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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2002-09-2755.
Submitted September 9, 2002
Accepted March 13, 2003
Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/ cnull mice model
Hidefumi Hiramatsu, Ryuta Nishikomori, Toshio Heike, Mamoru Ito, Kimio Kobayashi, Kenji Katamura, and Tatsutoshi Nakahata*
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Central Institute for Experimental Animals, Kawasaki, Japan
* Corresponding author; email: tnakaha{at}kuhp.kyoto-u.ac.jp.
Establishment of an assay capable of generating all classes of human lymphocytes from hematopoietic stem cells (HSCs) will provide new insight into the mechanism of human lymphopoiesis. Here, we report ontogenic, functional and histological examinations of reconstituted human lymphocytes in NOD/SCID/ cnull mice after transplantation of human cord blood (CB) CD34+ cells. Following the transplantation, not only human B and NK cells but also human T cells were invariably identified in these mice even though no human tissues were co-transplanted. Immature B cells resided mainly in bone marrow (BM) while mature B cells with surface Immunoglobulins were preferentially found in spleen. Natural Killer (NK) cells were identified both in BM and spleen. T cells were observed in various lymphoid organs but serial examinations after transplantation confirmed human T lymphopoiesis occurring in the thymus. These human lymphocytes were also functionally competent. Human IgM, IgA, and IgG were detected in sera of these mice. T cells showed a diverse repertoire of TCR V chains, proliferated in response to phytohemagglutinin and were cytotoxic against cell lines. NK activity was demonstrated using the K562 cell line. Immunohistochemical analysis revealed that human lymphocytes formed organized structures in spleen and thymus, which were analogous to those seen in humans. In the thymus, CD4 and CD8 double positive T cells were predominant and co-expressed CD1a and Ki-67, thereby supporting the notion that T lymphopoiesis was taking place. NOD/SCID/cnull mice will provide a unique model to investigate human lymphopoiesis without the co-transplantation of human tissues.
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