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Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice

Nature Medicine volume 4, pages 1253–1260 (1998)Cite this article

Abstract

Inherited deficiency of the CD40 ligand (X-linked hyper-IgM syndrome) is characterized by failure of immunoglobulin isotype switching and severe defects of cell-mediated immunity. To test the potential for gene transfer therapy to correct this disorder, we transduced murine bone marrow or thymic cells with a retroviral vector containing the cDNA for the murine CD40 ligand (CD40L) and injected them into CD40L –/– mice. Even low-level, constitutive expression of the transgene stimulated humoral and cellular immune functions in these mice. With extended follow-up, however, 12 of 19 treated mice developed T-lymphoproliferative disorders, ranging from polyclonal increases of lymphoblasts to overt monoclonal T-Lymphoblastic lymphomalymphomas that involved multiple organs. Our findings show that constitutive (rather than tightly regulated), low-level expression of CD40L can produce abnormal proliferative responses in developing T lymphocytes, apparently through aberrant interaction between CD40L + and TCRαβ + CD40 + thymocytes. Current methods of gene therapy may prove inappropriate for disorders involving highly regulated genes in essential positions in proliferative cascades.

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Figure 1: Demonstration of transgene expression.
Figure 2: Transduction efficiencies and RT–PCR analyses in mice transplanted with either corrected bone marrow (BMT) or vector control-transduced bone marrow.
Figure 3: Corrected bone marrow restores virus-specific immune responses.
Figure 4: Restoration of immunoglobulin subclass switching in response to specific antigens.
Figure 5: Phenotypic and genetic heterogeneity of thymic tumors.
Figure 6: Thymic homing of secondary lymphoma.
Figure 7: Expression of CD40L by thymic tumor cells.

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Acknowledgements

We thank S. Bodner for electron microscopy; M. Leventhal for immunohistochemistry; J. Gunelson, S. Wingo, A. Slusher and M. Holladay for technical assistance; and J. Gilbert for scientific editing. The work in the authors' laboratories is supported by United States Public Health Service grants AI-29579 to P.C.D.,AI-37597 to D.L.W., CA 78792 and CA 75014 to M.K.B., the Assisi Foundation and the American Lebanese Syrian Associated Charities(ALSAC).

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Authors and Affiliations

  1. Cell and Gene Therapy Program, St Jude Children's Research Hospital, 332 N. Lauderdale St, Memphis, 38105, Tennessee, USA

    Michael P. Brown & Jingfeng Zhao

  2. Department of Immunology, St Jude Children's Research Hospital, 332 N. Lauderdale St, Memphis, 38105, Tennessee, USA

    David J. Topham, Mark Y. Sangster, Kirsten J. Flynn, Sherri L. Surman, David L. Woodland & Peter C. Doherty

  3. Departments of Biological Structure and Immunology University of Washington, Seattle, 98195, Washington, USA

    Andrew G. Farr

  4. Department of Pathology, Children's Hospital Los Angeles, Los Angeles, 90027, California, USA

    Paul K. Pattengale

  5. Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin St, MC3-3320, Houston, 77030, Texas, USA

    Malcolm K. Brenner

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Brown, M., Topham, D., Sangster, M. et al. Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice. Nat Med 4, 1253–1260 (1998). https://doi.org/10.1038/3233

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