title: Donor bone marrow-derived dendritic cells prolong corneal allograft survival and promote an intragraft immunoregulatory milieu.
abstract: Investigations into cell therapies for application in organ transplantation have grown. Here, we describe the ex vivo generation of donor bone marrow-derived dendritic cells (BMDCs) and glucocorticoid-treated BMDCs with potent immunomodulatory properties for application in allogeneic transplantation. BMDCs were treated with dexamethasone (Dexa) to induce an immature, maturation-resistant phenotype. BMDC and Dexa BMDC phenotype, antigen presenting cell function, and immunomodulatory properties were fully characterized. Both populations display significant immunomodulatory properties, including, but not limited to, a significant increase in mRNA expression of programmed death-ligand 1 and indoleamine 2,3-dioxygenase. BMDCs and Dexa BMDCs display a profound impaired capacity to stimulate allogeneic lymphocytes. Moreover, in a fully MHC I/II mismatched rat corneal transplantation model, injection of donor-derived, untreated BMDC or Dexa BMDCs (1 × 10(6) cells, day -7) significantly prolonged corneal allograft survival without the need for additional immunosuppression. Although neovascularization was not reduced and evidence of donor-specific alloantibody response was detected, a significant reduction in allograft cellular infiltration combined with a significant increase in the ratio of intragraft FoxP3-expressing regulatory cells was observed. Our comprehensive analysis demonstrates the novel cellular therapeutic approach and significant effect of donor-derived, untreated BMDCs and Dexa BMDCs in preventing corneal allograft rejection.
authors.affiliation: College of Medicine, Nursing and Health Sciences, Regenerative Medicine Institute, National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland.
authors.forename: Lisa
authors.initials: L
authors.lastname: O'Flynn
authors.forename: Oliver
authors.initials: O
authors.lastname: Treacy
authors.forename: Aideen E
authors.initials: AE
authors.lastname: Ryan
authors.forename: Maurice
authors.initials: M
authors.lastname: Morcos
authors.forename: Marese
authors.initials: M
authors.lastname: Cregg
authors.forename: Jared
authors.initials: J
authors.lastname: Gerlach
authors.forename: Lokesh
authors.initials: L
authors.lastname: Joshi
authors.forename: Mikhail
authors.initials: M
authors.lastname: Nosov
authors.forename: Thomas
authors.initials: T
authors.lastname: Ritter
mesh_terms: D064591:Allografts; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D016039:Corneal Transplantation; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D007165:Immunosuppression Therapy; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D003907:Dexamethasone