Human Hematopoietic Stem Cells, Progenitors, and Peripheral Blood Lymphocytes as Targets for the Correction of Immune System Disorders via Gene Therapy

  • Karen E. Pollok
  • David A. Williams
Part of the Contemporary Immunology book series (CONTIM)


As genetic defects responsible for congenital disorders are delineated at the DNA level, it is possible to design strategies to express the corrected gene in autologousderived cells (1–3). A large number of gene therapy clinical trials encompassing a broad spectrum of human diseases are in progress (4,5). Therapies to prevent and treat human immunodeficiency virus (HIV) (6), adenosine deaminase deficiency associated with severe combined immunodeficiency disease (ADASCID) (7–11); lysosomal storage diseases (12,13), autoimmune diseases (3,14), as well as a variety of cancers (15), are ongoing. In this chapter, the authors will review the current status on gene transfer technology and discuss current findings on treatment of ADA SCID by gene therapy. In addition, five primary immunodeficiency diseases that affect the B- and T-cell lineages at various stages of differentiation will be highlighted, and the potential treatment of these diseases by gene therapy will be discussed.


Gene Therapy Gene Transfer Long Terminal Repeat Adenosine Deaminase Severe Combine Immunodeficiency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Williams, D. A. (1990) Expression of introduced genetic sequences in hematopoietic cells following retroviral-mediated gene transfer. Hum. Gene Ther. 1, 229–239.PubMedCrossRefGoogle Scholar
  2. 2.
    Brenner, M. K. (1996) Gene transfer to hematopoietic cells. Mol. Med. 335, 337–339.Google Scholar
  3. 3.
    Blau, H. M. and Springer, M. L. (1995) Gene therapy; a novel form of drug delivery. Mol. Med. 333, 1204–1207.Google Scholar
  4. 4.
    Kohn, D. B. (1997) Gene therapy for haematopoietic and lymphoid disorders. Clin. Exp. Immunol. 107, 54–57.PubMedGoogle Scholar
  5. 5.
    Rosenberg, S. A., Blaese, R. M., Brenner, M. K., Deisseroth, A. B., Ledley, F. D., Lotze, M. T., Wilson, J. M., Nabel, G. J., Cornetta, K., Economou, J. S., Freeman, S. M., Riddell, S. R., Oldfield, E., Gansbacher, B., Dunbar, C., Walker, R. E., Schuening, F. G., Roth, J. A., Crystal, R. G., Welsh, M. J., Culver, K., Heslop, H. E., Simons, J., Wilmott, R. W., and Aevischer, P., et al. Human gene marker/therapy clinical protocols. Hum. Gene Ther. 7, 1621–1647.Google Scholar
  6. 6.
    Lisziewicz, J. (1996) Tar decoys and trans-dominant gag mutant for HIV-1 gene therapy. Antibiot. Chemother. 48, 192–197.PubMedGoogle Scholar
  7. 7.
    Kohn, D. B., Weinberg, K. I., Nolta, J. A., Heiss, L. N., Lenarsky, C., Crooks, G. M., Hanley, M. E., Annett, G., Brooks, J. S., El-Khoureiy, A., Lawrence, K., Wells, S., Moen, R. C., Bastian, J., Williams-Herman, M. Elder, D. E., Wara, D. Bowen, T., Hershfield, M. S., Mullen, C. A., Blaese, R. M., and Parkman, R. (1995) Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency. Nat. Med. 1, 1–10.Google Scholar
  8. 8.
    Bordignon, C., Notarangelo, L. D., Nobili, N., Ferrari, G., Casorati, G., Panina, P., Mazzolari, E., Maggioni, D., Rossi, C., Servida, P., Ugazio, A. G., and Mavilio, F. (1995) Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- Immunodeficient patients. Science 270, 470–474.Google Scholar
  9. 9.
    Blaese, R. M., Culver, K. W., Miller, A. D., Carter, C. S., Fleisher, T., Clerici, M., Shearer, G., Chang, L., Chiang, Y., Tolstoshev, P., Greenblatt, J. J., Rosenberg, S. A., Klein, H., Berger, M., Mullen, C. A., Ramsey, W. J., Muul, L., Morgan, R. A., and Anderson, W. F. (1995) T-lymphocytedirected gene therapy for ADA- SCID, Initial trial results after 4 years. Science 270, 475–480.PubMedCrossRefGoogle Scholar
  10. 10.
    Hershfield, M. S., Chaffee, S., and Sorensen, R. U. (1993) Enzyme replacement therapy with polyethylene glycol-adenosine deaminase in adenosine deaminase deficiency: overview and case reports of three patients including two now receiving gene therapy. Ped. Res. 33, S42 - S47.CrossRefGoogle Scholar
  11. 11.
    Hoogerbrugge, P. M., van Beusechem, V. W., Fischer, A., Debree, M., le Deist, F., Perignon, J. L., Morgan, G., Gaspar, B., Fairbanks, L. D., Skeoch, C. H., Moseley, A., Harvey, M., Levinsky, R. J., and Valerio, D. (1996) Bone marrow gene transfer in three patients with adenosine deaminase deficiency. Gene Ther. 3, 179–183.PubMedGoogle Scholar
  12. 12.
    Dunbar, C. and Kohn, D. (1996) Retroviral mediated transfer of the cDNA for human glucocerebrosidase into hematopoietic stem cells of patients with Gaucher disease: a Phase I study. Hum. Gene Ther. 7, 231–253.PubMedCrossRefGoogle Scholar
  13. 13.
    Whitley C. B. (1996) Retroviral mediated gene transfer of the Iduronate-2-Sulfatase gene into lymphocytes for treatment of mild Hunter Syndrome (Mucopolysaccharidosis type II). Hum. Gene Ther. 7, 537–549.PubMedCrossRefGoogle Scholar
  14. 14.
    Evans, C. H. and Robbins, P. D. (1995) Progress toward the treatment of arthritis by gene therapy. Annals of Med. 27, 543–546.CrossRefGoogle Scholar
  15. 15.
    Roth, J. A. and Cristiano, R. J. (1997) Gene therapy for cancer: what have we done and where are we going? JNCI. 89, 21–39.PubMedCrossRefGoogle Scholar
  16. 16.
    Hershfield, M. S. (1995) PEG-ADA Replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. Clin. Immunol. Immunopath. 76, S228 - S232.CrossRefGoogle Scholar
  17. 17.
    Mulligan, R. C. (1993) The basic science of gene therapy. Science 260, 926–932.PubMedCrossRefGoogle Scholar
  18. 18.
    Dunbar, C. E. (1996) Gene transfer to hematopoietic stem cells: implications for gene therapy of human disease. Annu. Rev. Med. 47, 11–20.PubMedCrossRefGoogle Scholar
  19. 19.
    Watanabe, T., Kuszynski, C., Ino, K., Heimann, D. G., Shepard, H. M., Yasui, Y., Maneval, D. C., and Talmadge, J. E. (1996) Gene transfer into human bone marrow hematopoietic cells mediated by adenovirus vectors. Blood 87, 5032–5039.PubMedGoogle Scholar
  20. 20.
    Descamps, V., Duffour, M. T., Mathieu, M. C., Fernandez, N., Cordier, L., Abina, M. A., Kremer, E., Perricaudet, M., and Haddada, H. (1996) Strategies for cancer gene therapy using adenoviral vectors. J. Molec. Med. 74, 183–189.PubMedCrossRefGoogle Scholar
  21. 21.
    Trapnell, B. C. and Gorziglia, M. (1994) Gene therapy using adenoviral vectors. Curr. Opin. Biotechnol. 5, 617–625.PubMedCrossRefGoogle Scholar
  22. 22.
    Hardy, S., Kitamura, M., Harris-Stansil, T., Dai, Y., and Phipps. M. L. (1997) Construction of adenovirus vectors through cre-lox recombination. J. Virol. 71, 1842–1849.PubMedGoogle Scholar
  23. 23.
