Scientific Reports (Dec 2021)

CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation

  • Jian Fu,
  • Christian H. K. Lehmann,
  • Xinning Wang,
  • Mandy Wahlbuhl,
  • Ida Allabauer,
  • Benjamin Wilde,
  • Lukas Amon,
  • Sebastian Dolff,
  • Robert Cesnjevar,
  • Andreas Kribben,
  • Joachim Woelfle,
  • Wolfgang Rascher,
  • Peter F. Hoyer,
  • Diana Dudziak,
  • Oliver Witzke,
  • André Hoerning

DOI
https://doi.org/10.1038/s41598-021-03115-z
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 14

Abstract

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Abstract Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.