Author:
Fu Jian,Lehmann Christian H. K.,Wang Xinning,Wahlbuhl Mandy,Allabauer Ida,Wilde Benjamin,Amon Lukas,Dolff Sebastian,Cesnjevar Robert,Kribben Andreas,Woelfle Joachim,Rascher Wolfgang,Hoyer Peter F.,Dudziak Diana,Witzke Oliver,Hoerning André
Abstract
AbstractAllograft-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.
Funder
National Science Foundation China
Deutsche Forschungsgemeinschaft
Interdisziplinäres Zentrum für klinische Forschung, Universitätsklinikum Erlangen
Friedrich-Alexander-Universität Erlangen-Nürnberg
Publisher
Springer Science and Business Media LLC
Cited by
6 articles.
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