    Samulski, R. J., Zhu, X., Xiao, X., and Brook, J. D. (1991) Targeted integration of adenoassociated virus (AAV) into human chromosome 19. EMBO J.10, 3941–3950.Google Scholar
  24. 24.
    Chatterjee, S. and Wong, K. K., Jr. (1996) Adeno-associated virus vectors for gene therapy of the hematopoietic system. Curr. Top. Micro. Immunol. 218, 61–71.CrossRefGoogle Scholar
  25. 25.
    Podsakoff G., Wong, K. K., Jr., and Chatterjee, S. (1994) Stable and efficient gene transfer into non-dividing cells by adeno-associated virus (AAV)-based vectors. J. Virol. 68, 656–666.Google Scholar
  26. 26.
    Russell, D. W., Miller, A. D., and Alexander, I. E. (1994) Adeno-associated virus vectors preferentially transduce cells in S phase. Proc. Natl. Acad. Sci. USA 91, 8915–8919.PubMedCrossRefGoogle Scholar
  27. 27.
    Podsakoff, G., Shaughnessy, E. A., Lu, D., Wong, K. K. Jr., and Chatterjee, S. (1994) Long term in vivo reconstitution with murine marrow cells transduced with an adeno-associated virus vector. Blood 84, (S) 256a.Google Scholar
  28. 28.
    Einerhand, M. P. W. and Valero, D. (1992) Gene transfer into hematopoietic stem cells: prospects for human gene therapy. Curr. Top. Microbiol. Immunol. 177, 217–231.PubMedCrossRefGoogle Scholar
  29. 29.
    Miller, D. G., Adam, M. A., and Miller, A. D. (1990) Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol. Cell. Biol. 10, 4239–4242.PubMedGoogle Scholar
  30. 30.
    Larochelle, A., Vormoor, J., Hanenberg, H., Wang, J. C. Y., Bhatia, M., Lapidot, T., Moritz, T., Murdoch, B., Xiao, X. L., Kato, I., Williams, D. A., and Dick, J. E. (1996) Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy. Nat. Med. 2, 1329–1337.PubMedCrossRefGoogle Scholar
  31. 31.
    Luskey, B. D., Rosenblatt, M., Zsebo, K., and Williams, D. A. (1992) Stem cell factor, interleukin-3, and interleukin-6 promote retroviral-mediated gene transfer into murine hematopoietic stem cells. Blood 80, 396–402.PubMedGoogle Scholar
  32. 32.
    Donahue, R. E., Kessler, S. W., Bodine, D., McDonagh, K., Dunbar, C., Goodman, S., Agricola, B., Byrne, E., Raffeld, M., Moen, R., et al. (1992) Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J. Exp. Med. 176, 1125–1135.PubMedCrossRefGoogle Scholar
  33. 33.
    Miller, A. D. (1990) Retrovirus Packaging Cells. Hum. Gene Ther. 1, 5–14.PubMedCrossRefGoogle Scholar
  34. 34.
    Markowitz, M., Goff, S., and Bank, A. (1988) A safe packaging line for gene transfer: separating viral genes on two different plasmids. J. Virol. 62, 1120–1124.PubMedGoogle Scholar
  35. 35.
    Mavilio, F., Ferrari, G., Rossini, S., Nobili, N., Conini, C., Casorati, G., Traversari, C., and Bordignon, C. (1994) Peripheral blood lymphocytes as target cells of retroviral vector-mediated gene transfer. Blood 83, 1988–1997.PubMedGoogle Scholar
  36. 36.
    Ferrari, G., Rossini, S., Nobili, N., Maggioni, D., Garofalo, A., Giavazzi, R., Mavilio, F., and Bordignon, C. (1992) Transfer of the ADA gene into human ADA-deficient T lymphocytes reconstitutes specific immune functions. Blood 80, 1120–1124.PubMedGoogle Scholar
  37. 37.
    Sharma, S., Cantwell, M., Kipps, T. J., and Friedmann, T. (1996) Efficient infection of a human T-cell line and of human primary peripheral blood leukocytes with a pseudotyped retrovirus vector. Proc. Natl. Acad. Sci. USA 93, 11842–11847.PubMedCrossRefGoogle Scholar
  38. 38.
    Schumann, G., Qin, L., Rein, A., Natsoulis, G., Boeke, J. D. (1996) Therapeutic effect of gag-nuclease fusion protein on retrovirus-infected cell cultures. J. Virol. 70, 4329–4337.PubMedGoogle Scholar
  39. 39.
    Rogulski, K. R., Kim, J. H., Kim, S. H. and Freytag, S. O. (1997) Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolite suicide and radiosensitivity. Hum. Gene Ther. 8, 73–85.PubMedCrossRefGoogle Scholar
  40. 40.
    Gervaix, A., Li, X., Kraus, G., and Wong-Staal, F. (1997) Multigene antiviral vectors inhibit diverse human immunodeficiency virus type 1 clades. J. Virol. 71, 3048–3053.PubMedGoogle Scholar
  41. 41.
    Ghattas, I. R., Sanes, J. R., and Majors, J. E. (1991) The encephalomyocarditis virus internal ribosome entry sites allows efficient coexpression of two genes from a recombinant provirus in cultured cells and in embryos. Mol. Cell. Biol. 11, 5848–5859.PubMedGoogle Scholar
  42. 42.
    Candotti, F., Johnston, J. A., Puck, J. M., Sugamura, K., O’Shea, J. J., and Blaese, R. M. (1996) Retroviral-mediated gene correction for X-linked severed combined immunodeficiency. Blood 87, 3097–3102.PubMedGoogle Scholar
  43. 43.
    Medin, J. A., Makoto, M., Pawliuk, R., Jacobson, S., Amiri, M., Kluepfel-Stahl, S., Brady, R. O., Humphries, R. K., and Karlsson, S. (1996) A bicistronic therapeutic retroviral vector enables sorting of transduced CD34+ cells and corrects the enzyme deficiency in cells from Gaucher patients. Blood 87, 1754–1762.PubMedGoogle Scholar
  44. 44.
    Sokolic, R. A., Sekhsaria, S., Sugimoto, Y., Whiting-Theobald, N., Linton, G. F., Li, F., Gottesman, M. M., and Malech, H. L. (1996) A bicistronic retrovirus vector containing a picornavirus internal ribosome entry site allows for correction of X-linked CGD by selection for MDR1 expression. Blood 87, 42–50.PubMedGoogle Scholar
  45. 45.
    Hock, R. A., Miller, A. D., and Osborne, W. R. (1989) Expression of human adenosine deaminase from various strong promoters after gene transfer into human hematopoietic cell lines. Blood 74, 876–881.PubMedGoogle Scholar
  46. 46.
    Malik, P., Krall, W. J., Yu, X. J., Zhou, C., and Kohn, D. B. (1995) Retroviral-mediated gene expression in human myelomonocytic cells: a comparison of hematopoietic cell promoters to viral promoters. Blood 86, 2993–3005.PubMedGoogle Scholar
  47. 47.
    Li, C. L., Dwarki, V. J., and Verma, I. M. (1990) Expression of human a-globin and mouse/ human hybrid ß-globin genes in murine hemopoietic stem cells transduced by recombinant retroviruses. Proc. Natl. Acad. Sci. USA 87, 4349–4353PubMedCrossRefGoogle Scholar
  48. 48.
    Rixon, M. W., Harris, E. A. S., and Gelinas, R. E. (1990) Expression of the human y-globin gene after retroviral transfer to transformed erythroid cells. Biochemistry 29, 4393–4400.PubMedCrossRefGoogle Scholar
  49. 49.
    Bender, M. A., Miller, A. D., and Gelinas, R. E. (1988) Expression of the human ß-globin gene after retroviral transfer into murine erythroleukaemia cells and human BFU-E cells. Mol. Cell. Biol. 8, 1725–1735.PubMedGoogle Scholar
  50. 50.
