期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 19, 期 10, 页码 2705-2718出版社
WILEY
DOI: 10.1111/ajt.15523
关键词
animal models; murine, basic (laboratory) research; science; bronchiolitis obliterans (BOS); immunosuppression; immune modulation; lung disease; immune; inflammatory; lung transplantation; pulmonology; rejection; acute; rejection; chronic
资金
- UVA Cancer Center (Bioinformatics Core) [P30CA044579]
- Research Histology Core at the University of Virginia
- [1I01BX002299-01]
- [PO1 AI116501]
- [R01AI145108]
Despite standardized postoperative care, some lung transplant patients suffer multiple episodes of acute and chronic rejection while others avoid graft problems for reasons that are poorly understood. Using an established model of C57BL/10 to C57BL/6 minor antigen mismatched single lung transplantation, we now demonstrate that the recipient microbiota contributes to variability in the alloimmune response. Specifically, mice from the Envigo facility in Frederick, Maryland contain nearly double the number of CD4(+)Foxp3(+) regulatory T cells (T-regs) than mice from the Jackson facility in Bar Harbor, Maine or the Envigo facility in Indianapolis, Indiana (18 vs 9 vs 7%). Lung graft recipients from the Maryland facility thus do not develop acute or chronic rejection. Treatment with broad-spectrum antibiotics decreases T-regs and increases both acute and chronic graft rejection in otherwise tolerant strains of mice. Constitutive depletion of regulatory T cells, using Foxp3-driven expression of diphtheria toxin receptor, leads to the development of chronic rejection and supports the role of T-regs in both acute and chronic alloimmunity. Taken together, our data demonstrate that the microbiota of certain individuals may contribute to tolerance through T-reg-dependent mechanisms and challenges the practice of indiscriminate broad-spectrum antibiotic use in the perioperative period.
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