CORRECTION OR TRANSFER OF IMMUNODEFICIENCY DUE TO TNF-LT-ALPHA DELETION BY BONE-MARROW TRANSPLANTATION

Background: Mice with inactivated tumor necrosis factor (TNF) and lymp hotoxin alpha (LT alpha) genes have profound abnormalities of the immu ne system including lymphocytosis, lack of lymph nodes, undifferentiat ed spleen, hypoimmunoglobulinaemia, and defective Ig class switch. Her e, we asked whether this phenotype is due to incompetent lymphohemopoi etic progenitors or to a defective environment. Materials and Methods: Lethally irradiated TNF-LT alpha-deficient and wild-type mice receive d bone marrow cells from either TNF-LT alpha-deficient or wild-type mi ce. The reconstitution and transfer of the phenotype was followed by m orphological and functional analyses. Results: Bone marrow cells from wild-type mice restored the synthesis of TNF and LT alpha, corrected t he splenic microarchitecture, normalized the lymphocyte counts in the circulation, and repopulated the lamina propria with IgA-producing pla sma cells of TNF-LT alpha-deficient mice. Furthermore, the formation o f germinal centers in the spleen and the defective Ig class switch in response to a T-cell dependent antigen was corrected, while no lymph n odes were formed. Conversely, the TNF-LT alpha phenotype could be tran sferred 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 correcte d to a large extent by normal bone marrow cell transplantation The gen otype of the donor bone marrow cells determines the functional and str uctural phenotype of the TNF-LT alpha-deficient adult murine host, wit h the exception of lymph node formation. These findings may have thera peutic implications for the restoration of genetically defined immunod eficiencies in humans.