Post Transplantation High-Dose Cyclophosphamide Treatment Promotes Immune Tolerance After Skin, Solid Organ, and Vascularized Composite Allotransplantation.

G. Furtmüller,¹ B. Oh,¹ M. Fryer,^1,4 P. Akre,¹ S. Ganguly,² J. Dodd-o,³ D. Cooney,¹ G. Raimondi,¹ W. Lee,¹ L. Luznik,² G. Brandacher.¹

¹Department of Plastic and Reconstructive Surgery, Johns Hopkins Medicine, Baltimore, MD
²Immunology - Sydney Kimmel Cancer Center, Johns Hopkins Medicine, Baltimore, MD
³Department of Anesthesiology, Johns Hopkins Medicine, Baltimore, MD
⁴Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA.

Meeting: 2016 American Transplant Congress

Abstract number: 476

Keywords: Bone marrow transplantation, Mixed chimerism, Thymic tolerance, Tolerance

Session Information

Session Name: Concurrent Session: Bone Marrow Transplantation and Chimerism: Animal Models

Session Type: Concurrent Session

Date: Tuesday, June 14, 2016

Session Time: 4:30pm-6:00pm

Presentation Time: 4:42pm-4:54pm

Location: Room 313

Background: Developing novel approaches to minimize/avoid immunosuppression by induction of immune tolerance represents the prime task in the field of transplantation. Methods: Murine skin, heart, and VCA transplants were performed across a full MHC mismatch barrier. Recipients treatment comprised non-myeloablative TBI and T-cell depletion and a single dose of post-transplant cyclophosphamide. Donor BM and splenocytes (DBM) were injected at the time of transplantation. Post-transplant multi-lineage and Foxp3 chimerism as well as Vβ-TCR staining was performed. Donor-specific unresponsiveness was tested by MLR and 2[deg] skin and SOT. Results: Untreated animals rejected skin grafts, SOT and VCA acutely within 14±1 days, 9±2 days, and 8±1 days, respectively. The treatment regimen extended skin and SOT graft survival (32±8; 65±4, respectively). Additional DBM augmentation lead to allograft survival of >150 days in skin and SOT. However, indefinite graft survival of >250 days was observed in all animals receiving the induction regimen and a VCA ± DBM. In groups receiving a VCA ± DBM, donor chimerism was detected at 22.51±5.96% and 30.17±8.72%, respectively. Foxp3-chimerism showed recipient-derived Tregs predominantly contributing to the Treg pool (92.6±4.2%) in the early phase after transplantation (POD 14-30) whereas at later time points (POD 60-100) Foxp3+ cells were donor-derived (46.2±11.3%). Vβ-T cell receptor staining indicates an additional central tolerance mechanism. All long-term survivors showed donor-specific T cell unresponsiveness in-vitro (MLR) while demonstrated proliferation against 3rd party stimulators. In-vivo, tolerant animals accepted donor-matched secondary skin, while 3rd party FVB/N skin was acutely rejected. Donor-matched hearts were accepted long-term. Conclusion: Robust tolerance and immunosuppression-free long-term allograft survival can be induced with PTCy in stringent fully MHC mismatched murine models of skin, heart, and vascularized composite allotransplantation.

CITATION INFORMATION: Furtmüller G, Oh B, Fryer M, Akre P, Ganguly S, Dodd-o J, Cooney D, Raimondi G, Lee W, Luznik L, Brandacher G. Post Transplantation High-Dose Cyclophosphamide Treatment Promotes Immune Tolerance After Skin, Solid Organ, and Vascularized Composite Allotransplantation. Am J Transplant. 2016;16 (suppl 3).

To cite this abstract in AMA style:

Furtmüller G, Oh B, Fryer M, Akre P, Ganguly S, Dodd-o J, Cooney D, Raimondi G, Lee W, Luznik L, Brandacher G. Post Transplantation High-Dose Cyclophosphamide Treatment Promotes Immune Tolerance After Skin, Solid Organ, and Vascularized Composite Allotransplantation. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/post-transplantation-high-dose-cyclophosphamide-treatment-promotes-immune-tolerance-after-skin-solid-organ-and-vascularized-composite-allotransplantation/. Accessed November 21, 2024.

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