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The human immune response to red blood cell antigens as revealed by repertoire cloning

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Abstract

A major goal of current immunologic research is to develop specific therapeutic strategies by which the enormous diversity in immune response can be enhanced, attenuated, or eliminated, depending on the particular disease process. For nearly a century, the human immune response to red blood cell antigens has served as a paradigm for understanding the pathophysiology of autoimmune disorders and alloimmune reactions to foreign cells and tissues. Recent developments in molecular biology have facilitated the expression of immune repertoires in the form of immunoglobulin Fab fragments on the surface of filamentous bacteriophage. Such approaches have provided powerful means for producing monoclonal antibodies for research, clinical, and therapeutic applications. Our laboratory has combined these techniques with novel cell-surface selection methods to isolate extraordinarily large arrays of human antibodies to the clinically relevant red blood cell Rh(D) antigen. Our results have provided a comprehensive genetic and serologie analysis of anit-Rh(D) antibodies within single alloimmunized individuals thereby offering new insights into the development of human immune repertoires.

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References

  1. Landsteiner K: Uber Agglutinationserscheinungen normalen menschlichen Blutes. Klin Wschr 1901; 14:1132.

    Google Scholar 

  2. Donath J, Landsteiner K: Uber paroixysmale hamoglobinurie. Munchen Med Worchenshr 1904;51:1590–1593.

    Google Scholar 

  3. Siegel DL, Silberstein LE: Production of human red cell antibodies in bacteria by repertoire cloning. Transfusion 1992;32:45S.

    Google Scholar 

  4. Siegel DL, Silberstein LE: Isolation of recombinant human anti-Rh(D) antibodies from libraries expressed on M13 phage. Transfusion 1993;33:54S.

    Google Scholar 

  5. Siegel DL, Silberstein LE: Expression and characterization of recombinant anti-Rh(D) antibodies on filamentous phage: a model system for isolating human red blood cell antibodies by repertoire cloning. Blood 1994;83:2334–2344.

    PubMed  CAS  Google Scholar 

  6. Siegel DL: Isolation of human anti-red blood cell antibodies by repertoire cloning. Ann NY Acad Sci 1995;764:547–558.

    Article  PubMed  CAS  Google Scholar 

  7. Siegel D, Russell S, Chang T: A plethora of human monoclonal anti-Rh antibodies isolated using phage display and magnetically-activated cell sorting. Transfusion 1996;36:37S.

    Article  Google Scholar 

  8. Siegel D, Chang T: Isolation of cell surface-specific human monoclonal antibodies using phage display and magnetically-activated cell sorting, in Antibody Engineering: New Technologies, Applications, and Commercialization. Hori W (ed.), IBC, Boston, 1997.

    Google Scholar 

  9. Siegel DL, Chang TY, Russell SL, Bunya VY: Isolation of cell surface-specific human monoclonal antibodies using phage display and magnetically-activated cell sorting: Applications in immunohematology. J Immunol Methods 1997;206;73–85.

    Article  PubMed  CAS  Google Scholar 

  10. Gabra GS, Mitchell R: Anti-D immunoglobulin and immune thrombocytopenia—A problem in ethics in blood transfusion practice. Vox Sang 1988;54:246.

    PubMed  CAS  Google Scholar 

  11. Chernoff AI, Kelin HG, Sherman LA: Research opportunities in transfusion medicine: Report from an American Association of Blood Banks Think Tank. Transfusion 1989;29:711–742.

    Article  Google Scholar 

  12. Cartron J-P, Agre P: Rh blood group antigens: protein and gene structure. Semin Hematol 1993;30:193–208.

    PubMed  CAS  Google Scholar 

  13. Kohler G, Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975;256:495–497.

    Article  PubMed  CAS  Google Scholar 

  14. Winter G, Milstein C: Man-madeantibodies. Nature 1991;349:293–299.

    Article  PubMed  CAS  Google Scholar 

  15. Winter G, Griffiths AD, Hawkins RE, Hoogenboom HR: Making antibodies by phage display technology. Ann Rev Immunol 1994; 12:433–455.

    Article  CAS  Google Scholar 

  16. Stein LD, Sigal NH: Limiting dilution analysis of Epstein Barr virusinduced immunoglobulin production. Cell Immunol 1983;79:309–319.

    Article  PubMed  CAS  Google Scholar 

  17. Kozbor D, Roder JC: The production of monoclonal antibodies from human lymphocytes. Immunol Today 1983;4:72–79.

    Article  CAS  Google Scholar 

  18. Goossens D, Champomier F, Rouger P, Salmon C: Human monoclonal antibodies against blood group antigens. J Immunol Methods 1987;101:193–200.