    Novak, U., Ham, E. A. S., Forrester, W., Groudine, M., and Gelinas, R. (1990) High-level 1-globin expression after retroviral transfer of locus activation region-containing human f3-globin gene derivatives into murine erythroleukemia cells. Proc. Natl. Acad. Sci. USA 87, 3386–3390.PubMedCrossRefGoogle Scholar
  51. 51.
    Williams, D. A., Orkin, S. H., and Mulligan, R. C. (1986) Retrovirus-mediated gene transfer of human adensoine deaminase gene sequences into cells in culture and into murine hematopoietic cells in vivo. Proc. Natl. Acad. Sci. USA 83, 2566–2570.PubMedCrossRefGoogle Scholar
  52. 52.
    Williams, D. A., Lim, B., Spooner, E., Longtine, J., and Dexter, T. M. (1988) Restriction of expression of an integrated recombinant retrovirus in primary but not immortalized murine hematopoietic stem cells. Blood 71, 1738–1743.PubMedGoogle Scholar
  53. 53.
    Kantoff, P. W., Gillio, A, McLachlin, J. R., Flake, A. W. Eglitis, M. A., Moen, R., Karlsson, S., Kohn, D. B., Karson, E., Zwiebel, J. A., Bordignon, C., Hutton, J. J., Harrison, M. R., Blaese, R. M., Nienhuis, A., Gilboa, E., Zanjani, E. D., O’Reilly, R., and Anderson, W. F. (1986) Retroviral-mediated gene transfer into hematopoietic cells. Trans. Assoc. Amer. Phys. 99, 92–102.Google Scholar
  54. 54.
    Mclvor, R. S., Johnson, M. J., Miller, A. D., Pitts, S., Williams, S. R., Valerio, D., Martin, D. W., Jr., and Verma, I. R. (1987) Human purine nucleoside phosphorylase and adenosine deaminase: gene transfer into cultured cells and murine hematopoietic stem cells by using a recombinant amphotropic retrovirus. Mol. Cell. Biol. 7, 383–846.Google Scholar
  55. 55.
    Belmont, J. W., Macgregor, G. R., Wagner-Smith, K., Fletcher, F. A., Moore, K. A., Hawking, D., Villalon, D., Chang, S. M. W., and Caskey, C. T. (1988) Expression of human adenosine deaminase in murine hematopoietic cells. Mol. Cell. Biol. 8, 5116–5125.PubMedGoogle Scholar
  56. 56.
    Naldini, L., Blomer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F. H., Verma, I. M., and Trono, D. (1996) In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267.Google Scholar
  57. 57.
    Bieniasz, P. D., Weiss, R. A., and McClure, M. O. (1995) Cell cycle dependence of foamy retrovirus infection. J. Virol. 69, 7295–7299.PubMedGoogle Scholar
  58. 58.
    Russell, D. W. and Miller, A. D. (1996) Foamy virus vectors. J. Virol. 70, 217–222.PubMedGoogle Scholar
  59. 59.
    Culver, K. W., Anderson, W. F., and Blaese, R. M. (1991) Lymphocyte gene therapy. Hum. Gene Ther. 2, 107–109.PubMedCrossRefGoogle Scholar
  60. 60.
    van Beusechem, V. W. and Valerio, D. (1996) Gene transfer into hematopoietic stem cells of nonhuman primates. Hum. Gene Ther. 7, 1649–1668.PubMedCrossRefGoogle Scholar
  61. 61.
    Kiem, H. -P., Darovsky, B., von Kalle, C., Goehle, S., Graham, T., Miller, A. D., Storb, R., and Schuening, F. G. (1995) Long-term persistence of canine hematopoietic cells genetically marked by retrovirus vectors. Hum. Gene Ther. 7, 89–96.CrossRefGoogle Scholar
  62. 62.
    Bodine, D. M., Moritz,T., Donahue, R. E., Luskey, B. D., Kessler, S. W., Martin, D. I. K., Orkin, S. H., and Nienhuis, A. W., and Williams, D. A. (1993) Long-term in vivo expression of a murine adenosine deaminase gene in rhesus monkey hematopoietic cells of multiple lineages after retroviral mediated gene transfer into CD34+ bone marrow cells. Blood 82, 1975–1980.PubMedGoogle Scholar
  63. 63.
    Kaleko, M., Garcia, J. V., Osborne, W. R. A., and Miller, A. D. (1990) Expression of human adenosine deaminase in mice after transplantation of genetically-modified bone marrow. Blood 75, 1733–1741.PubMedGoogle Scholar
  64. 64.
    Lim, B., D. A. Williams, and Orkin, S. H. (1987) Retrovirus-mediated gene transfer of human adenosine deaminase: expression of functional enzyme in murine hematopoietic stem cells in vivo. Mol. Cell. Biol. 7, 3459–3465.Google Scholar
  65. 65.
    Moore, K. A., Fletcher, F. A., Villalon, D. K., Utter, A. E., and Belmont, J. W. (1990) Human adenosine deaminase expression in mice. Blood 75, 2085–2092.PubMedGoogle Scholar
  66. 66.
    Osborne, W. R. A., Hock, R. A., Kaleko, M., and Miller, A. D. (1990) Long-term expression of human adenosine deaminase in mice after transplantation of bone marrow infected with amphotropic retroviral vectors. Hum. Gene Ther. 1, 31–41.PubMedCrossRefGoogle Scholar
  67. 67.
    Lim, B., Apperly, J. F., Orkin, S. H., and Williams, D. A. (1989) Long-term expression of human adenosine deaminase in mice transplanted with retrovirus-infected hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 86, 8892–8896.PubMedCrossRefGoogle Scholar
  68. 68.
    Correll, P. H., Colilla, S., and Karlsson, S. (1994) Retroviral vector design for long-term expression in murine hematopoietic cells in vivo. Blood 84, 1812–1822.PubMedGoogle Scholar
  69. 69.
    Mullen, C. A., Snitzer, K., Culver, K. W., Morgan, R. A., Anderson, W. F., and Blaese, R. M. (1996) Molecular analysis of T lymphocyte-directed gene therapy for adenosine deaminase deficiency: long-term expression in vivo of genes introduced with a retroviral vector. Hum. Gene Ther. 7, 1123–1129.PubMedCrossRefGoogle Scholar
  70. 70.
    Culver, K. W., Morgan, R. A., Osborne, W. R. A., Lee, R. T., Lenschow, D., Able, C., Cornetta, K., Anderson, W. F., and Blaese, R. M. (1990) In vivo expression and survival of gene-modified T lymphocytes in rhesus monkeys. Hum. Gene Ther. 1, 399–410.PubMedCrossRefGoogle Scholar
  71. 71.
    Kantoff, P. W., Kohn, D. B., Mitsuya, H., Armentano, D., Sieberg, M., Zwiebel, J. A., Eglitis, M. A., McLachlin, J. R., Wiginto, D. A., Hutton, J. J., Horowitz, S. D., Gilboa, E., Blaese, R. M., and Anderson, W. F. (1986) Correction of adenosine deaminase deficiency in cultured human T and B cells by retrovirus-mediated gene transfer. Proc. Natl. Acad. Sci. USA 83, 6563–6567.PubMedCrossRefGoogle Scholar
  72. 72.
    Challita, P. and Kohn, D. B. (1994) Lack of expression from a retroviral vector after transduction of murine hematopoietic stem cells is associated with methylation in vivo. Proc. Natl. Acad. Sci. USA 91, 2567–2571.PubMedCrossRefGoogle Scholar
  73. 73.
