Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.

Autor: Hoeppli RE; Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., MacDonald KN; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada., Leclair P; Department of Pediatrics, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Fung VCW; Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Mojibian M; Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Gillies J; Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Rahavi SMR; Department of Pediatrics, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Campbell AIM; Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Gandhi SK; Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Pesenacker AM; Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Reid G; Department of Pediatrics, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Lim CJ; Department of Pediatrics, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada., Levings MK; Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
Jazyk: angličtina
Zdroj: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons [Am J Transplant] 2019 Jan; Vol. 19 (1), pp. 62-76. Date of Electronic Publication: 2018 Jun 13.
DOI: 10.1111/ajt.14936
Abstrakt: Cell-based therapy with CD4 + FOXP3 + regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3 + TBET + FOXP3 + T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4β7-integrin and CCR9. FOXP3 + RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.
(© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)
Databáze: MEDLINE
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