    Article  PubMed  CAS  Google Scholar 

  19. Andrzejewski C, Young PJ, Goldman J, Spitalnik SL, Silberstein LE: Production of human IgM warm-reacting red cell monoclonal autoantibodies by Epstein-Barr virus transformation. Transfusion 1989;29:196–200.

    Article  PubMed  CAS  Google Scholar 

  20. Brown NA, Miller G: Immunoglobulin expression by human B lymphocytes clonally transformed by EBV. J Immunol 1982;128:24–29.

    PubMed  CAS  Google Scholar 

  21. Casali P, Burastero SE, Nakamura M, Inghirami G, Notkins AL: Human lymphocytes making rheumatoid factor and antibodies to ssDNA belong to Leu-1 positive B-cell subset. Science 1987;236:77–81.

    Article  PubMed  CAS  Google Scholar 

  22. Roder JC, ColeS PC, Kozbor D:The EBV-hybridoma technique. Methods Enzymol 1986;121:140–167.

    Article  PubMed  CAS  Google Scholar 

  23. Levy R, Dilley J: Rescue of immunoglobulin secretion from human neoplastic lymphoid cells by somatic cell hybridization. Proc Natl Acad Sci USA 1978;75:2411–2415.

    Article  PubMed  CAS  Google Scholar 

  24. Croce CM, Shander M, Martinis J: Chromosomal location of the gene for human immunoglobulin heavy chains. Proc Natl Acad Sci USA 1979;76:3416–3419.

    Article  PubMed  CAS  Google Scholar 

  25. Croce CM, Shander M, Martinis J: Preferential retention of human chromosome 14 in mouse x human Bcellhybrids. Eur J Immunol 1980; 10:486–488.

    Article  CAS  Google Scholar 

  26. Thompson KM, Hough DW, Maddison PJ, Melamed MD, Hughes-Jones NC: The efficient production of stable human monoclonal antibody secreting hybridomas from EBV transformed lymphocytes using the mouse myeloma X63-Ag8.653 as a fusion partner. J Immunol Methods 1986;94:7–12.

    Article  PubMed  CAS  Google Scholar 

  27. Thompson KM, Melamed MD, Eagle K, Gorick BD, Gibson T, Holburn AM, et al.: Production of human monoclonal IgG and IgM antibodies with anti-D (Rh) specificity using heterohybridomas. Immunology 1986;58:157–160.

    PubMed  CAS  Google Scholar 

  28. Melamed MD, Thompson KM, Gibson T, Hughes-Jones NC: Requirements for the establishment of heterohybridomas secreting monoclonal human antibody to rhesus (D) blood group antigen. J Immunol Methods 1987;104:245–251.

    Article  PubMed  CAS  Google Scholar 

  29. Kumpel BM, Poole GD, Bradley BA: Human monoclonal anti-D antibodies. I. Their production, serology, quantitation, and potential use as blood grouping reagents. Br J Hematol 1989;71:125–129.

    CAS  Google Scholar 

  30. Rapaille A, Francois-Gerard C, Donnay D, Sondag-Thull D: Production of stable human-mouse hybridomas secreting monoclonal antibodies against Rh D and c antigens. Vox Sang 1993;64:161–166.

    PubMed  CAS  Google Scholar 

  31. Thompson JM, Lowe J, McDonald DF: Human monoclonal anti-D secreting heterohybridomas from peripheral B lymphocytes expanded in the CD40 system. J Immunol Methods 1994;175:137–140.

    Article  PubMed  CAS  Google Scholar 

  32. Lerner RA, Barbas CF, Kang AS, Burton DR: On the use of combinatorial antibody libraries to clone the “fossil record” of an individual’s immune response. Proc Natl Acad Sci USA 1991;88:9705, 9706.

    Google Scholar 

  33. Hoogenboom HR, Marks JD, Griffiths AD, Winter G: Building antibodies from their genes. Immunol Rev 1992;130:41–67.

    Article  PubMed  CAS  Google Scholar 

  34. Kang AS, Barbas CF, Janda KD, Benkovic SJ, Lerner RA: Linkage of recognition and replication functions by assembling combinatorial antibody Fab libraries along phage surfaces. Proc Natl Acad Sci USA 1991;88:4363–4366.

