TY - JOUR
T1 - Vendor-specific microbiome controls both acute and chronic murine lung allograft rejection by altering CD4+Foxp3+ regulatory T cell levels
AU - Guo, Yizhan
AU - Wang, Qing
AU - Li, Dongge
AU - Onyema, Oscar Okwudiri
AU - Mei, Zhongcheng
AU - Manafi, Amir
AU - Banerjee, Anirban
AU - Mahgoub, Bayan
AU - Stoler, Mark H.
AU - Barker, Thomas H.
AU - Wilkes, David S.
AU - Gelman, Andrew E.
AU - Kreisel, Daniel
AU - Krupnick, Alexander Sasha
N1 - Publisher Copyright:
© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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 (Tregs) 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 Tregs 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 Tregs in both acute and chronic alloimmunity. Taken together, our data demonstrate that the microbiota of certain individuals may contribute to tolerance through Treg-dependent mechanisms and challenges the practice of indiscriminate broad-spectrum antibiotic use in the perioperative period.
AB - 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 (Tregs) 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 Tregs 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 Tregs in both acute and chronic alloimmunity. Taken together, our data demonstrate that the microbiota of certain individuals may contribute to tolerance through Treg-dependent mechanisms and challenges the practice of indiscriminate broad-spectrum antibiotic use in the perioperative period.
KW - animal models: murine
KW - basic (laboratory) research/science
KW - bronchiolitis obliterans (BOS)
KW - immunosuppression/immune modulation
KW - lung disease: immune/inflammatory
KW - lung transplantation/pulmonology
KW - rejection: acute
KW - rejection: chronic
UR - http://www.scopus.com/inward/record.url?scp=85070094381&partnerID=8YFLogxK
U2 - 10.1111/ajt.15523
DO - 10.1111/ajt.15523
M3 - Article
C2 - 31278849
AN - SCOPUS:85070094381
SN - 1600-6135
VL - 19
SP - 2705
EP - 2718
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 10
ER -