Chronic graft-versus-host-disease in CD34+-humanized NSG mice is associated with human susceptibility HLA haplotypes for autoimmune disease

Sonntag, Katja; Eckert, Franziska; Welker, Christian; Müller, Holger M.; Müller, Friederike; Zips, Daniel; Sipos, Bence; Klein, Reinhild; Blank, Gregor; Feuchtinger, Tobias; Schumm, Michael; Handgretinger, Rupert; Schilbach, Karin

doi:10.1016/j.jaut.2015.06.006

Cited by 43 publications

(82 citation statements)

References 79 publications

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“…A solution might be to use fewer HSPCs for transplantation, with possible impairment in engraftment. Notably, we did not observe graft-versus-host disease, which is regularly seen in humanized NSG mice (72), at any time point.…”

Section: Downloaded Fromcontrasting

confidence: 48%

Differential Dynamics of HIV Infection in Humanized MISTRG versus MITRG Mice

Ivic

Rochat

et al. 2017

ImmunoHorizons

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Humanized mice are a powerful tool to study HIV in vivo. The recently generated mouse strains MITRG and MISTRG, which differ in human SIRPα expression, support an improved human myeloid lineage development from human hematopoietic stem and progenitor cells. The rationale of the study was the characterization of the two mouse strains during an HIV infection with CCR5- and CXCR4-tropic viruses. Upon HIV infection, we observed HIV dissemination and sustained viral load over 20 wk in peripheral blood in both reconstituted mouse strains. However, HIV RNA levels were significantly lower in MITRG mice compared with MISTRG mice during the first 8 wk postinfection. HIV-infected MISTRG mice showed lymphocyte activation and changes in lymphocyte subsets in blood and spleen, recapitulating hallmarks of HIV infection in humans. Depletion of murine tissue-resident macrophages in MITRG mice led to significantly elevated viral loads, and lymphocyte levels were similar to those in HIV-infected MISTRG mice. Depletion of CD8+ T cells in MISTRG mice before HIV infection resulted in substantially decreased CD4+ T cell levels, indicating functionality of human CD8+ T cells; depletion of CD4+CD8+ thymocytes may have contributed, in part, to the latter finding. In summary, MITRG and MISTRG mice represent novel HIV mouse models, despite differential HIV dynamics.

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Section: Downloaded Fromcontrasting

confidence: 48%

Differential Dynamics of HIV Infection in Humanized MISTRG versus MITRG Mice

Ivic

Rochat

et al. 2017

ImmunoHorizons

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“…Second, GvHD does usually not develop in HSC‐transplanted NSG. Only sporadic chronic GvHD with a late onset has been described in some mice, when transplanted with donor cells with an autoimmune‐prone haplotype (Sonntag et al , ). Third, histology did not reveal any signs for GvHD when we assessed colon and the liver periportal tracts, which are typically affected by GvHD (Fig EV5).…”

Section: Resultsmentioning

confidence: 99%

In vivo generation of human CD 19‐ CAR T cells results in B‐cell depletion and signs of cytokine release syndrome

et al. 2018

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Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B‐cell malignancies. Notwithstanding, CAR T‐cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19‐CAR T cells can be generated directly in vivo using the lentiviral vector CD8‐LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8+ T cells and efficacious elimination of CD19+ B cells. Further, upon injection of CD8‐LV into mice transplanted with human CD34+ cells, induction of CAR T cells and CD19+ B‐cell depletion was observed in 7 out of 10 treated animals. Notably, three mice showed elevated levels of human cytokines in plasma. Tissue‐invading CAR T cells and complete elimination of the B‐lymphocyte‐rich zones in spleen were indicative of a cytokine release syndrome. Our data demonstrate the feasibility of in vivo reprogramming of human CD8+ CAR T cells active against CD19+ cells, yet with similar adverse effects currently notorious in the clinical practice.

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“…A number of factors likely play a role in tolerizing T-cells to murine epitopes, including human T-cell selection utilizing murine DCs as well as peripheral tolerance mechanisms (53). As discussed, tolerance in the HSC and BLT models is incomplete and GvHD eventually develops 24 weeks after engraftment of human tissues (54,55).…”

Section: Development Of Humanized Mouse Models That Mitigate Gvhdmentioning

confidence: 99%

The Development of Next-generation PBMC Humanized Mice for Preclinical Investigation of Cancer Immunotherapeutic Agents

et al. 2020

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Investigation of the efficacy and mechanisms of human immuno-oncology agents has been hampered due to species-specific differences when utilizing preclinical mouse models. Peripheral blood mononuclear cell (PBMC) humanized mice provide a platform for investigating the modulation of the human immune-mediated antitumor response while circumventing the limitations of syngeneic model systems. Use of humanized mice has been stymied by model-specific limitations, some of which include the development of graft versus host disease, technical difficulty and cost associated with each humanized animal, and insufficient engraftment of some human immune subsets. Recent advances have addressed many of these limitations from which have emerged humanized models that are more clinically relevant. This review characterizes the expanded usage, advantages and limitations of humanized mice and provides insights into the development of the next generation of murine humanized models to further inform clinical applications of cancer immunotherapeutic agents.

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Chronic graft-versus-host-disease in CD34+-humanized NSG mice is associated with human susceptibility HLA haplotypes for autoimmune disease

Cited by 43 publications

References 79 publications

Differential Dynamics of HIV Infection in Humanized MISTRG versus MITRG Mice

Differential Dynamics of HIV Infection in Humanized MISTRG versus MITRG Mice

In vivo generation of human CD 19‐ CAR T cells results in B‐cell depletion and signs of cytokine release syndrome

The Development of Next-generation PBMC Humanized Mice for Preclinical Investigation of Cancer Immunotherapeutic Agents

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