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 severe 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 for the murine CD40 ligand (CD40L) and injected them into CD40L-/- mice. Even low-level, constitutive expression of the transgene stimulated humoral and cellular immune functions in these mice. With extended follow-up, however, 12 of 19 treated mice developed T-lymphoproliferative disorders, ranging from polyclonal increases of lymphoblasts to overt 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 responses in developing T lymphocytes, apparently through aberrant interaction between CD40L+ and TCRalphabeta+CD40+ thymocytes. Current methods of gene therapy may prove inappropriate for disorders involving highly regulated genes in essential positions in proliferative cascades.
Brown
M P
MP
Cell and Gene Therapy Program, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Topham
D J
DJ
Sangster
M Y
MY
Zhao
J
J
Flynn
K J
KJ
Surman
S L
SL
Woodland
D L
DL
Doherty
P C
PC
Farr
A G
AG
Pattengale
P K
PK
Brenner
M K
MK
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D023201:CD40 Ligand; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007111:Immunity, Cellular / Q000235:genetics; D008223:Lymphoma / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012190:Retroviridae / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D013953:Thymus Neoplasms / Q000276:immunology; D014161:Transduction, Genetic; D014779:Virus Replication; D014960:X Chromosome
D008562:Membrane Glycoproteins; D023201:CD40 Ligand