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Correction or Transfer of Immunodeficiency Due to TNF-LTα Deletion by Bone Marrow Transplantation

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Abstract

Background

Mice with inactivated tumor necrosis factor (TNF) and lymphotoxin α (LTα) genes have profound abnormalities of the immune system including lymphocytosis, lack of lymph nodes, undifferentiated spleen, hypoimmunoglobulinaemia, and defective Ig class switch. Here, we asked whether this phenotype is due to incompetent lymphohemopoietic progenitors or to a defective environment.

Materials and Methods

Lethally irradiated TNF-LTα-defident and wild-type mice received bone marrow cells from either TNF-LTα-deficient or wild-type mice. The reconstitution and transfer of the phenotype was followed by morphological and functional analyses.

Results

Bone marrow cells from wild-type mice restored the synthesis of TNF and LTα, corrected the splenic microarchitecture, normalized the lymphocyte counts in the circulation, and repopulated the lamina propria with IgA-producing plasma cells of TNF-LTα-deficient mice. Furthermore, the formation of germinal centers in the spleen and the defective Ig class switch in response to a T-cell dependent antigen was correαed, while no lymph nodes were formed. Conversely, the TNF-LTα phenotype could be transferred to wild-type mice by bone marrow transplantation after lethal irradiation.

Conclusions

These data demonstrate that most TNF- and LTα-producing cells are bone marrow derived and radiosensitive, and that the immunodeficiency due to TNF-LTα deletion can be corrected to a large extent by normal bone marrow cell transplantation. The genotype of the donor bone marrow cells determines the functional and structural phenotype of the TNF-LTα-deficient adult murine host, with the exception of lymph node formation. These findings may have therapeutic implications for the restoration of genetically defined imumunodeficiencies in humans.

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Acknowledgment

This work and M. Müller were supported by the Swiss National Science Foundation Grant 32–33966.92.

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Authors and Affiliations

  1. Institute of Toxicology, University of Zürich, Zürich, Switzerland

    Matthias Müller, Hans-Pietro Eugster, Michel Le Hir & Alexander Shakhov

  2. Preclinical Research, Sandoz Pharma, Basel, Switzerland

    Franco Di Padova, Claudine Maurer & Valerie F. J. Quesniaux

  3. Institute of Pathology, University of Basel, Schönbeinstrasse, 40, CH-4003, Basel, Switzerland

    Bernhard Ryffel

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  1. Matthias Müller
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  2. Hans-Pietro Eugster
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Müller, M., Eugster, HP., Le Hir, M. et al. Correction or Transfer of Immunodeficiency Due to TNF-LTα Deletion by Bone Marrow Transplantation. Mol Med 2, 247–255 (1996). https://doi.org/10.1007/BF03401621

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