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The composition of the microbiota modulates allograft rejection
Yuk Man Lei, … , Caroline Bartman, Maria-Luisa Alegre
Yuk Man Lei, … , Caroline Bartman, Maria-Luisa Alegre
Published June 20, 2016
Citation Information: J Clin Invest. 2016;126(7):2736-2744. https://doi.org/10.1172/JCI85295.
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Concise Communication Immunology Article has an altmetric score of 143

The composition of the microbiota modulates allograft rejection

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Abstract

Transplantation is the only cure for end-stage organ failure, but without immunosuppression, T cells rapidly reject allografts. While genetic disparities between donor and recipient are major determinants of the kinetics of transplant rejection, little is known about the contribution of environmental factors. Because colonized organs have worse transplant outcome than sterile organs, we tested the influence of host and donor microbiota on skin transplant rejection. Compared with untreated conventional mice, pretreatment of donors and recipients with broad-spectrum antibiotics (Abx) or use of germ-free (GF) donors and recipients resulted in prolonged survival of minor antigen–mismatched skin grafts. Increased graft survival correlated with reduced type I IFN signaling in antigen-presenting cells (APCs) and decreased priming of alloreactive T cells. Colonization of GF mice with fecal material from untreated conventional mice, but not from Abx-pretreated mice, enhanced the ability of APCs to prime alloreactive T cells and accelerated graft rejection, suggesting that alloimmunity is modulated by the composition of microbiota rather than the quantity of bacteria. Abx pretreatment of conventional mice also delayed rejection of major antigen–mismatched skin and MHC class II–mismatched cardiac allografts. This study demonstrates that Abx pretreatment prolongs graft survival, suggesting that targeting microbial constituents is a potential therapeutic strategy for enhancing graft acceptance.

Authors

Yuk Man Lei, Luqiu Chen, Ying Wang, Andrew T. Stefka, Luciana L. Molinero, Betty Theriault, Keston Aquino-Michaels, Ayelet S. Sivan, Cathryn R. Nagler, Thomas F. Gajewski, Anita S. Chong, Caroline Bartman, Maria-Luisa Alegre

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Figure 4

Abx pretreatment results in downregulation of the type I IFN pathway.

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Abx pretreatment results in downregulation of the type I IFN pathway.
(A...
(A and B) DCs from skin dLN of control and 10-day Abx-pretreated SPF mice were sorted, and cDNA was analyzed for gene expression profiling. (A) Examples of genes differentially expressed (n = 3 per group). (B) DAVID analysis of enriched pathways in DCs from control relative to Abx-treated groups. (C) Female B6 control and Ifnar–/– SPF mice were transplanted with skin grafts from males of the host genotype. Results are combined from 2 experiments. WT, n = 12; Ifnar–/–, n = 8. log-rank test. **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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