    Wilson, J. M., Danos, O., Grossman, M., Raulet, D. H., and Mulligan, R. C. (1990) Expression of human adenosine deaminase in mice reconstituted with retrovirus-transduced hematopoietic stem cells. Blood 71, 1738–1743.Google Scholar
  74. 74.
    van Beusechem, V., Kukler, A., Heidt, P. J., and Valerio, D. (1992) Long-term expression of human adenosine deaminase in rhesus monkeys transplanted with retrovirus-infected bone-marrow cells. Proc. Natl. Acad. Sci. USA. 89, 7640–7644.PubMedCrossRefGoogle Scholar
  75. 75.
    Riddell, S. R., Elliott, M., Lewinsohn, D. A., Gilbert, M. J., Wilson, L., Manley, S. A., Lupton, S. D., Overll, R. W., Reynolds, T. C., Corey, L., and Greenberg, P. D. (1996) T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat. Med. 2, 216–223.PubMedCrossRefGoogle Scholar
  76. 76.
    Sanes J., Rubenstein, J., and Nicolas, J. (1986) Use of a recombinant retrovirus to study post implantation cell lineage in mouse embryos. EMBO J. 5, 3133–3142.PubMedGoogle Scholar
  77. 77.
    Paul R., Morris, D., Hess, B., Dunn, J., and Overell, R. (1993) Increased viral titer through concentration of viral harvests from retroviral packaging cell lines. Hum. Gene Ther. 4, 609–615.PubMedCrossRefGoogle Scholar
  78. 78.
    Chuck, A. and Palsson, B. (1996a) Consistent and high rates of gene transfer can be obtained using the flow through transduction over a wide range of retroviral titers. Hum. Gene Ther. 7, 743–750.PubMedCrossRefGoogle Scholar
  79. 79.
    Kotani, H., Newton, P. B., Zhang, S., Chiang, Y., Otto, E., Weaver, L. Blaese, R. M., Anderson, W. F., and McGarrity, G. J. (1994) Improved methods of retroviral vector transduction and production for gene therapy. Hum. Gene Ther. 5, 19–28.Google Scholar
  80. 80.
    Coelen, R., Jose, D., and May, J. (1983) The effect of hexadimethrine bromide (polybrene) on the infection of primate retroviruses SSV1/SSAV1 and BaEV. Arch. Virol. 75, 307–311.PubMedCrossRefGoogle Scholar
  81. 81.
    Andreadis, S. and Palsson, B. O. (1997) Coupled effects of polybrene and calf serum on the efficiency ofretroviral transduction and the stability ofretroviral vectors. Hum. Gene Ther. 8, 285–291.PubMedCrossRefGoogle Scholar
  82. 82.
    Bagnis, C., Cischportich, C., Imbert, A., Van den Broeke, A., Cornet, V., and Mannoni, P. (1997) Efficiency of retroviral transduction into hematopoietic cells by cocultivation procedure does not correlate with viral titer. Cancer Gene Ther. 4, 5–8.PubMedGoogle Scholar
  83. 83.
    Xu, L. C., Young, H. A., Blanco, M., Kessler, S., Roberts, A. B., and Karlsson, S. (1994) Poor transduction efficiency of human hematopoietic progenitor cells by high titer amphotropic retrovirus producer cell clones. J. Virol. 68, 7634–7636.PubMedGoogle Scholar
  84. 84.
    Mayani, H., Little, M. T., Dragowska, W., et al. (1995) Differential effects of the hematopoietic inhibitors MIP1-a, TGF-ß, and TNF-a on cytokine-induced proliferation of subpopulations of CD34+ cells purified from cord blood and from liver. Exp. Hemat. 23, 422–427.PubMedGoogle Scholar
  85. 85.
    Miller, A. D. (1996) Cell-surface receptors for retroviruses and implications for gene transfer. Proc. Natl. Acad. Sci. USA 93, 11407–11413.PubMedCrossRefGoogle Scholar
  86. 86.
    Weiss, R. A., and Tailor, C. S. (1995) Retrovirus receptors. Cell 82, 531–533.PubMedCrossRefGoogle Scholar
  87. 87.
    Miller A. D., Garcia, J. V., von Suhr, N., Lynch, C. M., Wilson, C., and Eiden, M. V. (1991) Construction and properties of retrovirus packaging cells based on gibbon ape leukemia virus. J. Virol. 65, 2220–2224.PubMedGoogle Scholar
  88. 88.
    Bunnel, B. A., Muul, L. M., Donahue, R. E., Blaese, R. M., and Morgan, R. A. (1995) High-efficiency retroviral-mediated gene transfer into human and nonhuman primate peripheral blood lymphocytes. Proc. Natl. Acad. Sci. USA. 92, 7739–7743.CrossRefGoogle Scholar
  89. 89.
    Cosset, F. L., and Russell, S. J. (1996) Targeting retrovirus entry. Gene Ther. 3, 946–956.PubMedGoogle Scholar
  90. 90.
    Kasahara N., Dozy, A. M., Kan, Y. W. (1994) Tissue-specific targeting of retroviral vectors through ligand-receptor interactions. Science 266, 1373–1376.PubMedCrossRefGoogle Scholar
  91. 91.
    Valsesia-Wittmann, S., Morling, F. J., Nilson, B. H., Takeuchi, Y., Russell, S. J., and Cosset, F. L. (1996) Improvement of retroviral retargeting by using amino acid spacers between an additional binding domain and the N terminus of Moloney murine leukemia virus SU. J. Virol. 70, 2059–2064.Google Scholar
  92. 92.
    Schwarzenberger, P., Spence, S. E., Gooya, J. M., Michiel, D., Curiel, D. T., Ruscetti, F. W., and Keller, J. R. (1996) Targeted gene transfer to human hematopoietic progenitor cell lines through the c-kit receptor. Blood 87, 472–478.PubMedGoogle Scholar
  93. 93.
    Williams, D. A., Lenischka, I. R., Nathan, D. G., and Mulligan, R. C. (1984) Introduction of new genetic material into pluripotent stem cells of the mouse. Nature 310, 476–480.PubMedCrossRefGoogle Scholar
  94. 94.
    Dick, J. E., Magli, M. C., Huszar, D., Phillips, R. A., and Bernstein, A. (1985) Introduction of a selectable gene in primitive stem cells capable of long-term reconstitution of the hematopoietic system of w/wv mice. Cell 42, 71–79.PubMedCrossRefGoogle Scholar
  95. 95.
    Lemischka, I. R., Raulet, D. H., and Mulligan, R. C. (1986) Developmental potential and dynamic behavior of hematopoietic stem cells. Cell 45, 917–927.PubMedCrossRefGoogle Scholar
  96. 96.
    Hanenberg, H., Xiao, X. L., Dilloo, D., Hashino, K., Kato, I., and Williams, D. A. (1996) Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells. Nat. Med. 2, 876–882.PubMedCrossRefGoogle Scholar
  97. 97.
    Moritz, T., Dutt, P., Xiao, X., Carstanjen, D., Vik, T., Hanenberg, H., and Williams, D. A. (1996) Fibronectin improves transduction of reconstituting hematopoietic stem cells by retroviral vectors: evidence of direct viral binding to chymotryptic carboxy-terminal fragments. Blood 88, 855–862.PubMedGoogle Scholar
  98. 98.
    Moritz, T., Keller, D. C., and Williams, D. A. (1993) Human cord blood cells as targets for gene transfer: potential use in genetic therapies of severe combined immunodeficiency disease. J. Exp. Med. 178, 529–536.PubMedCrossRefGoogle Scholar
  99. 99.
    Moore, K. A., Deisseroth, A. B., Reading, C. L., Williams, D. E., and Belmont, J. W. (1992) Stromal support enhances cell-free retroviral vector transduction of human bone-marrow longterm culture-initiating cells. Blood 79, 1393–1399.PubMedGoogle Scholar
  100. 100.
    Toksoz, D., Zsebo, K. M., Smith, K. A., Hu, S., Brankow, D., Suggs, S. V., Martin, F. H., and Williams, D. A. (1992) Support of human hematopoiesis in long-term bone marrow cultures by murine stromal cells selectively expressing the membrane-bound and secreted forms of the human homolog of the steel gene product, stem cell factor. Proc. Natl. Acad. Sci. 89, 7350–7354.PubMedCrossRefGoogle Scholar
  101. 101.
