THYMIC LYMPHOPROLIFERATIVE DISEASE AFTER SUCCESSFUL CORRECTION OF CD40 LIGAND DEFICIENCY BY GENE-TRANSFER IN MICE

Inherited deficiency of the CD40 ligand (X-linked hyper-IgM syndrome) is characterized by failure of immunoglobulin isotype switching and se vere 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 fo r the murine CD40 ligand (CD40L) and injected them into CD40L(-/-) mic e.; Even low-level, constitutive expression of the transgene stimulate d humoral and cellular immune functions in these mice. With extended f ollow-up, however, 12 of 19 treated mice developed T-lymphoproliferati ve disorders, ranging from polyclonal increases of lymphoblasts to ove rt monoclonal T-lymphoblastic lymphomas that involved multiple organs. Our findings show that constitutive (rather than tightly regulated), low-level expression of CD40L can produce abnormal proliferative respo nses in developing T lymphocytes, apparently through aberrant interact ion between CD40L(+) and TCR alpha beta(+)CD40(+) thymocytes. Current methods of gene therapy may prove inappropriate for disorders involvin g highly regulated genes in essential positions in proliferative casca des.