TLR engagement prevents transplantation tolerance

L. Chen, T. Wang, P. Zhou, L. Ma, D. Yin, J. Shen, L. Molinero, T. Nozaki, T. Phillips, S. Uematsu, S. Akira, C. R. Wang, R. L. Fairchild, M. L. Alegre*, A. Chong

*Corresponding author for this work

Research output: Contribution to journalArticle

175 Scopus citations

Abstract

In many experimental models, heart, pancreas and kidney allografts are accepted long-term following costimulation-targeting therapies, whereas skin, lung and intestine resist the induction of tolerance under the same regimens. We noted that a common feature of the resistant organs is their constant exposure to commensal microbes and hypothesized that these microorganisms may stimulate Toll-like receptors (TLRs), promote alloresponses and prevent tolerance induction. This hypothesis prompts the predictions that TLR engagement at the time of transplantation should avert tolerance to heart allografts in animals treated with costimulation-targeting therapies, whereas inhibition of TLR signaling should promote tolerance to skin allografts under the same conditions. Indeed, engagement of a single TLR was sufficient to prevent anti-CD154-mediated long-term cardiac allograft acceptance and correlated with abolished intragraft recruitment of CD4+/FoxP3+ regulatory T cells and the development of linked-suppression. Conversely, a lack of donor and recipient MyD88-dependent signaling led to successful skin allograft acceptance in anti-CD154-treated animals. Thus, the status of TLR signaling contributes to the resistance versus susceptibility of organs to transplantation tolerance.

Original languageEnglish (US)
Pages (from-to)2282-2291
Number of pages10
JournalAmerican Journal of Transplantation
Volume6
Issue number10
DOIs
StatePublished - Oct 2006

Keywords

  • Anti-CD154
  • CCL17
  • CCL22 (MDC)
  • CpG
  • TLR
  • Tregs

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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    Chen, L., Wang, T., Zhou, P., Ma, L., Yin, D., Shen, J., Molinero, L., Nozaki, T., Phillips, T., Uematsu, S., Akira, S., Wang, C. R., Fairchild, R. L., Alegre, M. L., & Chong, A. (2006). TLR engagement prevents transplantation tolerance. American Journal of Transplantation, 6(10), 2282-2291. https://doi.org/10.1111/j.1600-6143.2006.01489.x