title: Humanized mice as a model for aberrant responses in human T cell immunotherapy.
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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Nalini K
authors.initials: NK
authors.lastname: Vudattu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Frank
authors.initials: F
authors.lastname: Waldron-Lynch
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Truman
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Songyan
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Paula
authors.initials: P
authors.lastname: Preston-Hurlburt
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520; and.
authors.forename: Richard
authors.initials: R
authors.lastname: Torres
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Maurice T
authors.initials: MT
authors.lastname: Raycroft
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mamula
authors.affiliation: 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.
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000097:blood / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D000074324:Ipilimumab; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous; D015431:Weight Loss / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D000074324:Ipilimumab; D050799:STAT5 Transcription Factor; C502540:teplizumab