Overcoming Xenoantigen Immunity to Enable Cellular Tracking and Gene Regulation with Immune-competent "NoGlow" Mice.

Autor:	Trotter TN; Department of Surgery, Duke University, Durham, North Carolina., Wilson A; Department of Pathology, Duke University, Durham, North Carolina., McBane J; Department of Surgery, Duke University, Durham, North Carolina., Dagotto CE; Department of Surgery, Duke University, Durham, North Carolina., Yang XY; Department of Surgery, Duke University, Durham, North Carolina., Wei JP; Department of Surgery, Duke University, Durham, North Carolina., Lei G; Department of Surgery, Duke University, Durham, North Carolina., Thrash H; Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina., Snyder JC; Department of Surgery, Duke University, Durham, North Carolina.; Department of Cell Biology, Duke University, Durham, North Carolina., Lyerly HK; Department of Surgery, Duke University, Durham, North Carolina.; Department of Pathology, Duke University, Durham, North Carolina.; Department of Integrative Immunobiology, Duke University, Durham, North Carolina., Hartman ZC; Department of Surgery, Duke University, Durham, North Carolina.; Department of Pathology, Duke University, Durham, North Carolina.; Department of Integrative Immunobiology, Duke University, Durham, North Carolina.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Apr 09; Vol. 4 (4), pp. 1050-1062.
DOI:	10.1158/2767-9764.CRC-24-0062
Abstrakt:	The ability to temporally regulate gene expression and track labeled cells makes animal models powerful biomedical tools. However, sudden expression of xenobiotic genes [e.g., GFP, luciferase (Luc), or rtTA3] can trigger inadvertent immunity that suppresses foreign protein expression or results in complete rejection of transplanted cells. Germline exposure to foreign antigens somewhat addresses these challenges; however, native fluorescence and bioluminescence abrogates the utility of reporter proteins and highly spatiotemporally restricted expression can lead to suboptimal xenoantigen tolerance. To overcome these unwanted immune responses and enable reliable cell tracking/gene regulation, we developed a novel mouse model that selectively expresses antigen-intact but nonfunctional forms of GFP and Luc, as well as rtTA3, after CRE-mediated recombination. Using tissue-specific CREs, we observed model and sex-based differences in immune tolerance to the encoded xenoantigens, illustrating the obstacles of tolerizing animals to foreign genes and validating the utility of these "NoGlow" mice to dissect mechanisms of central and peripheral tolerance. Critically, tissue unrestricted NoGlow mice possess no detectable background fluorescence or luminescence and exhibit limited adaptive immunity against encoded transgenic xenoantigens after vaccination. Moreover, we demonstrate that NoGlow mice allow tracking and tetracycline-inducible gene regulation of triple-transgenic cells expressing GFP/Luc/rtTA3, in contrast to transgene-negative immune-competent mice that eliminate these cells or prohibit metastatic seeding. Notably, this model enables de novo metastasis from orthotopically implanted, triple-transgenic tumor cells, despite high xenoantigen expression. Altogether, the NoGlow model provides a critical resource for in vivo studies across disciplines, including oncology, developmental biology, infectious disease, autoimmunity, and transplantation. Significance: Multitolerant NoGlow mice enable tracking and gene manipulation of transplanted tumor cells without immune-mediated rejection, thus providing a platform to investigate novel mechanisms of adaptive immunity related to metastasis, immunotherapy, and tolerance. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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