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Humanized Mice As a Model for Aberrant Responses in Human T Cell Immunotherapy Nalini K

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Humanized Mice As a Model for Aberrant Responses in Human T Cell Immunotherapy Nalini K Humanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy Nalini K. Vudattu, Frank Waldron-Lynch, Lucy A. Truman, Songyan Deng, Paula Preston-Hurlburt, Richard Torres, This information is current as Maurice T. Raycroft, Mark J. Mamula and Kevan C. Herold of September 23, 2021. J Immunol 2014; 193:587-596; Prepublished online 18 June 2014; doi: 10.4049/jimmunol.1302455 http://www.jimmunol.org/content/193/2/587 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/06/18/jimmunol.130245 Material 5.DCSupplemental http://www.jimmunol.org/ References This article cites 53 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/193/2/587.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Humanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy Nalini K. Vudattu,*,1 Frank Waldron-Lynch,*,1 Lucy A. Truman,* Songyan Deng,* Paula Preston-Hurlburt,* Richard Torres,† Maurice T. Raycroft,‡ Mark J. Mamula,‡ and Kevan C. Herold*,‡ 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, adrenal- itis, 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), Downloaded from 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-g 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+CD1272) 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2014, 193: 587–596. fforts to develop new treatments for human autoimmune participants (1, 2). Thus, an animal model system of autoimmunity diseases have been hampered by the lack of small-animal with human immune cells would be optimal. E models of the disease states and the inherent differences Many investigators have used “humanized” mice to study hu- between immune responses of human and murine cells. Studies man immune responses in vivo. These model systems have gen- of human autoimmune diseases have relied on the analysis of ro- erally involved transfer of mature human T cells or alternatively by guest on September 23, 2021 dent models or characterization of human cells ex vivo. However, murine cells that express human genes, but these systems do not studies of human cells in vitro cannot re-create the cellular dy- permit the study of human immune cells and responses after namics that may be important in the initiation, progression, and perturbations of cells that develop in and are tolerant to the host regulation of disease. Murine models have been relied on to pro- (3–9). A model system that can be used to study human autoim- vide insights into the pathologic mechanisms, but there are many mune disease in vivo has not been described. shortcomings of these models because of intrinsic differences be- After activation, T cells express CTLA-4, a transmembrane tween rodent and human immune systems (1). In some cases, the glycoprotein of the Ig superfamily. Its engagement delivers neg- failure to recognize the differences between rodent and human ative signals that circumvent the actions of the CD28-mediated immune responses has resulted in significant harm to clinical trial costimulatory pathway. CTLA-4 was first identified during a search for cytotoxic genes using subtractive hybridization, and subsequent studies in knockout mice showed its pivotal role in maintaining 2/2 *Department of Immunobiology, Yale University School of Medicine, New Haven, peripheral tolerance (10–13). CTLA-4 mice develop an auto- CT 06520; †Department of Laboratory Medicine, Yale University School of Medicine, ‡ immune lymphoproliferative disorder characterized by infiltration New Haven, CT 06520; and Department of Internal Medicine, Yale University + School of Medicine, New Haven, CT 06520 of CD4 T cells leading to multiorgan tissue destruction within 3– 1N.K.V. and F.W.-L. contributed equally to this work. 4 wk of age. A number of molecular mechanisms have been proposed for the functions of CTLA-4–mediated negative regu- Received for publication September 16, 2013. Accepted for publication May 15, 2014. lation in T cells, including competition for CD28 ligands, This work was supported by the Juvenile Diabetes Research Foundation (Grant 2006- disruption of CD28 localization in the immunological synapse, 1059 to K.C.H.) and the National Institutes of Health (Grants U19 AI082713, U01 decreased TCR signaling by PP2A and SHP-2, and limited en- AI102011, and R01 DK057846 to K.C.H. and Grant AR41032 to M.J.M.). gagement of T cells with APCs (14–18). These cell intrinsic Address correspondence and reprint requests to Dr. Kevan C. Herold, Yale Uni- mechanisms have been thought to account for the widespread versity, 300 George Street, #353E, New Haven, CT 06520. E-mail address: kevan. [email protected] activation and proliferation of T cells that is seen in CTLA-4– The online version of this article contains supplemental material. deficient mice, which may include cells with self-reactive TCRs Abbreviations used in this article: ALT, alanine aminotransferase; ANA, anti-nuclear leading to autoimmune disease (19–21). Ab; GVHD, graft-versus-host disease; hCD45+, human CD45+; hIg, human Ig; NSG, In addition, cell extrinsic factors may also account for autoim- 2/2 NOD/SCID IL-2gc ; SLE, systemic lupus erythematosus; Tconv, T conventional munity in the setting of CTLA-4 blockade. CTLA-4 is constitutively cell; Teff, T effector cell; Treg, T regulatory cell. expressed on CD4+ T regulatory cells (Tregs) (22), whereas it is Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 rapidly induced on T conventional cells (Tconvs) after TCR en- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302455 588 A HUMANIZED MOUSE MODEL OF AUTOIMMUNE DISEASE gagement (23), suggesting that CTLA-4 has an important role in Flowery Branch, GA) and 0.01% sodium azide (Sigma-Aldrich, St. Louis, both Treg and Tconv function. Recently, dual function of CTLA-4 MO). The FACS data were analyzed with FlowJo software (version 7.6.3). in Tregs and T effector cells (Teffs) to prevent autoimmunity has Treatment of mice been proposed (24). Yamaguchi et al. (25) showed that a triad of IL-2 repression, CTLA-4 expression, and antigenic stimulation is Each reconstituted mouse was given 500 mg ipilimumab (Bristol-Myers Squibb, New York, NY) or human Ig (hIg; Sigma, St. Louis, MO) with or a minimalistic requirement for conferring Treg-like suppressive without coadministration of teplizumab (MacroGenics; 5 mg) beginning the activity on Tconvs. day before ipilimumab i.p. every 4 d for a period of 40 d (35, 36). The mice Because of its role in maintaining tolerance and the enhanced were weighed regularly, and those that lost 15% of their baseline body weight cellular immune responses in its absence, blockade of CTLA-4 were sacrificed. with an mAb has been developed for the treatment of malignan- Histology and immunohistochemistry cies to activate tumor-specific effector cells (26). The anti-human The experimental mice were sacrificed after they had lost 15% of their body CTLA-4 mAb, ipilimumab, has been approved for the treatment weight or after 4 wk. Paraffin-embedded sections were prepared as pre- of metastatic melanoma and is also being tested in combination viously described (36). For immunohistochemistry, frozen sections were with other agents for treatment of refractory tumors. Blockade incubated for 15 min with 1% goat serum in PBS followed by avidin/biotin of CTLA-4 pathway resulted in an increased ratio of effector to blocking as per the manufacture’s protocol (Vector Laboratories, Burlin- game, CA). Anti-human CD4 (4B12), CD8 (CD/144B), CD19 (LE-CD19), Tregs (27), which has been proposed to account for the enhanced and CD68 (LP1) from Dako (Glostrup, Denmark) were applied to con- killing of tumors in anti–CTLA-4 mAb–treated patients.
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