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. 1991 Oct;88(4):1412–1417. doi: 10.1172/JCI115448

An in vivo animal model of gene therapy for leukocyte adhesion deficiency.

J C Krauss 1, L A Mayo-Bond 1, C E Rogers 1, K L Weber 1, R F Todd 3rd 1, J M Wilson 1
PMCID: PMC295613  PMID: 1680882

Abstract

Leukocyte adhesion deficiency (LAD) is an inherited disorder of leukocyte function that is caused by defects in the CD18 gene and is associated with diminished cell surface expression of CD11/CD18 proteins. We have developed an in vivo model for gene therapy of LAD. Recombinant retroviruses were used to transduce a functional human CD18 gene into murine bone marrow cells which were transplanted into lethally irradiated syngeneic recipients. A reliable flow cytometric assay for human CD18 in transplant recipients was developed based on: (a) the availability of human specific CD18 monoclonal antibodies and (b) the observation that human CD18 can form chimeric heterodimers with murine CD11a on the cell surface. Human CD18 was detected on leukocytes in a substantial number of transplant recipients for at least 6 mo suggesting that the gene had been transduced into stem cells. Expression was demonstrated in several lineages of a variety of hematopoietic tissues, but was consistently highest and most frequent in granulocytes. Murine granulocytes demonstrated appropriate posttranscriptional regulation of human CD18 in response to activation of protein kinase C. No apparent untoward effects of human CD18 expression were noted in transplant recipients. These studies suggest a specific strategy for LAD gene therapy that may be effective and safe.

