Topical application of soluble CD83 induces IDO-mediated immune modulation, increases Foxp3+ T cells, and prolongs allogeneic corneal graft survival

J Immunol. 2013 Aug 15;191(4):1965-75. doi: 10.4049/jimmunol.1201531. Epub 2013 Jul 12.

Abstract

Modulation of immune responses is one of the main research aims in transplant immunology. In this study, we investigate the local immunomodulatory properties of soluble CD83 (sCD83) at the graft-host interface using the high-risk corneal transplantation model. In this model, which mimics the inflammatory status and the preexisting vascularization of high-risk patients undergoing corneal transplantation, allogeneic donor corneas are transplanted onto sCD83-treated recipient animals. This model allows the direct and precise application of the immune modulator at the transplantation side. Interestingly, sCD83 was able to prolong graft survival after systemic application as well as after topical application, which is therapeutically more relevant. The therapeutic effect was accompanied by an increase in the frequency of regulatory T cells and was mediated by the immune-regulatory enzyme IDO and TGF-β. In vitro, sCD83 induced long-term IDO expression in both conventional and plasmacytoid dendritic cells via autocrine or paracrine production of TGF-β, a cytokine previously shown to be an essential mediator of IDO-dependent, long-term tolerance. These findings open new treatment avenues for local immune modulation after organ and tissue transplantation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Ophthalmic
  • Allografts
  • Animals
  • Antigens, CD / administration & dosage
  • Antigens, CD / immunology
  • Antigens, CD / therapeutic use*
  • Bone Marrow Cells / immunology
  • Cells, Cultured
  • Coculture Techniques
  • Corneal Transplantation*
  • Dendritic Cells / immunology
  • Drug Evaluation, Preclinical
  • Enzyme Induction / drug effects
  • Female
  • Forkhead Transcription Factors / analysis
  • Graft Enhancement, Immunologic*
  • Graft Survival
  • Immunoglobulins / administration & dosage
  • Immunoglobulins / immunology
  • Immunoglobulins / therapeutic use*
  • Immunologic Factors / administration & dosage
  • Immunologic Factors / immunology
  • Immunologic Factors / therapeutic use*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / biosynthesis
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / physiology*
  • Injections, Intraperitoneal
  • Membrane Glycoproteins / administration & dosage
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Premedication
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / immunology
  • Recombinant Proteins / therapeutic use
  • Solubility
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Transforming Growth Factor beta / administration & dosage
  • Transforming Growth Factor beta / physiology
  • Transforming Growth Factor beta / therapeutic use
  • Transplantation Tolerance / drug effects*

Substances

  • Antigens, CD
  • CD83 antigen
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • IDO1 protein, mouse
  • Immunoglobulins
  • Immunologic Factors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Membrane Glycoproteins
  • Recombinant Proteins
  • Transforming Growth Factor beta