    Hanenberg, H., Hashino, K., Konishi, H., Hock, R. A., Kato, I., and Williams, D. A. (1997) Optimization of fibronectin-assisted retroviral gene transfer into human CD34+ hematopoietic cells. Human Gene Ther. 8, 2193–2206.CrossRefGoogle Scholar
  102. 102.
    Yoder, M. C. and Williams, D. A. (1995) Matrix molecule interactions with hematopoietic stem cells. Exp. Hematol. 23, 961–967.PubMedGoogle Scholar
  103. 103.
    Ruoslahti, E. (1988) Fibronectin and its receptors. Ann. Rev. Biochem. 57, 375–413.PubMedCrossRefGoogle Scholar
  104. 104.
    Williams, D. A., Rios, M., Stephens, C., and Patel, V. P. (1991) Fibronectin and VLA-4 in hemotopoietic stem-cell-microenvironment interactions. Nature 352, 438–441.PubMedCrossRefGoogle Scholar
  105. 105.
    Kimizuka, F, Taguchi, Y., Ohdate, Y., Kawase, Y., Shimojo, T., Hashino, K., Kato, I., Sekiguchi, K., and Titani, K. (1991) Production and characterization of functional domains of human fibronectin expressed in Escherichia coli. J Biochem. 110, 284–291.PubMedGoogle Scholar
  106. 106.
    Culver, K., Cornetta, K., Morgan, R., Morecki, S., Aebersold, P., Kasid, A., Lotze, M., Rosenberg, S. A., Anderson, W. F., and Blaese, R. M. (1991) Lymphocytes as cellular vehicles for gene therapy in mouse and man. Proc. Natl. Acad. Sci. USA 88, 3155–3159.PubMedCrossRefGoogle Scholar
  107. 107.
    Hege, K. M. and Roberts, M. R. (1996) T-cell gene therapy. Curr. Opin. Biotech. 7, 629–634.PubMedCrossRefGoogle Scholar
  108. 108.
    Shimizu, Y., van Seventer, G. A., Ennis, E., Newman, W., Horgan, K. J., and Shaw, S. (1992) Crosslinking of the T cell-specific accessory molecules CD7 and CD28 modulates T cell adhesion. J. Exp Med. 175, 577–582.PubMedCrossRefGoogle Scholar
  109. 109.
    Shimizu, Y., van Seventer, G. A., Horgan, K. J., and Shaw, S. (1990) Regulated expression and binding of three VLA (131) integrin receptors on T cells. Nature 345, 250–253.PubMedCrossRefGoogle Scholar
  110. 110.
    Turcovski-Corrales, S. M., Fenton, R. G., Peltz, G., and Traub, D. D. (1995) CD28:B7 interactions promote T cell adhesion. Eur. J. Immunol. 25, 3087–3093.PubMedCrossRefGoogle Scholar
  111. 111.
    Bock, T. A., Orlic, D., Dunbar, C. E., Broxmeyer, H. E., and Bodine, D. M. (1995) Improved engraftment of human hematopoietic cells in severe combined immunodeficient (SCID) mice carrying human cytokine transgenes. J. Exp. Med. 182, 2037–2043.PubMedCrossRefGoogle Scholar
  112. 112.
    Lubin, I., Segall, H., Marcus, H., David, M., Kulova, L., Steinitz, M., Erlich, P., Gan, J., and Reisner, Y. (1994) Engraftment of human peripheral blood lymphocytes in normal strains of mice. Blood 83, 2368–2381.PubMedGoogle Scholar
  113. 113.
    Nolta, J., Dao, M., Wells, S., Smogorzewska, E., and Kohn, D. (1996) Transduction of pluripotent human hematopoietic stem cells demonstrated by clonal analysis after engraftment in immune deficient mice. Proc. Natl. Acad. Sci. USA. 93, 2414–2419.PubMedCrossRefGoogle Scholar
  114. 114.
    Champsiex, C., Marechal, V., Khazaal, I., Schwartz, O., Fournier, S., Schlegel, N., Dranoff, G., Danos, O., Blot, P., Vilmer, E., Heard, J. M., Peault, B., and Lehn, P. (1996) A cell surface marker gene transferred with a retroviral vector into CD34+ cord blood cells is expressed by their T-cell progeny in the SCID-hu thymus. Blood 88, 107–113.Google Scholar
  115. 115.
    Tary-Lehmann, M., Lehmann, P. V., Schols, D., Roncarolo, M. G., and Saxon, A. (1994) AntiSCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras. J. Exp. Med. 180, 1817–1827.PubMedCrossRefGoogle Scholar
  116. 116.
    Srour, E. F., Zanjani, E. D., Cometta, K., Traycoff, C. M., Flake, A. W., Hedrick, M., Brandt, J. E., Leemhuis, T., Hoffman, R. (1993) Persistence of human multilineage, self-renewing lymphohematopoietic stem cells in chimeric sheep. Blood 82, 3333–3342.PubMedGoogle Scholar
  117. 117.
    Zanjani, E. D., Srour, E. F., and Hoffman, R. (1995) Retention of long-term repopulating ability of xenogeneic transplanted purified adult human bone marrow hematopoietic stem cells in sheep. J. Lab. Clin. Med. 126, 24–28.PubMedGoogle Scholar
  118. 118.
    Hirschhorn, R. (1995) Adenosine deaminase deficiency: molecular basis and recent developments. Clin. Immun. Immunopath. 76, S219 — S227.PubMedCrossRefGoogle Scholar
  119. 119.
    Dong, R., Kameoka, J., Hegen, M., Tanaka, T., Xu, Y., Schlossman, S. F., and Morimoto, C. (1996) Characterization of adenosine deaminase binding to human CD26 on T cells and its biologic role in immune response. J. Immunol. 156, 1349–1355.PubMedGoogle Scholar
  120. 120.
    Parkman, R. (1986) The application of bone marrow transplantation to the treatment of genetic diseases. Science 232, 1373–1378.PubMedCrossRefGoogle Scholar
  121. 121.
    Fairbanks, L. D., Simmonds, A. A., Hoogerbrugge, P. M., van Beusechem, V. W., Valerio, D., Moseley, A., Levinsky, R. J., Gaspar, H. B., and Morgan, G. (1995) Biochemical and immunological status following gene therapy and PEG-ADA therapy for adenosine deaminase (ADA) deficiency, in Purine and Pyrimidine Metabolism in Man VIII. ( Sahota, A. and Taylor, M., eds.), Plenum Press, New York.Google Scholar
  122. 122.
    Braakman, E., van Beusechem, V. W., van Krimpen, B. A., Fischer, A., Bolhuis, R. L. H., and Valerio, D. (1992) Genetic correction of cultured T cells from an adenosine deaminase-deficient patient: characteristic of non-transduced and transduced T cells. Eur. J. Immunol. 22, 63–69.PubMedCrossRefGoogle Scholar
  123. 123.
    Ferrari, G., Rossini, S., Giavazzi, R., Maggioni, D., Nobili, N., Soldati, M., Ungers, G., Mavilio, F., Gilboa, E., and Bordignon, C. (1991) An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency. Science 251, 1363–1366.PubMedCrossRefGoogle Scholar
  124. 124.
    Leonard, W. J. (1996) The molecular basis of X-linked severe combined immunodeficiency: defective cytokine receptor signaling. Annu. Rev. Med. 47, 229–239.PubMedCrossRefGoogle Scholar
  125. 125.
    Puck, J. M., de Saint Basile, G., Schwarz, K., Fugmann, S., and Fischer, R. E. (1996) ILZRGbase: a database of yc-chain defects causing human X-SCID. Immunol. Today 17 Google Scholar
  126. 126.
