title: Correction or transfer of immunodeficiency due to TNF-LT alpha deletion by bone marrow transplantation.
abstract: BACKGROUND
  Mice with inactivated tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) 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.
  
  
  METHODS
  Lethally irradiated TNF-LT alpha-deficient and wild-type mice received bone marrow cells from either TNF-LT alpha-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 LT alpha, corrected the splenic microarchitecture, normalized the lymphocyte counts in the circulation, and repopulated the lamina propria with IgA-producing plasma cells of TNF-LT alpha-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 corrected, while no lymph nodes were formed. Conversely, the TNF-LT alpha phenotype could be transferred to wild-type mice by bone marrow transplantation after lethal irradiation.
  
  
  CONCLUSIONS
  These data demonstrate that most TNF- and LT alpha-producing cells are bone marrow derived and radiosensitive, and that the immunodeficiency due to TNF-LT alpha 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-LT alpha-deficient adult murine host, with the exception of lymph node formation. These findings may have therapeutic implications for the restoration of genetically defined immunodeficiencies in humans.
authors.affiliation: Institute of Toxicology, University of Zürich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: H P
authors.initials: HP
authors.lastname: Eugster
authors.forename: M
authors.initials: M
authors.lastname: Le Hir
authors.forename: A
authors.initials: A
authors.lastname: Shakhov
authors.forename: F
authors.initials: F
authors.lastname: Di Padova
authors.forename: C
authors.initials: C
authors.lastname: Maurer
authors.forename: V F
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: B
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003433:Crosses, Genetic; D017353:Gene Deletion; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology; D008218:Lymphocytosis / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D014916:Whole-Body Irradiation
chemical_list: D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha