Hematopoietic engraftment of XLA bone marrow CD34(+) cells in NOG/SCID mice.
OBJECTIVE
X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency associated with mutations of the BTK (Bruton agammaglobulinemia tyrosine kinase) gene. Non-functional BTK leads to a severe decline in peripheral B cells and profound pan-hypogammaglobulinemia. Substitutive immunoglobulin replacement therapy improves long-term survival but remains a symptomatic rather than curative treatment that does not provide an optimal quality of life. Hematopoietic stem cell gene therapy represents a potentially curative treatment. Thorough pre-clinical testing of innovative therapies requires that adequate disease models are available. Invalidation of the murine btk gene produces a phenotype that is less severe than the human disease; alternatively, xenotransplantation of human hematopoietic progenitors obtained from XLA patients may provide a model for testing new treatment procedures.


METHODS
The standard of care for XLA patients rarely offers an opportunity to collect peripheral blood or bone marrow (BM) hematopoietic progenitors; however, we had access to two BM samples obtained from such individuals. We analyzed hematopoietic engraftment of immunoselected CD34(+) cells from these samples in NOD/SCID/ gammac(null) (NOG) mice.


RESULTS
In both cases, human hematopoietic cells were readily detected in BM and thymus, and at low levels in spleen and peripheral blood. Unexpectedly, the early defect in B-lymphoid differentiation associated with XLA was not accurately reproduced in NOG mice, as large amounts of pre-B cells were found in BM.


CONCLUSIONS
These results support the existence of differences in environmental regulation of B-cell ontogeny between mice and humans. This questions the relevance of the NOG xenograft model for pre-clinical study of XLA gene therapy.
Moreau
Thomas
T
Institut Paoli-Calmettes, Centre de Thérapie Cellulaire et Génique, Marseille, France.
Bardin
Florence
F
Barlogis
Vincent
V
Le Deist
Françoise
F
Chabannon
Christian
C
Tonnelle
Cécile
C
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000097:blood / Q000276:immunology / Q000628:therapy*; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D001853:Bone Marrow; D002352:Carrier Proteins; D002454:Cell Differentiation; D002469:Cell Separation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D040181:Genetic Diseases, X-Linked / Q000097:blood / Q000276:immunology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000254:growth & development; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D011505:Protein-Tyrosine Kinases / Q000172:deficiency; D014183:Transplantation, Heterologous; D000099176:Noggin Protein
D000077329:Agammaglobulinaemia Tyrosine Kinase; D018952:Antigens, CD34; D002352:Carrier Proteins; D011505:Protein-Tyrosine Kinases; D000099176:Noggin Protein; C000625949:BTK protein, human; C000625951:Btk protein, mouse