Expansion of Regulatory T and B Cells in Swine Rendered Tolerant of Allogeneic Vascularized Composite Allografts via Mixed Chimerism

G. Saviane¹, A. Lellouch¹, A. Andrews¹, L. Lantieri², M. Randolph¹, G. Benichou¹, C. Cetrulo Jr¹

¹Center for Transplantation Sciences, Division of Plastic Surgery, Boston, MA, USA, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, Boston, MA, ²European Georges Pompidou Hospital, University of Paris, Department of Plastic Surgery, Paris, France

Meeting: 2019 American Transplant Congress

Abstract number: 305

Keywords: Bone marrow transplantation, Co-stimulation, Mixed chimerism, Tolerance

Session Information

Session Name: Concurrent Session: Basic & Clinical Science - VCA

Session Type: Concurrent Session

Date: Monday, June 3, 2019

Session Time: 2:30pm-4:00pm

Presentation Time: 3:06pm-3:18pm

Location: Room 209

*Purpose: Prevention of acute rejection of vascularized composite allografts (VCAs) requires ongoing systemic immunosuppression, which subject patients to infectious, metabolic, reno-vascular and neoplastic complications. It is, therefore, essential to design selective immune strategies to mitigate acute rejection of VCAs. In this study, we studied the influence of donor bone marrow transplantation and short-term immunosuppression on the immune response and rejection of MHC class I disparate VCAs in swine.

*Methods: Two days prior placement of MHC class I-mismatched VCAs, MGH swine were irradiated (whole body 3 Gy and thymic 7 Gy). Osteomyocutaneous hind limb VCAs were transplanted into MHC class I-mismatched recipients (n=8). Tacrolimus was administrated for 45 days (target level 10-15 ng/mL) along with CTLA4-Ig (20 mg/kg, POD 0, 4, 6) and anti-IL6R mAbs (10mg/kg, POD 0, 7, 14, 21, 28). Serial VCA skin and muscle biopsies were performed to assess allograft rejection. Donor hematopoietic chimerism was evaluated by FACS and the anti-donor alloresponse by T cells was monitored.

*Results: Three animals out of eight, which completed the protocol, showed no signs of rejection for 250-400 days. All tolerant swine displayed stable multilineage donor chimerism consisting of 90% myeloid cells, 60% T cells and 40% B cells. During the tolerance induction phase, we observed a massive expansion of double negative CD4^–CD8^–T cells producing IL-10 among peripheral blood mononuclear cells (PBMCs) of all tolerant swine. At the same time, recipient PBMCs were unable to mount a direct inflammatory T cell alloresponse (MLR) against donor cells while they proliferated upon exposure to third party cells and polyclonal stimulation. Finally, tolerance was associated with increased frequencies of CD5⁺B cells corresponding to transitional B1 and regulatory B cells.

*Conclusions: Tolerance of MHC class I disparate VCAs can be achieved via donor bone marrow transplantation and short-term immunosuppression in swine. This was associated with stable multilineage hematopoietic donor macro-chimerism and early expansion of regulatory T and B cells.

To cite this abstract in AMA style:

Saviane G, Lellouch A, Andrews A, Lantieri L, Randolph M, Benichou G, Jr CCetrulo. Expansion of Regulatory T and B Cells in Swine Rendered Tolerant of Allogeneic Vascularized Composite Allografts via Mixed Chimerism [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/expansion-of-regulatory-t-and-b-cells-in-swine-rendered-tolerant-of-allogeneic-vascularized-composite-allografts-via-mixed-chimerism/. Accessed November 22, 2024.

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