    Leonard, W. J., Noguchi, M., Russell, S. M., and McBride, O. W. (1994) The molecular basis of X-linked severe combined immunodeficiency: the role of the interleukin-2 receptor y chain as a common y chain, 7c. Immunol. Rev. 138, 61–86.PubMedCrossRefGoogle Scholar
  127. 127.
    Noguchi, M., Yi, H., Rosenblatt, H. M., Filipovich, A. H., Adelstein, A., Modl, W. S., McBride, O. W., and Leonard, W. J. (1993) Interleukin-2 receptor y chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73, 147–157.PubMedCrossRefGoogle Scholar
  128. 128.
    Puck, J. M., Deschenes, S. M., Porter, J. C., Dutra, A. S., Brown, C. J., Willard, H. F., and Henthorn, P. S. (1993) The interleukin-2 receptor y chain maps to Xg13. 1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum. Mol. Gen. 2, 1099–1104.PubMedCrossRefGoogle Scholar
  129. 129.
    Russell, S. M., Keegan, A. D., Harada, N., Nakamura, Y., Noguchi, M., Leland, P., Friedmann, M. C., Miyajima, A., Puri, R. K., Paul, W. E., and Leonard, W. J. (1993) Interleukin-2 receptor y chain: a functional component of the interleukin-4 receptor. Science 262, 1880–1883.PubMedCrossRefGoogle Scholar
  130. 130.
    Kondo, M., Takeshita, T., Ishii, N., Nakamura, M., Watanabe, S., Arai, K., and Sugamura, K. (1993) Sharing of the interleukin-2 (IL-2) receptor y chain between receptors for IL-2 and IL-4. Science 262, 1874–1876.PubMedCrossRefGoogle Scholar
  131. 131.
    Noguchi, M., Nakamura, Y., Russell, S. M., Ziegler, S. F., Tsang, M., Cao, X. G., and Leonard, W. J. (1993) Interleukin-2 receptor y chain: a functional component of the interleukin-7 receptor. Science 262, 1877–1880.PubMedCrossRefGoogle Scholar
  132. 132.
    Kondo, M., Takeshita, T., Higuchi, M., Nakamura, M., Sudo, T., Nishikawa, S., and Sugamura, K. (1994) Functional participation of the IL-2 receptor y chain in IL-7 receptor complexes. Science 364, 1453–1454.CrossRefGoogle Scholar
  133. 133.
    Russell, S. M., Johnston, J. A., Noguchi, M., Kawamura, M., Bacon, C. M., Friedmann, M., Berg, M., McVicar, D. W., Witthuhn, B. A., Silvennoinen, O., Goldman, A. S., Schmalstieg, F. C., Ihle, J. N., O’Shea, J. J., and Leonard, W. J. (1994) Interaction of IL-2R13 and yc chains with Jakl and Jak3: implications for XSCID and XCID. Science 266, 1042–1045.PubMedCrossRefGoogle Scholar
  134. 134.
    Giri, J. G., Ahdieh, M., Eisenman, J., Shanebeck, K., Grabstein, K., Kumaki, S., Namen, A., Park, L. S., Cosman, D., and Anderson, D. (1994) Utilization of the ß and y chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 13, 2822–2830.PubMedGoogle Scholar
  135. 135.
    Peschon J., Morrissey, P. J., Grabstein, K. H., Ramsdell, F. J., Maraskovsky, E., Gliniak, B. C., Park, L. S., Ziegler, S. F., Williams, D. E., Ware, C. B., Meyer, J. D., and Davison, B. L. (1994) Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960.PubMedCrossRefGoogle Scholar
  136. 136.
    Grabstein, K. H., Waldschmidt, T. J., Finkelman, F. D., Hess, B. W., Alpert, A. R., Boiani, N. E., Namen, A. E., and Morrissey, P. J. (1993) Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody. J. Exp Med. 178, 257–264.PubMedCrossRefGoogle Scholar
  137. 137.
    Boussiotis, V. A., Barber, D. L., Nakarai, T., Freeman, G. J., Gribben, J. G., Bernstein, G. M., D’Andrea, A. D., Ritz, J., and Nadler, L. M. (1994) Prevention of T cell anergy by signaling through the yc chain of the IL-2 receptor. Science 266, 1039–1050.PubMedCrossRefGoogle Scholar
  138. 138.
    Taylor, N, Uribe, L., Smith, S., Jahn, T., Kohn, D. B., and Weinberg, K. (1996) Correction of interleukin-2 receptor function in X-SCID lymphoblastoid cells by retrovirally mediated transfer of the y, gene. Blood 87, 3103–3107.PubMedGoogle Scholar
  139. 139.
    Hacein-Bey, B., Cavazzana-Calvo, M., Le Deist, F., Dautry-Varsat, A., Hivroz, C., Riviere, I., Danos, O., Heard, J. M., Sugamura, K., Fischer, A., and De Saint Basile, G. (1996) y gene transfer into SCID X1 patients’ B-cell lines restores normal high-affinity interleukin-2 receptor expression and function. Blood 87, 3108–3116.Google Scholar
  140. 140.
    Miyazaki, T., Kawahara, A., Fujii, H., Nakagawa, Y., Minami, Y., Liu, Z. -J., Oishi, I., Silvennoinen, O., Witthuhn, B. A., Ihle, J. N., and Taniguchi, T. (1994) Functional activation ofJakl and Jak3 by selective association with IL-2 receptor subunits. Science 266, 1045–1047.PubMedCrossRefGoogle Scholar
  141. 141.
    Qazilbash, M. H., Walsh. C. E., Russell, S. M., Noguchi, M., Mann, M. M., Leonard, W. J., and Liu, J. M. (1995) Retroviral vector for gene therapy of X-linked severe combined immunodeficiency syndrome. J. Hematother. 4, 91–98.Google Scholar
  142. 142.
    Ohbo, K., Takasawa, N., Ishii, N., Tanaka, N., Nakamura, M., and Sugamura, K. (1995) Functional analysis of the human interleukin-2 receptor y chain gene promoter. J. Biol. Chem. 270, 7479–7486.PubMedCrossRefGoogle Scholar
  143. 143.
    Cao, X., Shores, E. W., Hu-Li, J., Anver, M. R., Keisall, B. L., Russell, S. M., Drago, J., Noguchi, M., Grinberg, A., Bloom, E. T., Paul, W. E., Katz, S. I., Love, P. E., and Leonard, W. J. (1995) Defective lymphoid development in mice lacking expression of the common cytokine receptor y chain. Immunity 2, 223–238.PubMedCrossRefGoogle Scholar
  144. 144.
    DiSanto, J. P., Muller, W., Guy-Grand, D., Fischer, A., and Rajewsky, K. (1995) Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor y chain. Proc. Natl. Acad. Sci. USA 92, 377–381.PubMedCrossRefGoogle Scholar
  145. 145.
    Ohbo, K., Suda, T., Haashiyama, M., Mantani, A., Ikebe, M., Miyakawa, K., Moriyama, M., Nakamura, M., Katsuki, M., Takahashi, K., Yamamura, K., and Sugamura, K. (1996) Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor y chain. Blood 3, 956–967.Google Scholar
  146. 146.
    Henthorn, P. S., Somberg, R. L., Fimiani, V. M., Puck, J. M., Patterson, D. F., and Felsburg, P. J. (1994) IL-2Ry gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease. Genomics 23, 69–74.PubMedCrossRefGoogle Scholar
  147. 147.
    Somberg, R. L., Tipold, A., Hartnett, B. J., Moore, P. F., Henthorn, P. S., and Felsburg, P. J. (1996) Postnatal development of T cells in dogs with X-linked severe combined immunodeficiency. J. Immunol. 156, 1431–1435.PubMedGoogle Scholar
  148. 148.
