Combined treatment with regulatory T cells and vascularized bone marrow transplantation creates mixed chimerism and induces donor-specific tolerance to vascularized composite allografts without cytoreductive conditioning

Jeng Yee Lin, Feng Chou Tsai, Christopher Glenn Wallace, Wei Chao Huang, Fu Chan Wei, Shuen Kuei Liao

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Cotreatment with regulatory T cells (Treg) and conventional allogeneic bone marrow transplantation (BMT) successfully induced durable chimerism and tolerance to nonvascularized skin allografts without cytoreductive conditioning in mice. We sought to determine whether T reg treatment combined with vascularized BMT (VBMT) could create mixed chimerism and induce tolerance to vascularized composite allografts (VCAs) without cytoreductive conditioning in rats. Methods: Recipient Lewis rats treated (day 0) with or without naturally sorted Treg (3 × 106) from Lewis rat spleen and lymph nodes received costimulation blockade (anti-CD154 monoclonal antibody, days 0 and 1 and CTLA-4 immunoglobin, days 2, 4, and 6), rapamycin (days -1, 0, and 2), and concurrent transplantation of fully mismatched allogeneic donor VCAs (day 0) from the Brown Norway rat hindlimb containing VBMT. The mixed chimerism level was assessed monthly using flow cytometry. Survival of VCAs and occurrence of graft-versus-host disease were assessed clinically and histologically. Results: The combination of T reg and VBMT treatment led to long-term multilineage hematopoietic mixed chimerism (12-18%) and long-term donor-specific tolerance to VCAs (89% acceptance rate). Neither stable mixed chimerism nor VCA acceptance was observed in recipients without Treg treatment. Graft-versus-host disease did not occur in the VBMT recipients. Conclusions: Cotreatment with Treg and VBMT created stable mixed chimerism and induced long-term donor-specific tolerance to VCAs without requiring cytoreductive conditioning. This noncytoreductive Treg-VBMT protocol has potential for clinical application in VCAs.

Original languageEnglish
Pages (from-to)974-981
Number of pages8
JournalJournal of Surgical Research
Volume178
Issue number2
DOIs
Publication statusPublished - Dec 2012

Fingerprint

Composite Tissue Allografts
Chimerism
Regulatory T-Lymphocytes
Bone Marrow Transplantation
Graft vs Host Disease
Therapeutics
Homologous Transplantation
Sirolimus
Hindlimb
Allografts
Flow Cytometry
Spleen
Transplantation
Lymph Nodes
Monoclonal Antibodies
Skin

Keywords

  • Graft-versus-host disease
  • Mixed chimerism
  • Regulatory T cells
  • T
  • Vascularized bone marrow transplantation
  • Vascularized composite allograft

ASJC Scopus subject areas

  • Surgery

Cite this

Combined treatment with regulatory T cells and vascularized bone marrow transplantation creates mixed chimerism and induces donor-specific tolerance to vascularized composite allografts without cytoreductive conditioning. / Lin, Jeng Yee; Tsai, Feng Chou; Wallace, Christopher Glenn; Huang, Wei Chao; Wei, Fu Chan; Liao, Shuen Kuei.

In: Journal of Surgical Research, Vol. 178, No. 2, 12.2012, p. 974-981.

Research output: Contribution to journalArticle

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abstract = "Background: Cotreatment with regulatory T cells (Treg) and conventional allogeneic bone marrow transplantation (BMT) successfully induced durable chimerism and tolerance to nonvascularized skin allografts without cytoreductive conditioning in mice. We sought to determine whether T reg treatment combined with vascularized BMT (VBMT) could create mixed chimerism and induce tolerance to vascularized composite allografts (VCAs) without cytoreductive conditioning in rats. Methods: Recipient Lewis rats treated (day 0) with or without naturally sorted Treg (3 × 106) from Lewis rat spleen and lymph nodes received costimulation blockade (anti-CD154 monoclonal antibody, days 0 and 1 and CTLA-4 immunoglobin, days 2, 4, and 6), rapamycin (days -1, 0, and 2), and concurrent transplantation of fully mismatched allogeneic donor VCAs (day 0) from the Brown Norway rat hindlimb containing VBMT. The mixed chimerism level was assessed monthly using flow cytometry. Survival of VCAs and occurrence of graft-versus-host disease were assessed clinically and histologically. Results: The combination of T reg and VBMT treatment led to long-term multilineage hematopoietic mixed chimerism (12-18{\%}) and long-term donor-specific tolerance to VCAs (89{\%} acceptance rate). Neither stable mixed chimerism nor VCA acceptance was observed in recipients without Treg treatment. Graft-versus-host disease did not occur in the VBMT recipients. Conclusions: Cotreatment with Treg and VBMT created stable mixed chimerism and induced long-term donor-specific tolerance to VCAs without requiring cytoreductive conditioning. This noncytoreductive Treg-VBMT protocol has potential for clinical application in VCAs.",
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T1 - Combined treatment with regulatory T cells and vascularized bone marrow transplantation creates mixed chimerism and induces donor-specific tolerance to vascularized composite allografts without cytoreductive conditioning

