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.
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.
Authors: Waldemar J Racki; Laurence Covassin; Michael Brehm; Stephen Pino; Ronald Ignotz; Raymond Dunn; Joseph Laning; Susannah K Graves; Aldo A Rossini; Leonard D Shultz; Dale L Greiner Journal: Transplantation Date: 2010-03-15 Impact factor: 4.939
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Authors: David W Mathes; Mark A Randolph; Mario G Solari; Jamal A Nazzal; G Petur Nielsen; J Scott Arn; David H Sachs; W P Andrew Lee Journal: Transplantation Date: 2003-01-15 Impact factor: 4.939
Authors: Joerg Ermann; Petra Hoffmann; Matthias Edinger; Suparna Dutt; Francis G Blankenberg; John P Higgins; Robert S Negrin; C Garrison Fathman; Samuel Strober Journal: Blood Date: 2004-11-16 Impact factor: 22.113
Authors: G Blank; C Welker; J Haarer; M Sterk; S Nadalin; V A C Yañez; T O Joos; A Menrad; D Snell; G LaCorcia; A Königsrainer; R Handgretinger; K Schilbach Journal: Bone Marrow Transplant Date: 2014-11-17 Impact factor: 5.483
Authors: Timothy E Dudek; Daniel C No; Edward Seung; Vladimir D Vrbanac; Lena Fadda; Priyasma Bhoumik; Christian L Boutwell; Karen A Power; Adrianne D Gladden; Laura Battis; Elizabeth F Mellors; Trevor R Tivey; Xiaojiang Gao; Marcus Altfeld; Andrew D Luster; Andrew M Tager; Todd M Allen Journal: Sci Transl Med Date: 2012-07-18 Impact factor: 17.956