    Buckley, R. H., Schiff, S. E., Roberts, J. L., Markert, M. L., Peters, W., Williams, L. W., and Ward, E. (1993) Haploidentical bone marrow stem cell tranplantation in human severe combined immunodeficiency. Semin. Hematol. 30, 92–101.PubMedGoogle Scholar
  149. 149.
    Cavazzana-Calvo, M., Hacein-Bey, S., de Saint Basile, G., De Coene, C., Self, F., Le Deist, F., and Fischer, A. (1996) Role of interleukin-2 (IL-2), IL-7, and IL-15 in natural killer cell differentiation from cord blood hematopoietic progenitor cells and from y, transduced severe combined immunodeficiency X1 bone marrow cells. Blood 88, 3901–3909.PubMedGoogle Scholar
  150. 150.
    Sutkowski, N., Kuo, M., Varela-Echavarria, A., Dougherty, J. P., and Ron, Y. (1994) A murine model for B-lymphocyte somatic cell gene therapy. Proc. Natl. Acad. Sci. USA 91, 8875–8879.PubMedCrossRefGoogle Scholar
  151. 151.
    Noelle, R. J. (1995) The role of gp39 (CD40L) in immunity Clin. Immunol. Immunopath. 76, S203 - S207.CrossRefGoogle Scholar
  152. 152.
    Rosen F. S., Cooper, M. D., and Wedgwood, R. J. P. (1995) The primary immunodeficiencies. NEJM 333, 431–440.PubMedCrossRefGoogle Scholar
  153. 153.
    Allen, R., Armitage, R. J., Conley, M. E., Rosenblatt, H., Jenkis, N. A., Copeland, N. G., Bedell, M. A., Edilhoff, S., Desteche, C. M., Simoneaux, D. K., Fanslow, W. C., Belmont, J., and Spriggs, M. K. (1993) CD40 ligand gene defects responsible for X-linked hyper IgM syndrome. Science 259, 990–993.PubMedCrossRefGoogle Scholar
  154. 154.
    Aruffo, A., Farrington, M., Hollenbaugh, D., Xu, L., Milatovich, A., Nonoyama, S., Bejorath, J., Grosmaire, L. S., Stenkamp, R., Neubauer, M., Roberts, R. L., Noelle, R. J., Ledbetter, J. A., Francke, U., and Ochs, H. D. (1993) The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked Hyper-IgM Syndrome. Cell 72, 291–300.PubMedCrossRefGoogle Scholar
  155. 155.
    Korthauer, U., Graf, D., Mages, H. W., Briere, F., Padayachee, M., Malcolm, S., Ugazio, A. G., Notarangelo, L. D., and Kroczek, R. A. (1993) Defective expression of T cell CD40 ligand causes X-linked immunodeficiency with hyper IgM. Nature 361, 539–541.PubMedCrossRefGoogle Scholar
  156. 156.
    DiSanto, J. P., Bonnefoy, J. Y., Gauchat, J. F., Fischer, A., and de Saint Basile, G. (1993) CD40 ligand mutations in the X-linked form of hyper -IgM syndrome. Nature 361, 541–543.PubMedCrossRefGoogle Scholar
  157. 157.
    Fuleihan, R., Ramesu, N., Loh, R., Jabara, H., Rosen, F. S., Chatila, T., Fu, S. M., Stamenkovic, I., and Geha, R. S. (1993) Defective expression of the CD40-ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc. Natl. Acad. Sci. USA 90, 2170–2173.PubMedCrossRefGoogle Scholar
  158. 158.
    Banchereau, J., Bazan, F., Blanchard, D., Briere, F., Galizzi, J. P., van Kooten, C., Liu, Y. J., Rousset, F., and Saeland, S. (1994) The CD40 antigen and its ligand. Annu. Rev. Immunol. 12, 881–922.PubMedCrossRefGoogle Scholar
  159. 159.
    Banchereau, J., de Paoli, P., Valle, A., Garcia, E., and Rousset, F. (1991) Long term human B cell lines dependent on interleukin 4 and antibody to CD40. Science 291, 70–72.CrossRefGoogle Scholar
  160. 160.
    Rousset, F., Garcia, E., and Banchereau, J. (1991) Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen. J. Exp. Med. 173, 671–682.CrossRefGoogle Scholar
  161. 161.
    Kehry, M. R. (1996) CD40-mediated signaling in B cells. J. Immunol. 156, 2345–2348.PubMedGoogle Scholar
  162. 162.
    Foy, T. M., Shepherd, D. M., Durie, F. H., Aruffo, A., Ledbetter, J. A., and Noelle, R. J. (1993) In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity II Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. J. Exp. Med. 178, 1567–1575.PubMedCrossRefGoogle Scholar
  163. 163.
    Shapira, S., Vercelli, D., Jabara, H., Fu, S. M., and Geha, R. (1992) Molecular analysis of the induction of IgE synthesis in human B cells by IL-4 and engagement of CD40 antigen. J. Exp. Med. 175, 289–292.PubMedCrossRefGoogle Scholar
  164. 164.
    Vercelli, D., Jabara, H. H., Arai, K., and Geha, R. S. (1989) Induction of human IgE synthesis requires interleukin-4 and T/B cell interactions involving the T cell receptor/CD3 complex and MHC class II antigens. J. Exp. Med. 169, 1295–1307.PubMedCrossRefGoogle Scholar
  165. 165.
    Vercelli, D. and Geha, R. S. (1991) Regulation of IgE synthesis in humans: a tale of two signals. J. Allergy Clin. lmmunol. 88, 285–295.CrossRefGoogle Scholar
  166. 166.
    Armitage, R. J., Fanslow, W. C., Stockbine, L., Sato, T. A., Clifford, K. N., Macduff, B. M., Anderson, D. M., Glimpel, S. D., Davis-Smith, T., Maliszewski, C. R., Clark, E. A., Smith, C. A., Grabstein, K. H., Cosman, D., and Spriggs, M. K. (1992) Molecular and biological characterization of a murine ligand for CD40. Nature 357, 80–82.PubMedCrossRefGoogle Scholar
  167. 167.
    Hollenbaugh, D., Gosmaire, L., Kullas, C. D., Chalupny, N. J., Noelle, R. J., Stamenkovic, I., Ledvetter, J. A., and Aruffo, A. (1992) The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. EMBO J. 11, 4313–4321.PubMedGoogle Scholar
  168. 168.
    Notarangelo, L. D., et al. (1996) CD40Lbase, a database of CD40L gene mutations causing X-linked hyper-IgM syndrome. Immuol. Today 17, 511–516.Google Scholar
  169. 169.
    Ramesh, N., Morio, T., Fuleihan, R., Worm, M., Horner, A., Tsitsikov, E., Castigli, E., and Geha, R. S. (1995) CD40–CD40 ligand (CD40L) interactions and X-linked HyperlgM Syndrome (HIGMX-1). Clin. Immunol. Immunopath. 76, S208 - S213.CrossRefGoogle Scholar
  170. 170.
    Xu, J., Foy, T. M., Laman, J. D., Elliott, E. A., Dunn, J. J., Waldschmidt, T. J., Elsemore, J., Noelle, R. J., and Flavell, R. A. (1994) Mice deficient for the CD40 ligand. Immunity 1, 423–431.Google Scholar
  171. 171.
    Kawabe, T., Naka, T., Yoshida, K., Tanaka, T., Fujiwara, H., Suematsu, S., Yoshida, N., Kishimoto, T., and Kikutani, H. (1994) The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1, 167–178.PubMedCrossRefGoogle Scholar
  172. 172.
    Durandy, A., Hivroz, C., Mazerolles, F., Schiff, C., Bernard, F., Jouanguy, E., Revy, P., DiSanto, J. P., Gauchat, J. F., Gauchat, J. Y., Bonnefoy, J. Y., Casanova, J. L., and Fischer, A. (1997) Abnormal CD40-mediated activation pathway in B lymphocytes from patients with Hyper-IgM Syndrome and normal CD40 ligand expression. J. Immunol. 158, 2576–2584.PubMedGoogle Scholar
  173. 173.