    Article  PubMed  CAS  Google Scholar 

  35. Barbas CF, Kang AS, Lerner RA, Benkovic SJ: Assembly of combinatorial antibody libraries on phage surfaces: The gene III site. Proc Natl Acad Sci USA 1991; 88:7978–7982.

    Article  PubMed  CAS  Google Scholar 

  36. Hoogenboom HR, Griffiths AD, Johnson KS, Chiswell DJ, Hudson P, Winter G: Multi-subunit proteins on the surface of filamentous phage: Methodologies for displaying antibody (Fab) heavy and light chains. Nucleic Acids Res 1991; 19:4133–4137.

    Article  PubMed  CAS  Google Scholar 

  37. Hexham JM, Furmaniak J, Pegg C, Burton DR, Smith BR: Cloning of a human autoimmune response: Preparation and sequencing of a human anti-thyroglobulin autoantibody using a combinatorial approach. Autoimmunity 1992;12: 135–141.

    PubMed  CAS  Google Scholar 

  38. Griffiths AD, Malmqvist M, Marks JD, Bye JM, Embleton MJ, McCafferty J, et al.: Human anti-self antibodies with high specificity from phage display libraries. EMBO J 1993;12:725–734.

    PubMed  CAS  Google Scholar 

  39. Chazenbalk GD, Portolano S, Russo D, Hutchison JS, Rapoport B, Mc-Lachlan S: Human organ-specific autoimmune disease: Molecular cloning and expression of an autoantibody gene repertoire for a major autoantigen reveals an antigenic immunodominant region and restricted immunoglobulin gene usage in the target organ. J Clin Invest 1993;92:62–74.

    PubMed  CAS  Google Scholar 

  40. Portolano S, McLachlan SM, Rapoport B: High affinity, thyroidspecific human autoantibodies displayed on the surface of filamentous phage use V genes similar to other autoantibodies. J Immunol 1993;151:2839–2851.

    PubMed  CAS  Google Scholar 

  41. Cha S, Leung PS, Gershwin ME, Fletcher MP, Ansari AA, Coppel RL: Combinatorial autoantibodies to dihydrolipoamide acetyltransferase, the major autoantigen of primary biliary cirrhosis. Proc Natl Acad Sci USA 1993;90:2527–2531.

    Article  PubMed  CAS  Google Scholar 

  42. Barbas SM, Ditzel HJ, Salonen EM, Yang WP, Silverman GJ, Burton DR: Human autoantibody recognition of DNA. Proc Natl Acad Sci USA 1995;92:2529–2533.

    Article  PubMed  CAS  Google Scholar 

  43. Eggena M, Targan SR, Iwanczyk L, Vidrich A, Gordon LK, Braun J: Phage display cloning and characterization of an immunogenetic marker (perinuclear anti-neutrophil cytoplasmic antibody) in ulcerative colitis. J Immunol 1996;156:4005–4011.

    PubMed  CAS  Google Scholar 

  44. Schier R, Bye J, Apell G, McCall A, Adams GP, Malmqvist M, et al.: Isolation of high-affinity monomeric human anti-c-erbB-2 single chain Fv using affinity-driven selection. J Molec Biol 1996;255:28–43.

    Article  PubMed  CAS  Google Scholar 

  45. Roben P, Barbas SM, Sandoval L, Lecerf JM, Stollar BD, Solomon A, et al.: Repertoire cloning of lupus anti-DNA autoantibodies. J Clin Invest 1996;98:2827–2837.

    Article  PubMed  CAS  Google Scholar 

  46. Burton DR, Barbas CF, Persson MMA, Koenig S, Chanock RM, Lerner RA: A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc Natl Acad Sci USA 1991;88:10, 134–10,137.

    Google Scholar 

  47. Zebedee SL, Barbas CF, Horn Y-L, Caothien RH, Graff R, DeGraw J, et al.: Human combinatorial antibody libraries to hepatitis B surface antigen. Proc Natl Acad Sci USA 1992;89:3175–3179.

    Article  PubMed  CAS  Google Scholar 

  48. Barbas CF, Crowe JEJ, Cababa D, Jones TM, Zebedee SL, Murphy BR, etal.: Human monoclonal Fab fragments derived from a combinatorial library bind to respiratory syncytial virus F glycoprotein and neutralize infectivity. Proc Natl Acad Sci USA 1992;89:10, 164–10,168.

    Article  Google Scholar 

  49. Williamson RA, Burioni R, Sanna PP, Partridge LJ, Barbas CF, Burton D: Human monoclonal antibodies against a plethora of viral pathogens from single combinatorial libraries. Proc Natl Acad Sci USA 1993;90:4141–4145.