AU - Lin, Jeng Yee

AU - Tsai, Feng Chou

AU - Wallace, Christopher Glenn

AU - Huang, Wei Chao

AU - Wei, Fu Chan

AU - Liao, Shuen Kuei

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N2 - Background: Cotreatment with regulatory T cells (Treg) and conventional allogeneic bone marrow transplantation (BMT) successfully induced durable chimerism and tolerance to nonvascularized skin allografts without cytoreductive conditioning in mice. We sought to determine whether T reg treatment combined with vascularized BMT (VBMT) could create mixed chimerism and induce tolerance to vascularized composite allografts (VCAs) without cytoreductive conditioning in rats. Methods: Recipient Lewis rats treated (day 0) with or without naturally sorted Treg (3 × 106) from Lewis rat spleen and lymph nodes received costimulation blockade (anti-CD154 monoclonal antibody, days 0 and 1 and CTLA-4 immunoglobin, days 2, 4, and 6), rapamycin (days -1, 0, and 2), and concurrent transplantation of fully mismatched allogeneic donor VCAs (day 0) from the Brown Norway rat hindlimb containing VBMT. The mixed chimerism level was assessed monthly using flow cytometry. Survival of VCAs and occurrence of graft-versus-host disease were assessed clinically and histologically. Results: The combination of T reg and VBMT treatment led to long-term multilineage hematopoietic mixed chimerism (12-18%) and long-term donor-specific tolerance to VCAs (89% acceptance rate). Neither stable mixed chimerism nor VCA acceptance was observed in recipients without Treg treatment. Graft-versus-host disease did not occur in the VBMT recipients. Conclusions: Cotreatment with Treg and VBMT created stable mixed chimerism and induced long-term donor-specific tolerance to VCAs without requiring cytoreductive conditioning. This noncytoreductive Treg-VBMT protocol has potential for clinical application in VCAs.

AB - Background: Cotreatment with regulatory T cells (Treg) and conventional allogeneic bone marrow transplantation (BMT) successfully induced durable chimerism and tolerance to nonvascularized skin allografts without cytoreductive conditioning in mice. We sought to determine whether T reg treatment combined with vascularized BMT (VBMT) could create mixed chimerism and induce tolerance to vascularized composite allografts (VCAs) without cytoreductive conditioning in rats. Methods: Recipient Lewis rats treated (day 0) with or without naturally sorted Treg (3 × 106) from Lewis rat spleen and lymph nodes received costimulation blockade (anti-CD154 monoclonal antibody, days 0 and 1 and CTLA-4 immunoglobin, days 2, 4, and 6), rapamycin (days -1, 0, and 2), and concurrent transplantation of fully mismatched allogeneic donor VCAs (day 0) from the Brown Norway rat hindlimb containing VBMT. The mixed chimerism level was assessed monthly using flow cytometry. Survival of VCAs and occurrence of graft-versus-host disease were assessed clinically and histologically. Results: The combination of T reg and VBMT treatment led to long-term multilineage hematopoietic mixed chimerism (12-18%) and long-term donor-specific tolerance to VCAs (89% acceptance rate). Neither stable mixed chimerism nor VCA acceptance was observed in recipients without Treg treatment. Graft-versus-host disease did not occur in the VBMT recipients. Conclusions: Cotreatment with Treg and VBMT created stable mixed chimerism and induced long-term donor-specific tolerance to VCAs without requiring cytoreductive conditioning. This noncytoreductive Treg-VBMT protocol has potential for clinical application in VCAs.

KW - Graft-versus-host disease

KW - Mixed chimerism

KW - Regulatory T cells

KW - T

KW - Vascularized bone marrow transplantation

KW - Vascularized composite allograft

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