Research Article: Development of Functional Human NK Cells in an Immunodeficient Mouse Model with the Ability to Provide Protection against Tumor Challenge

Date Published: December 21, 2009

Publisher: Public Library of Science

Author(s): Amanda Kwant-Mitchell, Elishka A. Pek, Kenneth L. Rosenthal, Ali A. Ashkar, Johan K. Sandberg.

Abstract: Studies of human NK cells and their role in tumor suppression have largely been restricted to in vitro experiments which lack the complexity of whole organisms, or mouse models which differ significantly from humans. In this study we showed that, in contrast to C57BL/6 Rag2−/−/γc−/− and NOD/Scid mice, newborn BALB/c Rag2−/−/γc−/− mice can support the development of human NK cells and CD56+ T cells after intrahepatic injection with hematopoietic stem cells. The human CD56+ cells in BALB/c Rag2−/−/γc−/− mice were able to produce IFN-γ in response to human IL-15 and polyI:C. NK cells from reconstituted Rag2−/−/γc−/− mice were also able to kill and inhibit the growth of K562 cells in vitro and were able to produce IFN-γ in response to stimulation with K562 cells. In vivo, reconstituted Rag2−/−/γc−/− mice had higher survival rates after K562 challenge compared to non-reconstituted Rag2−/−/γc−/− mice and were able to control tumor burden in various organs. Reconstituted Rag2−/−/γc−/− mice represent a model in which functional human NK and CD56+ T cells can develop from stem cells and can thus be used to study human disease in a more clinically relevant environment.

Partial Text: Mouse models are used extensively for the study of human disease in many fields including cancer. Although mice have provided valuable insights into disease initiation, progression and therapy, they do not accurately represent human immune responses and results obtained in mice are therefore difficult to extrapolate to humans. Although it is clear that humans cannot be used as subjects in many experiments, a model which better represents the human response would be a logical step forward. A humanized mouse model represents a valuable means of assessing human immune responses to diseases such as cancer.

NK cells are a vital component of the innate immune system and have long been implicated in the detection and elimination of tumor cells [30]. In this study, we examined whether immunodeficient mice could support the development of human NK and NKT like (CD56+/CD3+) cells in various tissues and whether these cells could effectively target human K562 tumor cells.



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