Dysregulated Treg repair responses lead to chronic rejection after heart transplantation.

Autor:	Warunek JJ; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and.; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Fan L; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and.; School of Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China., Zhang X; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and.; School of Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China., Wang S; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and.; Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Sanders SM; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and., Li T; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and.; Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China., Mathews LR; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and., Dwyer GK; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and.; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Wood-Trageser MA; Department of Pathology University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Traczek S; Department of Pathology University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Lesniak A; Department of Pathology University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Baron K; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and.; Department of Infectious Disease and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA., Spencer H; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and., Bou Saba J; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and., León Colón E; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Tabib T; Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Lafyatis R; Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Ross MA; Department of Cell Biology and.; Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Demetris AJ; Department of Pathology University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Watkins SC; Department of Cell Biology and.; Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Webber SA; University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA., Abou-Daya KI; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and., Turnquist HR; Thomas E. Starzl Transplantation Institute.; Department of Surgery, and.; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2024 Dec 02; Vol. 134 (23). Date of Electronic Publication: 2024 Dec 02.
DOI:	10.1172/JCI173593
Abstrakt:	Chronic rejection (CR) after organ transplantation is alloimmune injury manifested by graft vascular remodeling and fibrosis that is resistant to immunosuppression. Single-cell RNA-Seq analysis of MHC class II-mismatched (MHCII-mismatched) heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating macrophages and Tregs. Using IL-33-deficient donor mice, we show that graft fibroblast-derived IL-33 potently induced amphiregulin (Areg) expression by recipient Tregs. The assessment of clinical samples also confirmed increased expression of Areg by intragraft Tregs also during rejection. Areg is an EGF secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessment of recipient mice with Treg-specific deletion of Areg surprisingly uncovered that Treg secretion of Areg contributed to CR. Specifically, heart transplants from recipients with Areg-deficient Tregs showed less fibrosis, vasculopathy, and vessel-associated fibrotic niches populated by recipient T cells. Mechanistically, we show that Treg-secreted Areg functioned to increase fibroblast proliferation. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Tregs contributed to the progression of CR.
Databáze:	MEDLINE
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