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Donor bone-marrow CXCR4+ Foxp3+ T-regulatory cells are essential for costimulation blockade-induced long-term survival of murine limb transplants.
Wang, Liqing; Wang, Zhonglin; Han, Rongxiang; Samanta, Arabinda; Ge, Guanghui; Levin, L Scott; Levine, Matthew H; Hancock, Wayne W.
Afiliação
  • Wang L; Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Wang Z; Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Han R; Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Samanta A; Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Ge G; Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Levin LS; Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Levine MH; Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Hancock WW; Department of Surgery, Division of Plastic Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Sci Rep ; 10(1): 9292, 2020 06 09.
Article em En | MEDLINE | ID: mdl-32518311
ABSTRACT
Vascularized composite allotransplantation (VCA) allows tissue replacement after devastating loss but is currently limited in application and may be more widely performed if maintenance immunosuppression was not essential for graft acceptance. We tested whether peri-transplant costimulation blockade could prolong VCA survival and required donor bone-marrow cells, given that bone-marrow might promote graft immunogenicity or graft-versus-host disease. Peritransplant CD154 mAb/rapamycin (RPM) induced long-term orthotopic hindlimb VCA survival (BALB/c->C57BL/6), as did CTLA4Ig/RPM. Surprisingly, success of either protocol required a bone-marrow-associated, radiation-sensitive cell population, since long-bone removal or pre-transplant donor irradiation prevented long-term engraftment. Rejection also occurred if Rag1-/- donors were used, or if donors were treated with a CXCR4 inhibitor to mobilize donor BM cells pre-transplant. Donor bone-marrow contained a large population of Foxp3+ T-regulatory (Treg) cells, and donor Foxp3+ Treg depletion, by diphtheria toxin administration to DEREG donor mice whose Foxp3+ Treg cells expressed diphtheria toxin receptor, restored rejection with either protocol. Rejection also occurred if CXCR4 was deleted from donor Tregs pre-transplant. Hence, long-term VCA survival is possible across a full MHC disparity using peritransplant costimulation blockade-based approaches, but unexpectedly, the efficacy of costimulation blockade requires the presence of a radiation-sensitive, CXCR4+ Foxp3+ Treg population resident within donor BM.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transplante de Medula Óssea / Linfócitos T Reguladores / Extremidades / Alotransplante de Tecidos Compostos Vascularizados / Sobrevivência de Enxerto Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transplante de Medula Óssea / Linfócitos T Reguladores / Extremidades / Alotransplante de Tecidos Compostos Vascularizados / Sobrevivência de Enxerto Idioma: En Ano de publicação: 2020 Tipo de documento: Article