    Article  PubMed  CAS  Google Scholar 

  50. Sasano M, Burton DR, Silverman GJ: Molecular selection of human antibodies with an unconventional bacterial B cell antigen. J Immunol 1993;151:5822–5839.

    PubMed  CAS  Google Scholar 

  51. Crowe JEJ, Murphy BR, Chanock RM, Williamson RA, Barbas CFI, Burton DR: Recombinant human respiratory syncytial virus (RSV) monoclonal antibody Fab is effective therapeutically when introduced directly into the lungs of RSV-infected mice. Proc Natl Acad Sci USA 1994;91:1386–1390.

    Article  PubMed  CAS  Google Scholar 

  52. Barbas CFI, Hu D, Dunlop N, Sawyer L, Cababa D, Hendry RM, et al.: In vitro evolution of a neutralizing human antibody to human immunodeficiency virus type 1 to enhance affinity and broaden strain cross-reactivity. Proc Natl Acad Sci USA 1994;91:3809–3813.

    Article  PubMed  CAS  Google Scholar 

  53. Cai X, Garen A: A melanoma-specific VH antibody cloned from a fusion phage library of a vaccinated melanoma patient. Proc Natl Acad Sci USA 1996;93:6280–6285.

    Article  PubMed  CAS  Google Scholar 

  54. Barbas CF, Burton DR: Selection and evolution of high-affinity human anti-viral antibodies. Trends Biotechnol 1996;14:230–234.

    Article  PubMed  CAS  Google Scholar 

  55. Marks C, Marks JD: Phage libraries—a new route to clinically useful antibodies. N Engl J Med 1996; 335:730–733.

    Article  PubMed  CAS  Google Scholar 

  56. Pereira S, Maruyama H, Siegel D, Van Belle P, Elder D, Curtis P, et al.: A model system for detection and isolation of a tumor cell surface antigen using antibody phage display. J Immunol Methods 1997;203:11–24.

    Article  PubMed  CAS  Google Scholar 

  57. Agre P, Saboori AM, Asimos A, Smith BL: Purification and partial characterization of the Mr 30,000 integral membrane protein associated with the erythrocyte Rh(D) antigen. J Biol Chem 1987;262: 17, 497–17,503.

    Google Scholar 

  58. Marks JD, Ouwehand WH, Bye JM, Finnem R, Gorick BD, Voak D, et al.: Human antibody fragments specific for human blood group antigens from a phage display library. Bio/Technology 1993;11:1145–1149.

    PubMed  CAS  Google Scholar 

  59. Cai X, Garen A: Anti-melanoma antibodies from melanoma patients immunized with genetically modified autologous tumor cells: selection of specific antibodies from single-chain Fv fusion phage libraries. Proc Natl Acad Sci USA 1995;92:6537–6541.

    Article  PubMed  CAS  Google Scholar 

  60. Barbas CF, Lerner RA: Combinatorial immunoglobulin libraries on the surface of phage (Phabs): Rapid selection of antigen-specific Fabs. Methods: A Companion to Methods Enzymol 1991;2:119–124.

    Article  CAS  Google Scholar 

  61. Vengelen-Tyler V: Technical Manual, (12th ed.). American Association of Blood Banks, Bethesda, 1996.

    Google Scholar 

  62. Tomlinson IM, Williams SC, Corbett SJ, Cox JPL, Winter G: V Base sequence directory, 1996, http://www.mrc-cpe.cam.ac.uk/ imt-doc/vbase-home-page.html.

  63. Mollison PL, Engelfreit CP, Contreras M: Blood Transfusion in Clinical Medicine (9th ed.). Blackwell Scientific Publications, Oxford, 1993.

    Google Scholar 

  64. Cartron J, Rouillac C, Le Van Kim C, Mouro I, Colin Y: Tentative model for the mapping of D epitopes on the RhD polypeptide. Transfusion Clin Biologique 1996;3:497–503.

    Article  CAS  Google Scholar 

  65. Bye JM, Carter C, Cui Y, Gorick BD, Songsivilai S, Winter G, et al.: Germline variable region gene segment derivation of human monoclonal anti-Rh(D) antibodies. J Clin Invest 1992;90:2481–2490.

    PubMed  CAS  Google Scholar 

  66. Boucher G, Broly H, Lemieux R: Restricted use of cationic germline VH gene segments in human Rh(D) red cell antibodies. Blood 1997;89:3277–3286.

