Background aims: 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.