Analysis of molecular mechanism of antibody deficiencies and development of their therapeutics

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Since 1981, a total of ten HLA-matched or -partially matched bone marrow transplantations (BMT) were performed on patients with severe combined immunodeficiency (SCID) at the Department of Pediatrics of the Nagoya University Hospital. Nine of these patients survived, but two X-linked SCID (X-SCID) patients showed a persistent deficiency of antibody production, despite their normal T cell functions and the existence of a normal number of B cells. Bone marrow condioning was not performed in the BMT for SCID and normal to elevated number of B cells exists before BMT in case of X-SCID patients. Therefore, it can be speculated that a chimeric state of donor-derived T cells and recipient-derived B cells persists for a long period. As antibody production were consistently recovered after HLA-matched BMT in this situation, persistent deficiency of antibody production seems not to be due to intrinsically defective B cells from patients, but to be due to defects of T cell- B cell cooperation. To evaluate this hypothesis and to get a clue to clarify the pathogenesis of primary antibody deficiency diseases, we analyzed the chimeric states and the in vitro antibody production of these patients. The results demonstrated that patient-derived B cells persists for a long period after BMT for X-SCID,that the degree of defective gc did not affect the persistent defects of antibody production, and that B cells ; seemed to be in a state similar to an antigen-unresponsiveness. Further study in necessary to clarify the mechanism of the unresponsiveness. I will continue to study the pathogenesis of antibody deficiencies to develop better methods for diagnosis and treatments.