Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
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 July 1, 2016; First published June 20, 2016
Citation Information: J Clin Invest. 2016;126(7):2736-2744. https://doi.org/10.1172/JCI85295.
View: Text | PDF
Categories: Concise Communication Immunology Transplantation

The composition of the microbiota modulates allograft rejection

  • Text
  • PDF
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

×

Figure 1

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

Options: View larger image (or click on image) Download as PowerPoint
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.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts