Donor-derived, tolerogenic dendritic cells suppress immune rejection in the indirect allosensitization-dominant setting of corneal transplantation

Journal of Leukocyte Biology

Sunil K. Chauhan¹  Hiroki Ueno¹  Parisa Emami-naeini¹  Reza Dana¹  Takaaki Hattori¹  Daniel R. Saban¹  Toshinari Funaki¹ 

[1] Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USASchepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USASchepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA

关键词: indirect pathway;    direct pathway;    tolerance;    regulatory DC;   

DOI  :  10.1189/jlb.1011500

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Significant interest has been focused on the use of ex vivo-manipulated DCs to optimally induce transplant tolerance and promote allograft survival. Although it is understood that donor-derived, tolerogenic DCs suppress the direct pathway of allosensitization, whether such DCs can similarly suppress the indirect pathway remains unclear. We therefore used the murine model of corneal transplantation to address this, as these allografts are rejected in an indirect pathway-dominant manner. Interestingly, recipients administered with donor bone marrow-derived DCregs, generated via culturing with GM-CSF, IL-10, and TGF-β1, significantly prolonged survival of corneal allografts. Correspondingly, these recipients demonstrated a potent reduction in the frequency of indirectly allosensitized T cells, as determined by ELISPOT. Examination of DCregs relative to mDCs or iDCs showed a resistance to up-regulation of MHC-II and costimulatory molecules, as well as an impaired capacity to stimulate MLRs. In vivo, DCreg administration in corneal-allografted recipients led to inhibition of CD4+IFN-γ+ T cell frequencies and an associated increase in Foxp3 expression in the Treg compartment. We conclude that donor-derived, tolerogenic DCs significantly suppress the indirect pathway, thereby identifying a novel regulatory mechanism for these cells in transplantation.

【 授权许可】

Unknown