Post-Transplant High Dose Cyclophosphamide Treatment Induces Thymus-Independent Immune Tolerance of Vascularized Composite Allografts via Complete Depletion of the Alloreactive TCR Repertoire.
1Plastic and Reconstructive Surgery, Johns Hopkins University, Baltimore, MD
2Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD
3Department for Comparative Pathobiology, Johns Hopkins University, Baltimore, MD
4Department of Anesthesiology, Johns Hopkins University, Baltimore, MD.
Meeting: 2018 American Transplant Congress
Abstract number: A411
Keywords: Bone marrow transplantation, Thymus, Tolerance
Session Information
Session Name: Poster Session A: Tolerance / Immune Deviation
Session Type: Poster Session
Date: Saturday, June 2, 2018
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
Background: Treatment with PT/Cy in the setting of combined donor bone marrow transplantation and VCA has shown encouraging results with regards to chimerism induction and consecutive tolerance in murine models. Methods: Using next generation TCR sequencing technology (Adaptive Biotechnology) alloreactive T cell frequencies were determined before and after VCA transplantation in mice. T cells were purified from PBMCs from Balb/c and C57BL6 animals (N=3ea) prior to transplantation and co-cultured in MLRs to identify both donor and host reactive T cells clones in naive mice. Based on the MLR combinations, VCA (orthotopic hind limb) were performed. Recipient animals were treated with a non-myeloablative dose of TBI and a T-cell depleting antibody 24 hours prior to transplantation and a single high dose of cyclophosphamide on POD 3 (PT/Cy). Pretransplant MLR samples were compared to PBMCs on POD 60 post transplantation. Furthermore, VCA transplantation using the PT/cy protocol were performed in thymectomized mice. Results: Untreated thymectomized and wildtype VCA recipients (n=5/group) rejected allografts acutely with a mean survival of 8 ± 1. The PT/Cy treatment prolonged VCA survival in wildtype (N=17, >150 days) and thymectomized recipients (N=10, >110 days) long term. Mixed chimerism was shown in VCA recipients at 22.51% ± 5.96% and at 24.96 ± 4.12 in thymectomized recipients. Pre-transplant MLR-derived T cell samples showed enriched MLR-specific clones over control stimulations in both HvG and GvH directions with >95% of these clones being undetectable in the peripheral blood at POD 60 post transplantation. Conclusion: Tolerance in this VCA model is mediated by complete depletion of alloreactive T cells in both HvG and GvH direction independent of the presence of a functional thymus.
CITATION INFORMATION: Furtmüller G., Oh B., Sidhom J., Fryer M., Malek V., Zhou X., Cooney D., Brayton C., Dodd-o J., Ganguly S., Raimondi G., Lee W., Luznik L., Brandacher G. Post-Transplant High Dose Cyclophosphamide Treatment Induces Thymus-Independent Immune Tolerance of Vascularized Composite Allografts via Complete Depletion of the Alloreactive TCR Repertoire. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Furtmüller G, Oh B, Sidhom J, Fryer M, Malek V, Zhou X, Cooney D, Brayton C, Dodd-o J, Ganguly S, Raimondi G, Lee W, Luznik L, Brandacher G. Post-Transplant High Dose Cyclophosphamide Treatment Induces Thymus-Independent Immune Tolerance of Vascularized Composite Allografts via Complete Depletion of the Alloreactive TCR Repertoire. [abstract]. https://atcmeetingabstracts.com/abstract/post-transplant-high-dose-cyclophosphamide-treatment-induces-thymus-independent-immune-tolerance-of-vascularized-composite-allografts-via-complete-depletion-of-the-alloreactive-tcr-repertoire/. Accessed October 10, 2024.« Back to 2018 American Transplant Congress