    Schwarz, K., Nonoyama, S., Peitsch, M. C., de Saint Basile, G., Espanol, T., Fasth, A., Fischer, A., Freitag, K., Friedrich, W., Fugmann, S., Hossle, H., Jones, A., Kinnon, C., Meindl, A., Notarangelo, L. D., Weschsler, A., Weiss, M., and Ochs, H. D. (1996) WASPbase: a database of WAS- and XLT-causing mutations. Immunol. Today 17, 496–502.PubMedGoogle Scholar
  174. 174.
    Gerwin, N., Friedrich, C., Perez-Atayde, A., Rosen, F. S., and Gutierrez-Ramos, J. C. (1996) Multiple antigens are altered on T and B lymphocytes from peripheral blood and spleen of patients with Wiskott-Aldrich syndrome. Clin. Exp. Immunol. 106, 208–217.PubMedCrossRefGoogle Scholar
  175. 175.
    Kawabata, K., Nagasawa, M., Mono, T., Okawa, H., and Yata, J. (1996) Decreased alpha/beta heterodimer among CD8 molecules of peripheral blood T cells in Wiskott-Aldrich syndrome. Clin. Immunol. Immunopath. 81, 129–135.CrossRefGoogle Scholar
  176. 176.
    Kwan, S. -P., Hagemann, T L, Radtke, B. E., Blaese, R. M., and Rosen, F. S. (1995) Identifications of mutations in the Wiskott-Aldrich syndrome gene and characterization of a polymorphic dinucleotide repeat at DXS6940, adjacent to the disease gene. Proc. Natl. Acad. Sci. USA 92, 4706–4710.PubMedCrossRefGoogle Scholar
  177. 177.
    Symons, M., Deny, J. M. J., Karlak, B., Jiang, S., Lemahieu, V., McCormick, F., Francke, U., and Abo, A. (1996) Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. Cell 84, 723–734.PubMedCrossRefGoogle Scholar
  178. 178.
    Cory, G. O. C., MacCarthy-Morrogh, L., Banin, S., Gout, I., Brickell, P. M., Levinsky, R. J., Kinnon, C., and Lovering, R. C. (1996) Evidence that the Wiskott-Aldrich Syndrome protein may be involved in lymphoid cell signaling pathways. J. Immunol. 157, 3791–3795.PubMedGoogle Scholar
  179. 179.
    Kolluri, R., Tolias, K. F., Carpenter, C. L., Rosen, F. S., and Kirchhausen, T. (1996) Direct interaction of the Wiskott-Aldrich syndrome protein with the GTPase Cdc42. Proc. Natl. Acad. Sci. USA 93, 5615–5618.PubMedCrossRefGoogle Scholar
  180. 180.
    Stowers L., Yelon, D., Berg, L. J., and Chant, J. (1995) Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42. Proc. Natl. Acad. Sci. USA 92, 5027–5031.PubMedCrossRefGoogle Scholar
  181. 181.
    Sideras, P. and Smith, C. I. (1995) Molecular and cellular aspects of X-linked agammaglobulinemia. Adv. Immunol. 59, 135–233.PubMedCrossRefGoogle Scholar
  182. 182.
    Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., and Bentley, D. R. (1993) The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein tyrosine kinases. Nature 361, 226–233.PubMedCrossRefGoogle Scholar
  183. 183.
    Smith, C. I., Baskin, B., Humire-Greiff, P., Zhou, J. N., Olsson, P. G., Maniar, H. S., Kjellen, P., Lambris, J. D., Christenson, B., Hammarstrom, L., Bentley, D., Vetrie, D., Islam, K. B., Vorechovsky, I., and Sideras, P. (1994) Expression of Bruton’s agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J. Immunol. 152, 557–565.PubMedGoogle Scholar
  184. 184.
    de Weers, M., Verschuren, M. C., Kraakman, M. E., Mensink, R. G., Schuurman, R. K., van Dongen, J. J., and Hendriks, R. W. (1993) The Bruton’s tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages. Eur. J. Immunol. 23, 3109–3114.PubMedCrossRefGoogle Scholar
  185. 185.
    Conley, M. E. (1985) B cells in patients with X-linked aggammaglobulinemia. J. Immunol. 134, 3070–3074.PubMedGoogle Scholar
  186. 186.
    Kerner, J. D., Appleby, M. W., Mohr, R. N., Chien, S., Rawlings, D. J., Maliszewski, C. R., Witte, O. N., and Perlmutter, R. M. (1995) Impaired expansion of mouse B cell progenitors lacking Btk. Immunity 3, 301–312.PubMedCrossRefGoogle Scholar
  187. 187.
    Arpaia, E., Shahar, M., Dadi, H., Cohen, A., and Roifman, C. M. (1994) Defective T cell receptor signaling and CD8+thymic selection in humans lacking ZAP kinase. Cell 76, 947–958.PubMedCrossRefGoogle Scholar
  188. 188.
    Elder, M. E., Lin, D., Clever, J., Chan, A. C., Hope, T. J., Weiss, A., and Parslow, T. G. (1994) Human severe immunodeficiency due to a defect in ZAP-70, a T cell tyrosinase kinase. Science 264, 1596–1601.PubMedCrossRefGoogle Scholar
  189. 189.
    Chan, A. C., Kadlecek, T., Elder, M., Filipovich, A., Grey, J., Iwashima, M., Parslow, T., and Weiss, A. (1994) ZAP-70 protein tyrosine kinase deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264, 1599–1601.PubMedCrossRefGoogle Scholar
  190. 190.
    Chan, A. C., van Oers, N. S. C., Tran, A., Turka, L., Law, C. L., Ryan, J. C., Clark, E. A., and Weiss, A. (1994) Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling. J. Immunol. 152, 4758–4766.PubMedGoogle Scholar
  191. 191.
    Taylor, N., Bacon, K. B., Smith, S., Jahn, T, Kadlecek, T. A., Uribe, L., Kohn, D. B., Gelfand, E. W., Weiss, A., and Weinberg, K. (1996) Reconstitution of T cell receptor signaling in ZAP70-deficient cells by retroviral transduction of the ZAP-70 gene. J. Exp. Med. 184, 2031–2036.PubMedCrossRefGoogle Scholar
  192. 192.
    Negishi, I., Motoyams, N., Nakayama, K. -I., Nakayama, K., Senju, S., Hatakeyama, S., Zhang, Q., Chan, A. C., and Loh, D. Y. (1995) Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435–438.PubMedCrossRefGoogle Scholar
  193. 193.
    Rosenzweig, M., Marks, D. F., Zhu, H., Hempel, D., Mansfield, K. G., Sehgal, P. K., Kalams, S., Scadden, D. T., and Johnson, R. P. In vitro T lymphopoiesis of Human and Rhesus CD34+ progenitor cells. Blood 87 4040–4048.Google Scholar
  194. 194.
    Emerson, S. G. (1996) Ex vivo expansion of hematopoietic precursors, progenitors, and stem cells: the next generation of cellular therapeutics. Blood 87, 3082–3088.Google Scholar
  195. 195.
    Pollock, J. D., Williams, D. A., Gifford, M. A., Li, L. L., Du, X., Fisherman, J., Orkin, S. H., Doerschuk, C. M., and Dinauer, M. C. (1996) Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat. Gen. 9, 202–209.CrossRefGoogle Scholar
  196. 196.
    Bjorgvinsdottir, H., Ding, C., Pech, N., Gifford, M. A., Li, L. L., and Dinauer, M. C. (1997) Retroviral-mediated gene transfer of gp9lphox into bone marrow cells rescues defect in host defense against Aspergillus fumigatus in murine X-linked chronic granulomatous disease. Blood 89, 41–48.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Karen E. Pollok
  • David A. Williams

There are no affiliations available

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