Hematopoietic engraftment of XLA bone marrow CD34⁺cells in NOG/SCID mice

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/cnull (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.