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J Immunol. 2014 Jul 15;193(2):587-96. doi: 10.4049/jimmunol.1302455. Epub 2014 Jun 18.

Humanized mice as a model for aberrant responses in human T cell immunotherapy.

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
2
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520; and.
3
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
4
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520 kevan.herold@yale.edu.

Abstract

Immune-deficient mice, reconstituted with human stem cells, have been used to analyze human immune responses in vivo. Although they have been used to study immune responses to xenografts, allografts, and pathogens, there have not been models of autoimmune disease in which the mechanisms of the pathologic process can be analyzed. We have found that reconstituted "humanized" mice treated with anti-CTLA-4 Ab (ipilimumab) develop autoimmune disease characterized by hepatitis, adrenalitis, sialitis, anti-nuclear Abs, and weight loss. Induction of autoimmunity involved activation of T cells and cytokine production, and increased infiltration of APCs. When anti-CTLA-4 mAb-treated mice were cotreated with anti-CD3 mAb (teplizumab), hepatitis and anti-nuclear Abs were no longer seen and weight loss did not occur. The anti-CD3 blocked proliferation and activation of T cells, release of IFN-γ and TNF, macrophage infiltration, and release of IP-10 that was induced with anti-CTLA-4 mAb. We also found increased levels of T regulatory cells (CD25(+)CD127(-)) in the spleen and mesenteric lymph nodes in the mice treated with both Abs and greater constitutive phosphorylation of STAT5 in T regulatory cells in spleen cells compared with mice treated with anti-CTLA-4 mAb alone. We describe a model of human autoimmune disease in vivo. Humanized mice may be useful for understanding the mechanisms of biologics that are used in patients. Hepatitis, lymphadenopathy, and other inflammatory sequelae are adverse effects of ipilimumab treatment in humans, and this study may provide insights into this pathogenesis and the effects of immunologics on autoimmunity.

PMID:
24943216
PMCID:
PMC4123131
DOI:
10.4049/jimmunol.1302455
[Indexed for MEDLINE]
Free PMC Article

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