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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

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 1

Abx pretreatment results in prolonged skin graft survival and reduced bacterial diversity.

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Abx pretreatment results in prolonged skin graft survival and reduced ba...
(A) B6 females untreated or pretreated for 10 days with Abx received a skin graft from B6 males untreated or pretreated for 10 days with Abx. SPF → SPF, n = 12; SPF (Abx) → SPF, n = 5; SPF → SPF (Abx), n = 5; Abx → Abx, n = 19; syngeneic, n = 5. log-rank test. (B) Bacterial load by qPCR in fecal samples of GF and SPF B6 females at the indicated time points after initiation of Abx treatment. n = 3 (1 SPF and 1 GF samples shown for reference). LOD, level of detection. (C–E) Bacterial DNA was isolated from gut and skin of female SPF controls and age-matched mice on day 10 of Abx treatment and was analyzed by high-throughput sequencing. Data are displayed as richness (C), diversity (D), and PCA (E). Each line (C) and dot (B and E) represents an individual mouse. PC1, principal component 1; Exp, experiment. Bars (D) represent the mean ± SEM of 4 mice per group. (C–E) Results are representative of 4 experiments with n = 3–4. *P < 0.05; ***P < 0.001, Student’s t test.

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

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