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Selected References

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  1. Anderson D. C., Schmalsteig F. C., Finegold M. J., Hughes B. J., Rothlein R., Miller L. J., Kohl S., Tosi M. F., Jacobs R. L., Waldrop T. C. The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis. 1985 Oct;152(4):668–689. doi: 10.1093/infdis/152.4.668. [DOI] [PubMed] [Google Scholar]
  2. Anderson D. C., Springer T. A. Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins. Annu Rev Med. 1987;38:175–194. doi: 10.1146/annurev.me.38.020187.001135. [DOI] [PubMed] [Google Scholar]
  3. Arnaout M. A., Hakim R. M., Todd R. F., 3rd, Dana N., Colten H. R. Increased expression of an adhesion-promoting surface glycoprotein in the granulocytopenia of hemodialysis. N Engl J Med. 1985 Feb 21;312(8):457–462. doi: 10.1056/NEJM198502213120801. [DOI] [PubMed] [Google Scholar]
  4. Aruffo A., Seed B. Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8573–8577. doi: 10.1073/pnas.84.23.8573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boshart M., Weber F., Jahn G., Dorsch-Häsler K., Fleckenstein B., Schaffner W. A very strong enhancer is located upstream of an immediate early gene of human cytomegalovirus. Cell. 1985 Jun;41(2):521–530. doi: 10.1016/s0092-8674(85)80025-8. [DOI] [PubMed] [Google Scholar]
  6. Coffman R. L. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development. Immunol Rev. 1982;69:5–23. doi: 10.1111/j.1600-065x.1983.tb00446.x. [DOI] [PubMed] [Google Scholar]
  7. Dana N., Clayton L. K., Tennen D. G., Pierce M. W., Lachmann P. J., Law S. A., Arnaout M. A. Leukocytes from four patients with complete or partial Leu-CAM deficiency contain the common beta-subunit precursor and beta-subunit messenger RNA. J Clin Invest. 1987 Mar;79(3):1010–1015. doi: 10.1172/JCI112868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dana N., Todd R. F., 3rd, Pitt J., Springer T. A., Arnaout M. A. Deficiency of a surface membrane glycoprotein (Mo1) in man. J Clin Invest. 1984 Jan;73(1):153–159. doi: 10.1172/JCI111186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Holmes K. L., Langdon W. Y., Fredrickson T. N., Coffman R. L., Hoffman P. M., Hartley J. W., Morse H. C., 3rd Analysis of neoplasms induced by Cas-Br-M MuLV tumor extracts. J Immunol. 1986 Jul 15;137(2):679–688. [PubMed] [Google Scholar]
  10. Kishimoto T. K., Hollander N., Roberts T. M., Anderson D. C., Springer T. A. Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency. Cell. 1987 Jul 17;50(2):193–202. doi: 10.1016/0092-8674(87)90215-7. [DOI] [PubMed] [Google Scholar]
  11. Kishimoto T. K., O'Conner K., Springer T. A. Leukocyte adhesion deficiency. Aberrant splicing of a conserved integrin sequence causes a moderate deficiency phenotype. J Biol Chem. 1989 Feb 25;264(6):3588–3595. [PubMed] [Google Scholar]
  12. Le Deist F., Blanche S., Keable H., Gaud C., Pham H., Descamp-Latscha B., Wahn V., Griscelli C., Fischer A. Successful HLA nonidentical bone marrow transplantation in three patients with the leukocyte adhesion deficiency. Blood. 1989 Jul;74(1):512–516. [PubMed] [Google Scholar]
  13. Miller L. J., Bainton D. F., Borregaard N., Springer T. A. Stimulated mobilization of monocyte Mac-1 and p150,95 adhesion proteins from an intracellular vesicular compartment to the cell surface. J Clin Invest. 1987 Aug;80(2):535–544. doi: 10.1172/JCI113102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. O'Shea J. J., Brown E. J., Seligmann B. E., Metcalf J. A., Frank M. M., Gallin J. I. Evidence for distinct intracellular pools of receptors for C3b and C3bi in human neutrophils. J Immunol. 1985 Apr;134(4):2580–2587. [PubMed] [Google Scholar]
  15. Sanchez-Madrid F., Nagy J. A., Robbins E., Simon P., Springer T. A. A human leukocyte differentiation antigen family with distinct alpha-subunits and a common beta-subunit: the lymphocyte function-associated antigen (LFA-1), the C3bi complement receptor (OKM1/Mac-1), and the p150,95 molecule. J Exp Med. 1983 Dec 1;158(6):1785–1803. doi: 10.1084/jem.158.6.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Springer T. A., Thompson W. S., Miller L. J., Schmalstieg F. C., Anderson D. C. Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis. J Exp Med. 1984 Dec 1;160(6):1901–1918. doi: 10.1084/jem.160.6.1901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Springer T., Galfrè G., Secher D. S., Milstein C. Monoclonal xenogeneic antibodies to murine cell surface antigens: identification of novel leukocyte differentiation antigens. Eur J Immunol. 1978 Aug;8(8):539–551. doi: 10.1002/eji.1830080802. [DOI] [PubMed] [Google Scholar]
  18. Todd R. F., 3rd, Arnaout M. A., Rosin R. E., Crowley C. A., Peters W. A., Babior B. M. Subcellular localization of the large subunit of Mo1 (Mo1 alpha; formerly gp 110), a surface glycoprotein associated with neutrophil adhesion. J Clin Invest. 1984 Oct;74(4):1280–1290. doi: 10.1172/JCI111538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Todd R. F., 3rd, Freyer D. R. The CD11/CD18 leukocyte glycoprotein deficiency. Hematol Oncol Clin North Am. 1988 Mar;2(1):13–31. [PubMed] [Google Scholar]
  20. Updyke T. V., Nicolson G. L. Immunoaffinity isolation of membrane antigens with biotinylated monoclonal antibodies and streptavidin-agarose. Methods Enzymol. 1986;121:717–725. doi: 10.1016/0076-6879(86)21070-8. [DOI] [PubMed] [Google Scholar]
  21. Wilson J. M., Danos O., Grossman M., Raulet D. H., Mulligan R. C. Expression of human adenosine deaminase in mice reconstituted with retrovirus-transduced hematopoietic stem cells. Proc Natl Acad Sci U S A. 1990 Jan;87(1):439–443. doi: 10.1073/pnas.87.1.439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wilson J. M., Ping A. J., Krauss J. C., Mayo-Bond L., Rogers C. E., Anderson D. C., Todd R. F. Correction of CD18-deficient lymphocytes by retrovirus-mediated gene transfer. Science. 1990 Jun 15;248(4961):1413–1416. doi: 10.1126/science.1972597. [DOI] [PubMed] [Google Scholar]
  23. Wright S. D., Rao P. E., Van Voorhis W. C., Craigmyle L. S., Iida K., Talle M. A., Westberg E. F., Goldstein G., Silverstein S. C. Identification of the C3bi receptor of human monocytes and macrophages by using monoclonal antibodies. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5699–5703. doi: 10.1073/pnas.80.18.5699. [DOI] [PMC free article] [PubMed] [Google Scholar]

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