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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-07-2024.
Submitted July 8, 2002
Accepted March 3, 2003
Human NK cell development in NOD/SCID mice engrafted with cord blood CD34+ cells
Christian P Kalberer, Uwe Siegler, and Aleksandra Wodnar-Filipowicz*
Experimental Hematology, Department of Research, University Hospital Basel, Basel, Switzerland
* Corresponding author; email: Aleksandra.Wodnar-Filipowicz{at}unibas.ch.
Definition of the cytokine environment which regulates the maturation of human natural killer (NK) cells has been largely based on in vitro assays due to lack of suitable animal models. Here we describe conditions leading to the development of human NK cells in NOD/SCID mice engrafted with hematopoietic CD34+ precursor cells from cord blood. Following 1 week-long in vivo treatment with various combinations of interleukin (IL)-15, flt3 ligand, stem cell factor, IL-2, IL-12 and megakaryocyte growth and differentiation factor, CD56+CD3- cells were generated in the bone marrow (BM), spleen and peripheral blood (PB), comprising 5% - 15% of human CD45+ cells. Human NK cells of NOD/SCID mouse origin closely resembled NK cells from human peripheral blood with respect to phenotypic characteristics, interferon (IFN)- production and cytotoxicity against HLA class I-deficient K562 targets in vitro and anti-tumor activity against K562 erythroleukemia in vivo. In the absence of growth factor treatment, CD56+ cells were present only at background levels but CD34+CD7+ and CD34-CD7+ lymphoid precursors with NK cell differentiation potential were detected in BM and spleen of chimeric NOD/SCID mice for up to 5 months after transplantation. Our results demonstrate that limitations in human NK cell development in the murine microenvironment can be overcome by treatment with NK cell growth-promoting human cytokines, resulting in maturation of IFN- producing cytotoxic NK cells. These studies establish conditions to explore human NK cell development and function in vivo in the NOD/SCID mouse model.
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