Post-Transplant High Dose Cyclophosphamide Treatment Induces Thymus-Independent Immune Tolerance of Vascularized Composite Allografts via Complete Depletion of the Alloreactive TCR Repertoire.

G. Furtmüller,¹ B. Oh,¹ J. Sidhom,² M. Fryer,¹ V. Malek,¹ X. Zhou,¹ D. Cooney,¹ C. Brayton,³ J. Dodd-o,⁴ S. Ganguly,² G. Raimondi,¹ W. Lee,¹ L. Luznik,² G. Brandacher.¹

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 November 23, 2024.

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