    PubMed  CAS  Google Scholar 

  67. Abelson N, Rawson A: Studies of blood group antibodies. II. Fractionation of Rh antibodies by anioncation cellulose exchange chromatography. J Immunol 1959;83:49.

    PubMed  CAS  Google Scholar 

  68. Blancher A, Socha WW: Antihuman red cell monoclonal antibodies produced by macaque-mouse heterohybridomas. J Med Primatol 1991;20:352–356.

    PubMed  CAS  Google Scholar 

  69. Blancher A, Ruffie J, Socha WW: The R-C-E-F blood group system of chimpanzees: serology and genetics. J Med Primatol 1993;22:13–18.

    PubMed  CAS  Google Scholar 

  70. Samuelsson A, Chiodi F, Ohman P, Putkonen P, Norrby E, Persson MA: Chimeric macaque/human Fab molecules neutralize simian immunodeficiency virus. Virology 1995;207:495–502.

    Article  PubMed  CAS  Google Scholar 

  71. Chang T, Siegel D: Isolation of a highly mutated human anti-B antibody from a phage-display library. Transfusion 1997;37:895.

    Google Scholar 

  72. Siegel DL, Silberstein LE: Acquired hemolytic anemia, in Current Diagnosis 8, Conn RB (ed.), Saunders, Philadelphia, 1991, pp. 559–563.

    Google Scholar 

  73. Siegel DL, Silberstein LE: Red cell antigen specificities and autoimmune hemolytic anemias; in Agre PC, Cartron J-P (eds.): Protein Blood Group Antigens of the Human Red Cell: Structure, Function, and Clinical Significance, The Johns Hopkins University Press, Baltimore, 1992, pp. 193–208.

    Google Scholar 

  74. Siegel DL, Silberstein LE: Structural analyses of red cell autoantibodies, in immunobiology of Transfusion Medicine, Garratty G (ed.), Dekker, New York, 1994, pp. 387–399.

    Google Scholar 

  75. Siegel DL, Silberstein LE: Redblood cell autoantibodies; in Anderson KC, Ness PM (eds.): Scientific Basis of Transfusion Medicine: Implications for Clinical Practice, Saunders, Philadelphia, 1994, pp. 517–526.

    Google Scholar 

  76. Czerwinski M, Siegel D, Spitalnik S: Selected light chains combine with a given heavy chain to confer anti-N specificity. Transfusion 1995;35:59S.

    Article  Google Scholar 

  77. Czerwinski M, Siegel DL, Moore JS, Spitalnik PF, Spitalnik SL: Construction of bacteriophage expressing mouse monoclonal Fab fragments directed against the human MN glycophorin blood group antigens. Transfusion 1995;35:137–144.

    Article  PubMed  CAS  Google Scholar 

  78. Czerwinski M, Siegel D, Spitalnik S: Molecular approaches for isolating high affinity Fab fragments useful in blood group serology. Transfusion, in press.

  79. Wang L, Radic M, Siegel D, Chang T, Bracy J, Galili U: Cloning of anti-Gal Fabs from combinatorial phage display libraries: Comparison of Fab expression in pComb3H and pComb8 phage. Mol Immunol, in press.

  80. Pereira S, Van Belle P, Elder D, Maruyama H, Jacob L, Sivanandham M, et al.: Combinatorial antibodies against human malignant melanoma. Hybridoma 1997;16:11–16.

    PubMed  CAS  Google Scholar 

  81. Herlyn D, Pereira S, Maruyama H, Van Belle P, Elder D, Jacob L, et al.: Identification of tumor antigens using antibody phage display; in Thibeault C (ed.): Antibody Engineering: New Technologies, Applications, and Commercialization, IBC, Boston, 1996.

    Google Scholar 

  82. Lomas C, McColl K, Tippett P: Further complexities of the Rh antigen D disclosed by testing category DII cells with monoclonal anti-D. Trans Med 1993;3:67–69.

    CAS  Google Scholar 

  83. Devereux J, Haeberline P, Smithies O: A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res 1984; 12:387–395.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Pathology and Lababoratory Medicine, University of Pennsylvania School of Medicine Center, Rm 207 Morgan Bldg. 36th and Hamilton Walk, 19104, Philadelphia, PA

    Don L. Siegel

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Siegel, D.L. The human immune response to red blood cell antigens as revealed by repertoire cloning. Immunol Res 17, 239–251 (1998). https://doi.org/10.1007/BF02786448

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