دورية أكاديمية
أعرض في EDS

T-Cell Mediated Immune Rejection of Beta-2-Microglobulin Knockout Induced Pluripotent Stem Cell-Derived Kidney Organoids.

التفاصيل البيبلوغرافية
العنوان: T-Cell Mediated Immune Rejection of Beta-2-Microglobulin Knockout Induced Pluripotent Stem Cell-Derived Kidney Organoids.
المؤلفون: Gaykema LH; Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands.; Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands., van Nieuwland RY; Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands., Lievers E; Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands., Moerkerk WBJ; Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands., de Klerk JA; Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands., Dumas SJ; Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands.; The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center (LUMC), Leiden, The Netherlands., Kers J; Department of Pathology, Leiden University Medical Center (LUMC), Leiden, The Netherlands., Zaldumbide A; Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands., van den Berg CW; Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands.; The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center (LUMC), Leiden, The Netherlands., Rabelink TJ; Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands.; The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center (LUMC), Leiden, The Netherlands.
المصدر: Stem cells translational medicine [Stem Cells Transl Med] 2024 Jan 12; Vol. 13 (1), pp. 69-82.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 101578022 Publication Model: Print Cited Medium: Internet ISSN: 2157-6580 (Electronic) Linking ISSN: 21576564 NLM ISO Abbreviation: Stem Cells Transl Med Subsets: MEDLINE
أسماء مطبوعة: Publication: 2022- : Oxford : Oxford University Press
Original Publication: Durham, NC : AlphaMed Press
مواضيع طبية MeSH: Induced Pluripotent Stem Cells*/metabolism, Animals ; Humans ; Mice ; HLA Antigens/metabolism ; Kidney ; Leukocytes, Mononuclear ; Mice, Knockout ; Organoids ; beta 2-Microglobulin/metabolism
مستخلص: Immune evasive induced pluripotent stem cell (iPSC)-derived kidney organoids, known as "stealth" organoids, hold promise for clinical transplantation. To address immune rejection, we investigated the impact of genetically modifying human leukocyte antigen (HLA) class I in kidney organoids prior to transplantation. By using CRISPR-Cas9, we successfully knocked out beta-2-microglobulin (B2M), resulting in iPSCs devoid of HLA class I surface expression. In vitro, the B2M knockout protected kidney organoids derived from these iPSCs against T-cell rejection. To assess in vivo protection, unmodified (control) and B2M-/- kidney organoids were transplanted into humanized mice engrafted with human peripheral blood mononuclear cells (PBMCs). Successful engraftment of human PBMCs was confirmed, and after 4 weeks, we observed no discernible difference in the infiltration rate, proliferation, or cytotoxicity of CD4+ and CD8+ T cells between control and B2M-/- organoids. Both groups of organoids showed compromised tissue integrity, displaying tubulitis and loss of tubule integrity. Notably, while B2M-/- organoids failed to express HLA class I on their cell surface, there was preexisting expression of HLA class II in both control and B2M-/- organoids transplanted into mice with human PBMCs. HLA class II expression was not limited to antigen-presenting cells but also evident in epithelial cells of the kidney organoid, posing an additional immunological challenge to its transplantation. Consequently, we conclude that B2M knockout alone is insufficient to protect iPSC-derived kidney organoids from T-cell-mediated immune rejection. Additionally, our findings suggest that modulating HLA class II signaling will be necessary to prevent rejection following transplantation.
(© The Author(s) 2023. Published by Oxford University Press.)
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معلومات مُعتمدة: 2020-01 LUF/Stichting Prof. Jaap de Graeff-Lingling Wiyadharma Fonds; NNF21CC0073729 Novo Nordisk Foundation
فهرسة مساهمة: Keywords: CRISPR; T cell; differentiation; immunogenicity; induced pluripotent stem cells (iPSCs); kidney; transplantation
المشرفين على المادة: 0 (HLA Antigens)
0 (beta 2-Microglobulin)
تواريخ الأحداث: Date Created: 20231016 Date Completed: 20240117 Latest Revision: 20240117
رمز التحديث: 20240117
مُعرف محوري في PubMed: PMC10785221
DOI: 10.1093/stcltm/szad069
PMID: 37843402
قاعدة البيانات: MEDLINE
الوصف
تدمد:2157-6580
DOI:10.1093/stcltm/szad069