Survival and Proliferation of Human NK Cells in Humanized Mice

Natural killer (NK) cells play a critical role in the innate immune system and represent the first line of defense against pathogens and tumor cells. Involved in immune surveillance, NK cells patrol the body looking for infected or cancerous cells. While other immune cells recognize the presence of antibodies on the MHC receptor of infected cells before a response is initiated, NK cells have the ability to respond to stressed cells in the absence of the MHC receptor, allowing a much faster immune response. The lack or downregulation of MHC receptors on the surface of target cells triggers NK cell cytotoxicity and the secretion of IFN-γ and TNF-α, allowing NK cells to destroy the tumor and virus-infected cells. At the same time, NK cells stimulate and guide other cells, including lymphocytes (T and B cells) of the adaptive immune system, to the area of infection to help increase the immune response and generate memory and effector cells that aid in forming a strong response if the infection should arise again.

Cancer immune surveillance of NK cells has made these cells a focus of adoptive immune cell therapy, however, a major limitation to the development of NK cell therapies has been the lack of efficient methods to generate adequate numbers of NK cells for clinical efficacy and a good translational pre-clinical models in which to test the survival, function, and safety of adoptively transferred immune cells. Additionally, to establish the survival of NK cells in vivo, IL-2 cytokine supplementation is administered, consequently, this cytokine can cause severe toxicities in clinical applications.

Expansion of Functional Human NK Cells

To address these issues, Vahedi et al. first repeated a previous experiment by Denman et al., whereby cord blood NK cells were expanded in the presence of special feeder cells (artificial antigen-presenting cells (APCs), K562-mb-IL-21) and IL-2 supplementation. NK cells were shown to be functional by the secretion of high levels of IFN-γ and TNF-α after stimulation with IL-18, IL-15, and IL-12. Previous studies by Denman et al also demonstrated that these NK cells show potent cytotoxicity against tumor targets.

Human NK Cells in Humanized Mice

To show survival and possible proliferation of ex vivo expanded NK cells in vivo, the authors established an NRG humanized mouse model using cord blood-derived CD34+ hematopoietic stem cells. Once engraftment was confirmed, cord blood autologous expanded functional NK cells were adoptively transferred into reconstituted mice. Expanded NK cells nearly doubled by day 7 and persisted beyond day 14 without exogenous cytokines, verifying that ex vivo expanded NK cells were able to survive and proliferate in vivo without exogenous IL-2 cytokine supplementation.

The results of this brief report demonstrate that the ex vivo expansion of NK cells, in the presence of special feeder cells and IL-2 supplementation, survive and proliferate in an autologous humanized mouse model without the need for in vivo IL-2 administration, allowing the potential to negate the cytotoxic effects of IL-2 on the host. In addition, the results “support the use of expanded NK cells as a feasible cancer therapy and provide a novel humanized model within which to test the effects of adoptively transferred cells prior to clinical application.”

At StemExpress, we offer high-quality cord blood CD34+ hematopoietic stem cells and NK cells that can be used in studies focusing on clinical efficacy and pre-clinical in vivo humanized mice studies. Let us help with your research needs. Please contact one of our sales specialists for inquiries at 530-303-3828 or 888-415-4215.

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