Abstract 5665: NOD-scid IL2rg null (NSG) mice deficient in murine MHC Class I and Class II expression support engraftment of functional human T cells in the absence of acute xenogeneic GVHD following injection of PBMC
| العنوان: | Abstract 5665: NOD-scid IL2rg null (NSG) mice deficient in murine MHC Class I and Class II expression support engraftment of functional human T cells in the absence of acute xenogeneic GVHD following injection of PBMC |
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| المؤلفون: | Ben Low, Dale L. Greiner, Michael V. Wiles, Leonard D. Shultz, Roland Tisch, James G. Keck, Laurie L. Kenney, Michael A. Brehm, Lisa M. Burzenski |
| المصدر: | Cancer Research. 78:5665-5665 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Cancer Research, MHC class II, biology, T cell, Nod, Peripheral blood mononuclear cell, medicine.anatomical_structure, Immune system, Oncology, Immunology, MHC class I, biology.protein, medicine, Antibody, CD8 |
| الوصف: | The study of human immune system-tumor interactions has been limited historically by a paucity of models that fully reproduce human immune system function. Humanized mice are emerging as an exciting platform to study human immuno-oncology and provide preclinical tools to test cutting edge immunotherapies. An effective and simplistic approach to engraft immunodeficient mice with functional human T cells is the injection of human peripheral blood mononuclear cells (PBMC). This PBMC engraftment model (termed Hu-PBL-SCID mice) has supported studies of human infectious agents, allograft rejection, and human T cell immune function. The Hu-PBL-SCID model has also supported studies of human immune system-tumor interactions following injection of human PBMC into immunodeficient mice implanted with patient-derived (PDX) tumors. However, a major limitation of this model is the development of acute xenogeneic graft-versus-host disease (GVHD) due to human T cell recognition of murine MHC class I and class II. To address this limitation, we created two strains of NSG mice that lack murine MHC antigens, one by crossing NSG-B2Mnull with NSG-(IA IEnull) mice, the second by knocking out the MHC class II IAb gene in NSG-(Kb Db)null mice using TALEN technology. We observed that human IgG clearance was rapid in NSG-B2Mnull (IA IEnull) mice that lack functional FcRn activity whereas clearance in NSG-(Kb Db)null (IAnull) mice was comparable to that observed in NSG mice. Injection of human PBMC into both strains led to engraftment of human T cells that exhibited an approximate 3:1 CD4:CD8 ratio with long term engraftment and without development of acute GVHD. The engrafted human T cells were functional as documented by their ability to reject human islet allografts. Administration of human recombinant IL2 using AAV-IL2 to NSG-(Kb Db)null (IAnull) mice resulted in increased human CD45 cell engraftment, including heightened levels of human Tregs. However, high IL2 levels led to the development of acute GVHD. Moreover, NSG-(Kb Db)null (IAnull) mice injected with a PDX tumor and PBMC from an allogeneic donor supported significant tumor growth in the absence of acute GVHD. These data document that NSG mice deficient in murine MHC class I and class II can support studies of human immune system-tumor interactions in the absence of acute GVHD and provide a model for evaluation of human antibody therapeutics. Citation Format: Michael A. Brehm, Michael Wiles, Laurie Kenney, Ben Low, Roland M. Tisch, Lisa Burzenski, James G. Keck, Dale L. Greiner, Leonard D. Shultz. NOD-scid IL2rgnull (NSG) mice deficient in murine MHC Class I and Class II expression support engraftment of functional human T cells in the absence of acute xenogeneic GVHD following injection of PBMC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5665. |
| تدمد: | 1538-7445 0008-5472 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::d4a06e8b0d8d733b100a09f5d2baf8a3Test https://doi.org/10.1158/1538-7445.am2018-5665Test |
| رقم الانضمام: | edsair.doi...........d4a06e8b0d8d733b100a09f5d2baf8a3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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