Humanized mice for immune system investigation: progress, promise and challenges

Shultz, Leonard D.; Brehm, Michael A.; Garcia, J. Victor; Greiner, Dale L.

doi:10.1038/nri3311

Cited by 829 publications

(878 citation statements)

References 127 publications

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“…Currently the hu-BLT mouse model has been used mostly to study HIV-1 and a limited number of other viruses (9,(11)(12)(13)(14). Little is known whether this model can be used to study KSHV infection, for which there is no good small-animal model to study its infection and disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…However, these models have low levels and limited functionality of the human immune cells, and the extent of infection and gene expression was limited because of the limited reconstituted human cell repertoire. The new generation of BLT model uses the NSG parental mouse strain, which yielded more severely immunocompromised mice to achieve far superior human cell engraftment (11). This is also the only mouse model that can generate the human mucosal immune system and a human MHC restricted antigen-specific humoral and cellular response (17).…”

Section: Discussionmentioning

confidence: 99%

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Humanized-BLT mouse model of Kaposi’s sarcoma-associated herpesvirus infection

Wang

Kang

Kumar

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Lack of an effective small-animal model to study the Kaposi's sarcoma-associated herpesvirus (KSHV) infection in vivo has hampered studies on the pathogenesis and transmission of KSHV. The objective of our study was to determine whether the humanized BLT (bone marrow, liver, and thymus) mouse (hu-BLT) model generated from NOD/SCID/IL2rγ mice can be a useful model for studying KSHV infection. We have tested KSHV infection of hu-BLT mice via various routes of infection, including oral and intravaginal routes, to mimic natural routes of transmission, with recombinant KSHV over a 1-or 3-mo period. Infection was determined by measuring viral DNA, latent and lytic viral transcripts and antigens in various tissues by PCR, in situ hybridization, and immunohistochemical staining. KSHV DNA, as well as both latent and lytic viral transcripts and proteins, were detected in various tissues, via various routes of infection. Using double-labeled immune-fluorescence confocal microscopy, we found that KSHV can establish infection in human B cells and macrophages. Our results demonstrate that KSHV can establish a robust infection in the hu-BLT mice, via different routes of infection, including the oral mucosa which is the most common natural route of infection. This hu-BLT mouse not only will be a useful model for studying the pathogenesis of KSHV in vivo but can potentially be used to study the routes and spread of viral infection in the infected host. T he Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), also known as the human herpesvirus 8, was first identified from KS tissues in 1994 (1). It is the etiologic agent for KS and is also associated with primary effusion lymphoma (PEL) and multicentric Castleman's disease (2). More recently it was also found to be associated with KSHV-associated inflammatory cytokine syndrome (3). Although substantial progress has been made in characterizing the virus, there are still many unanswered questions such as how KSHV infection can lead to disease manifestation and whether latent or lytic induction of KSHV are associated with malignancies. One of the reasons is a lack of a good small-animal model to study KSHV infection in vivo, which has hampered studies on how KSHV infects, spreads, and how it interacts with the host and ultimately leads to disease pathogenesis. Moreover, currently there is no vaccine against KSHV infection, and there is need for an effective animal model to evaluate the efficacy of vaccines if they are developed and for the testing of antiviral regimens.An ideal model should have relatively short generation time, reproduce rapidly, be inexpensive to maintain and house, and be easy to manipulate. An example is a rodent model that can be infected by KSHV effectively. Several small-rodent models have been tested for KSHV infection. The models include transplantation with both human KSHV-infected B lymphoma cells and primary human peripheral blood mononuclear cells in the SCID mouse (4), injection of KSHV into the human skin engrafted or the transplant of the SCID mice...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Humanized-BLT mouse model of Kaposi’s sarcoma-associated herpesvirus infection

Wang

Kang

Kumar

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the interaction between human immune cells and the murine microenvironment may be negatively influenced by inter-species molecular variations that compromise the ability of the former to mount an appropriate immune response. 279,280 Thus, although attempts are being made to limit such variations, 281 experimental models that allow for the proper evaluation of ICD in the human system require further improvements. Finally, the procedure outlined above for the identification of novel ICD inducers assesses the biochemical processes that are required for the immunogenicity of anthracycline-induced cell death.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Consensus guidelines for the detection of immunogenic cell death

et al. 2014

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“…Humanized animal models, particularly mice, have reached some significant milestones, allowing reconstruction of human hematopoiesis and immunity. A variety of human disease conditions have been recapitulated in humanized mice, identifying mechanisms of relapse and suggesting novel therapeutic strategies (10). Future studies should increase the predictive capabilities of these models and facilitate the creation and use of humanized models based on large animal species (11), which can more reliably inform clinical trials.…”

Section: Testing Ipscs In Animal Disease Modelsmentioning

confidence: 99%

Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics

Harding

Mirochnitchenko

2014

Journal of Biological Chemistry

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Induced pluripotent stem cells (iPSCs) and their differentiated derivatives can potentially be applied to cell-based therapy for human diseases. The properties of iPSCs are being studied intensively both to understand the basic biology of pluripotency and cellular differentiation and to solve problems associated with therapeutic applications. Examples of specific preclinical applications summarized briefly in this minireview include the use of iPSCs to treat diseases of the liver, nervous system, eye, and heart and metabolic conditions such as diabetes. Early stage studies illustrate the potential of iPSC-derived cells and have identified several challenges that must be addressed before moving to clinical trials. These include rigorous quality control and efficient production of required cell populations, improvement of cell survival and engraftment, and development of technologies to monitor transplanted cell behavior for extended periods of time. Problems related to immune rejection, genetic instability, and tumorigenicity must be solved. Testing the efficacy of iPSC-based therapies requires further improvement of animal models precisely recapitulating human disease conditions. The breakthrough discovery that specific sets of transcription factors can reprogram cell fate and generate induced pluripotent stem cells (iPSCs) 2 from various cell types has opened many new possibilities for research on cell states, differentiation, pluripotency, and general cell identity but, most importantly, has catalyzed the development of a whole new field of regenerative medicine (1). The field is still in a relatively early stage regarding a clear understanding of underlying developmental processes, cell behavior, and biological effects after cellgrafting experiments. The use of iPSCs and their products for human applications poses many new challenges from the experimental and regulatory points of view due to the unique properties of the cells and novel mechanism of their action.

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Humanized mice for immune system investigation: progress, promise and challenges

Cited by 829 publications

References 127 publications

Humanized-BLT mouse model of Kaposi’s sarcoma-associated herpesvirus infection

Humanized-BLT mouse model of Kaposi’s sarcoma-associated herpesvirus infection

Consensus guidelines for the detection of immunogenic cell death

Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics

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