivo VA Jr, Lombard LA, Gray GS, Nadler LM . Cloning of B7–2: a CTLA-4 counter-receptor that costimulates human T cell proliferation Science 1993 262: 909–911

    Article  CAS  PubMed  Google Scholar 

  5. Freeman GJ, Freedman AS, Segil JM, Lee G, Whitman JF, Nadler LM . B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells J Immunol 1989 143: 2714–2722

    CAS  PubMed  Google Scholar 

  6. Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP . CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones Nature 1992 356: 607–609

    Article  CAS  PubMed  Google Scholar 

  7. Sansom DM . Review article: CD28, CTLA-4 and their ligands: who does what and to whom? Immunology 2000 101: 169–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zheng Z, Takahashi M, Aoki S, Toba K, Liu A, Osman Y, Takahashi H, Tsukada N, Suzuki N, Nikkuni K, Furukawa T, Koike T, Aizawa Y . Expression patterns of costimulatory molecules on cells derived from human hematological malignancies J Exp Clin Cancer Res 1998 17: 251–258

    CAS  PubMed  Google Scholar 

  9. Maeda A, Yamamoto K, Yamashita K, Asagoe K, Nohgawa M, Kita K, Iwasaki H, Ueda T, Takahashi A, Sasada M . The expression of co-stimulatory molecules and their relationship to the prognosis of human acute myeloid leukaemia: poor prognosis of B7–2-positive leukaemia Br J Haematol 1998 102: 1257–1262

    Article  CAS  PubMed  Google Scholar 

  10. Pope B, Brown RD, Gibson J, Yuen E, Joshua D . B7–2-positive myeloma: incidence, clinical characteristics, prognostic significance, and implications for tumor immunotherapy Blood 2000 96: 1274–1279

    CAS  PubMed  Google Scholar 

  11. Heaney ML, Golde DW . Soluble cytokine receptors Blood 1996 87: 847–857

    CAS  PubMed  Google Scholar 

  12. Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, Barr PJ, Mountz JD . Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule Science 1994 263: 1759–1762

    Article  CAS  PubMed  Google Scholar 

  13. Younes A, Snell V, Consoli U, Clodi K, Zhao S, Palmer JL, Thomas EK, Armitage RJ, Andreeff M . Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic leukaemia Br J Haematol 1998 100: 135–141

    Article  CAS  PubMed  Google Scholar 

  14. McHugh RS, Ratnoff WD, Gilmartin R, Sell KW, Selvaraj P . Detection of a soluble form of B7–1 (CD80) in synovial fluid from patients with arthritis using monoclonal antibodies against distinct epitopes of human B7–1 Clin Immunol Immunopathol 1998 87: 50–59

    Article  CAS  PubMed  Google Scholar 

  15. Davis TA, Craighead N, Williams AJ, Scadron A, June CH, Lee KP . Primary porcine endothelial cells express membrane-bound B7–2 (CD86) and a soluble factor that co-stimulate cyclosporin A-resistant and CD28- dependent human T cell proliferation Int Immunol 1996 8: 1099–1111

    Article  CAS  PubMed  Google Scholar 

  16. Yang S, Sim GK . New forms of dog CD80 and CD86 transcripts that encode secreted B7 molecules Immunogenetics 1999 50: 349–353

    Article  CAS  PubMed  Google Scholar 

  17. Faas SJ, Giannoni MA, Mickle AP, Kiesecker CL, Reed DJ, Wu D, Fodor WL, Mueller JP, Matis LA, Rother RP . Primary structure and functional characterization of a soluble, alternatively spliced form of B7–1 J Immunol 2000 164: 6340–6348

    Article  CAS  PubMed  Google Scholar 

  18. Jeannin P, Magistrelli G, Aubry JP, Caron G, Gauchat JF, Renno T, Herbault N, Goetsch L, Blaecke A, Dietrich PY, Bonnefoy JY, Delneste Y . Soluble CD86 is a costimulatory molecule for human T lymphocytes Immunity 2000 13: 303–312

    Article  CAS  PubMed  Google Scholar 

  19. Hock BD, Fearnley DB, Boyce A, McLellan AD, Sorg RV, Summers KL, Hart DNJ . Human dendritic cells express a 95 kDa activation/differentiation antigen defined by CMRF-56 Tissue Antigens 1999 53: 320–334

    Article  CAS  PubMed  Google Scholar 

  20. Schuh R, Kremmer E, Ego E, Wasiliu M, Thierfelder S . Determination of monoclonal antibody specificity by immunoadsorption and Western blotting J Immunol Methods 1992 152: 59–67

    Article  CAS  PubMed  Google Scholar 

  21. Marafioti T, Hummel M, Foss HD, Laumen H, Korbjuhn P, Anagnostopoulos I, Lammert H, Demel G, Theil J, Wirth T, Stein H . Hodgkin and Reed–Sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription Blood 2000 95: 1443–1450

