Biologics and donor bone marrow cells for targeted immunomodulation in vascularized composite allotransplantation

A translational trial in swine

G. S. Wachtman, E. G. Wimmers, V. S. Gorantla, C. H. Lin, S. Schneeberger, J. V. Unadkat, X. X. Zheng, Gerald Brandacher, W P Andrew Lee

Research output: Contribution to journalArticle

Abstract

Introduction: Bone marrow (BM) infusion following organ transplantation is a prerequisite for potential donor-antigen-specific tolerance induction. We developed a preclinical swine model to determine the optimal dose of BM cells to achieve microchimerism. Furthermore, induction therapy was optimized by augmenting the BM infusion with biologics in the form of costimulatory blockade: cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4-Ig). Materials and Methods: Yucatan miniature swine (n = 12) underwent total body and thymic irradiation for cytodepletion. Animal groups received 15, 30, or 60 million cells per kilogram of whole unmodified BM. The optimal dose of BM cell infusion (BMT) was then applied to subsequent experiments evaluating the addition of CTLA4lg. Group 1 (control) received no treatment. Group 2 received FK506 only; group 3 received irradiation, BMT, and FK506; group 4 received FK506 and CTLA4-lg. Results: Microchimerism was established in all animals after BM cell infusion; at postoperative day 9, it was significantly increased for 60 million cells per kilogram (P =.0001). Transplanted animals in group 1 rejected the allograft 5 to 8 days after transplantation. Group 2 rejected the allograft (skin and muscle) 30 to 32 days after transplantation (2 days after cessation of immunosuppression). Group 3 rejected the skin portion of the allograft at 50, 52, and 53 days posttransplant. Remaining allograft components (muscle, bone, nerve, vessel) survived indefinitely. Group 4 animals demonstrated significantly prolonged muscle survival beyond 150 days posttransplant; the skin component survived past 150 days in two of three animals. Skin and muscle histology in all long-term surviving animals were normal. Conclusions: BM cell infusion with 60 million cells per kilogram results in stable levels of microchimerism. The addition of costimulatory blockade (CTLA4lg) prolonged allograft skin survival and overall graft survival. Such targeted immunomodulatory protocols might facilitate immune tolerance and eliminate the need for multidrug immunosuppression to maintain graft survival after vascularized composite allotransplantation.

Original languageEnglish (US)
Pages (from-to)3541-3544
Number of pages4
JournalTransplantation Proceedings
Volume43
Issue number9
DOIs
StatePublished - Nov 2011

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Vascularized Composite Allotransplantation
Immunomodulation
Biological Products
Bone Marrow Cells
Swine
Allografts
Chimerism
Tacrolimus
Skin
Muscles
Bone Marrow
Graft Survival
Immunosuppression
Transplantation
CTLA-4 Antigen
Miniature Swine
Immune Tolerance
Whole-Body Irradiation
Organ Transplantation
Immunoglobulins

ASJC Scopus subject areas

  • Surgery
  • Transplantation

Cite this

Biologics and donor bone marrow cells for targeted immunomodulation in vascularized composite allotransplantation : A translational trial in swine. / Wachtman, G. S.; Wimmers, E. G.; Gorantla, V. S.; Lin, C. H.; Schneeberger, S.; Unadkat, J. V.; Zheng, X. X.; Brandacher, Gerald; Lee, W P Andrew.

In: Transplantation Proceedings, Vol. 43, No. 9, 11.2011, p. 3541-3544.

Research output: Contribution to journalArticle

Wachtman, G. S. ; Wimmers, E. G. ; Gorantla, V. S. ; Lin, C. H. ; Schneeberger, S. ; Unadkat, J. V. ; Zheng, X. X. ; Brandacher, Gerald ; Lee, W P Andrew. / Biologics and donor bone marrow cells for targeted immunomodulation in vascularized composite allotransplantation : A translational trial in swine. In: Transplantation Proceedings. 2011 ; Vol. 43, No. 9. pp. 3541-3544.
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T2 - A translational trial in swine

AU - Wachtman, G. S.

AU - Wimmers, E. G.

AU - Gorantla, V. S.

AU - Lin, C. H.

AU - Schneeberger, S.

AU - Unadkat, J. V.

AU - Zheng, X. X.

AU - Brandacher, Gerald

AU - Lee, W P Andrew

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N2 - Introduction: Bone marrow (BM) infusion following organ transplantation is a prerequisite for potential donor-antigen-specific tolerance induction. We developed a preclinical swine model to determine the optimal dose of BM cells to achieve microchimerism. Furthermore, induction therapy was optimized by augmenting the BM infusion with biologics in the form of costimulatory blockade: cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4-Ig). Materials and Methods: Yucatan miniature swine (n = 12) underwent total body and thymic irradiation for cytodepletion. Animal groups received 15, 30, or 60 million cells per kilogram of whole unmodified BM. The optimal dose of BM cell infusion (BMT) was then applied to subsequent experiments evaluating the addition of CTLA4lg. Group 1 (control) received no treatment. Group 2 received FK506 only; group 3 received irradiation, BMT, and FK506; group 4 received FK506 and CTLA4-lg. Results: Microchimerism was established in all animals after BM cell infusion; at postoperative day 9, it was significantly increased for 60 million cells per kilogram (P =.0001). Transplanted animals in group 1 rejected the allograft 5 to 8 days after transplantation. Group 2 rejected the allograft (skin and muscle) 30 to 32 days after transplantation (2 days after cessation of immunosuppression). Group 3 rejected the skin portion of the allograft at 50, 52, and 53 days posttransplant. Remaining allograft components (muscle, bone, nerve, vessel) survived indefinitely. Group 4 animals demonstrated significantly prolonged muscle survival beyond 150 days posttransplant; the skin component survived past 150 days in two of three animals. Skin and muscle histology in all long-term surviving animals were normal. Conclusions: BM cell infusion with 60 million cells per kilogram results in stable levels of microchimerism. The addition of costimulatory blockade (CTLA4lg) prolonged allograft skin survival and overall graft survival. Such targeted immunomodulatory protocols might facilitate immune tolerance and eliminate the need for multidrug immunosuppression to maintain graft survival after vascularized composite allotransplantation.

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