Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model.
BACKGROUND
Composite tissue transplantation effectively reconstructs the most complex defects, but its use is limited because of harmful immunosuppression and the high susceptibility of skin to rejection. Development of tolerance is an ideal solution, and protocols using regulatory T cells (Tregs) to achieve this have been promising in experimental animal models. The aim of this study was to investigate the ability of human Tregs to regulate immune responses to a human skin allograft in vivo.


METHODS
We isolated and expanded naturally occurring CD127loCD25+CD4+ human Tregs from peripheral blood mononuclear cells (PBMCs) and examined their phenotype and suppressive activity in vitro. Using a clinically relevant chimeric humanized mouse system, we transplanted mice with human skin grafts followed by allogeneic populations of PBMCs with or without Tregs derived from the same PBMC donor.


RESULTS
Ex vivo-expanded Tregs maintain the appropriate Treg markers and retain suppressive activity against allostimulated and polyclonally stimulated autologous PBMCs in vitro. Mice receiving allogeneic PBMCs alone consistently reject human skin grafts, whereas those also receiving Tregs display stable long-term human skin transplant survival along with a reduction in the CD8+ human cellular graft infiltrate.


CONCLUSIONS
We show for the first time the unique ability of human Tregs to prevent the rejection of a skin allograft in vivo, highlighting the therapeutic potential of these cells clinically.
Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Fadi
F
Issa
Joanna
J
Hester
Ryoichi
R
Goto
Satish N
SN
Nadig
Tim E
TE
Goodacre
Kathryn
K
Wood
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006680:HLA Antigens / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007165:Immunosuppression Therapy; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D012867:Skin / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology*; D013518:Surgery, Plastic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000276:immunology*
D006680:HLA Antigens; D053699:Interleukin-7 Receptor alpha Subunit