    CAS  PubMed  Google Scholar 

  22. McLellan AD, Starling GC, Williams LA, Hock BD, Hart DN . Activation of human peripheral blood dendritic cells induces the CD86 co-stimulatory molecule Eur J Immunol 1995 25: 2064–2068

    Article  CAS  PubMed  Google Scholar 

  23. Rennert P, Furlong K, Jellis C, Greenfield E, Freeman GJ, Ueda Y, Levine B, June CH, Gray GS . The IgV domain of human B7–2 (CD86) is sufficient to co-stimulate T lymphocytes and induce cytokine secretion Int Immunol 1997 9: 805–813

    Article  CAS  PubMed  Google Scholar 

  24. Gerstmayer B, Pessara U, Wels W . Construction and expression in the yeast Pichia pastoris of functionally active soluble forms of the human costimulatory molecules B7–1 and B7–2 and the B7 counter-receptor CTLA-4 FEBS Lett 1997 407: 63–68

    Article  CAS  PubMed  Google Scholar 

  25. Runyon K, Lee K, Zuberek K, Collins M, Leonard JP, Dunussi-Joannopoulos K . The combination of chemotherapy and systemic immunotherapy with soluble B7-immunoglobulin G leads to cure of murine leukemia and lymphoma and demonstration of tumor-specific memory responses Blood 2001 97: 2420–2426

    Article  CAS  PubMed  Google Scholar 

  26. Sturmhoefel K, Lee K, Gray GS, Thomas J, Zollner R, O'Toole M, Swiniarski H, Dorner A, Wolf SF . Potent activity of soluble B7-IgG fusion proteins in therapy of established tumors and as vaccine adjuvant Cancer Res 1999 59: 4964–4972

    CAS  PubMed  Google Scholar 

  27. Flo J, Tisminetzky S, Baralle F . Codelivery of DNA coding for the soluble form of CD86 results in the down-regulation of the immune response to DNA vaccines Cell Immunol 2001 209: 120–131

    Article  CAS  PubMed  Google Scholar 

  28. Inaba H, Komada Y, Li QS, Zhang XL, Tanaka S, Azuma E, Yamamoto H, Sakurai M . mRNA expression of variant Fas molecules in acute leukemia cells Am J Hematol 1999 62: 150–158

    Article  CAS  PubMed  Google Scholar 

  29. Chiao JW, Heil M, Arlin Z, Lutton JD, Choi YS, Leung K . Suppression of lymphocyte activation and functions by a leukemia cell-derived inhibitor Proc Natl Acad Sci USA 1986 83: 3432–3436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Buggins AG, Lea N, Gaken J, Darling D, Farzaneh F, Mufti GJ, Hirst WJ . Effect of costimulation and the microenvironment on antigen presentation by leukemic cells Blood 1999 94: 3479–3490

    CAS  PubMed  Google Scholar 

  31. Beguin Y, Lampertz S, De Groote D, Igot D, Malaise M, Fillet G . Soluble CD23 and other receptors (CD4, CD8, CD25, CD71) in serum of patients with chronic lymphocytic leukemia Leukemia 1993 7: 2019–2025

    CAS  PubMed  Google Scholar 

  32. Srivastava MD, Srivastava A, Srivastava BI . Soluble interleukin-2 receptor, soluble CD8 and soluble intercellular adhesion molecule-1 levels in hematologic malignancies Leuk Lymphoma 1994 12: 241–251

    Article  CAS  PubMed  Google Scholar 

  33. Greenfield EA, Howard E, Paradis T, Nguyen K, Benazzo F, McLean P, Hollsberg P, Davis G, Hafler DA, Sharpe AH, Freeman GJ, Kuchroo VK . B7.2 expressed by T cells does not induce CD28-mediated costimulatory activity but retains CTLA4 binding: implications for induction of antitumor immunity to T cell tumors J Immunol 1997 19: 19

    Google Scholar 

  34. Timmerman JM, Levy R . Dendritic cell vaccines for cancer immunotherapy Ann Rev Med 1999 50: 507–529

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Lisa Haring and James Dekker for their technical assistance and Dr Robert Peach (Bristol-Myers Sqibb) who generously provided the recombinant CD86-Ig for this study. We are grateful to Drs Spearing, Heaton, Gibbons and Ganly for providing patient samples and information. This work was supported by the Canterbury Medical Research Foundation and the New Zealand Lotteries Grant Board.

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Hock, B., Patton, W., Budhia, S. et al. Human plasma contains a soluble form of CD86 which is present at elevated levels in some leukaemia patients. Leukemia 16, 865–873 (2002). https://doi.org/10.1038/sj.leu.2402466

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