A Novel Post-Transplant High-Dose Cyclophosphamide-Based Regimen to Promote Immune Tolerance After VCA

G. Furtmüller,¹ M. Fryer,¹ B. Oh,¹ S. Ganguly,² J. Izzi,³ D. Cooney,¹ G. Raimondi,¹ W. Lee,¹ L. Luznik,² G. Brandacher.¹

¹Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
²Immunology - Sydney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
³Department of Research Animal Resources, Johns Hopkins University, Baltimore, MD.

Meeting: 2015 American Transplant Congress

Abstract number: A261

Keywords: Bone marrow, Graft survival, T cell activation, Tolerance

Session Information

Session Name: Poster Session A: Preclinical Immunosuppression and Tolerance

Session Type: Poster Session

Date: Saturday, May 2, 2015

Session Time: 5:30pm-7:30pm

Presentation Time: 5:30pm-7:30pm

Location: Exhibit Hall E

Background: VCA has become a viable treatment option for devastating tissue defects. However, the life-long need of immunosuppressive medications curtails the wider use of VCA. Methods: Skin, SOT (heart), and VCA were performed across a full MHC mismatch barrier from Balb/c to C57BL6. Recipient animals were treated with a non-myeloablative dose of total body irradiation and a T-cell depleting antibody 24 hours prior to transplantation. In selected groups, donor BM and splenocytes were injected at the time of transplantation. CyP was administered on POD 3 (PTCy). Peripheral blood multi-lineage chimerism and Vβ-TCR staining was performed. Donor-specific unresponsiveness was tested by MLR and by 2° skin and SOT. Results: Controls (n=5/group) rejected skin, SOT and VCAs acutely with a mean survival of 14±1, 9±2, and 8±1, days respectively. The conditioning regimen + PTCy extended skin survival to 32±8 days (n=5). The addition of donor BM lead to indefinite allograft survival (>150 days) in 4/5 skin allograft and 2/3 heart recipients. All VCA recipients (n=10) showed indefinite graft survival (>150 days) regardless of additional donor BM cell infusion. Mixed chimerism analysis showed engraftment of donor BM in groups receiving BM at the time of skin/heart transplantation (6.8%±3.1%). In VCA recipients significantly higher donor chimerism was detected at 22.51%±5.96% and 30.17%±8.72%, respectively. Vβ-TCR staining showed decreased expression of donor-specific TCRs in all animals with long-term surviving allografts. Long-term survivors showed donor-specific T cell unresponsiveness in MLRs while maintaining reactivity against 3rd party stimulators. In-vivo, tolerant animals challenged with 2° skin transplants accepted donor matched Balb/c skin (100 days) while 3rd party FVB/N skin was acutely rejected (15±2 days). Donor-matched 2° SOT were accepted long term (>50 days) without any signs of rejection. Conclusion: The results demonstrate that the treatment induces robust tolerance in a fully MHC mismatched model of skin, SOT, and VCA implying a crucial role of the intragraft vascularized bone component.

To cite this abstract in AMA style:

Furtmüller G, Fryer M, Oh B, Ganguly S, Izzi J, Cooney D, Raimondi G, Lee W, Luznik L, Brandacher G. A Novel Post-Transplant High-Dose Cyclophosphamide-Based Regimen to Promote Immune Tolerance After VCA [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/a-novel-post-transplant-high-dose-cyclophosphamide-based-regimen-to-promote-immune-tolerance-after-vca/. Accessed November 21, 2024.

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