We have shown that vascularized bone marrow (VBM) prolongs vascularized composite allograft survival in nonhuman primates (NHP). To explore the potential for chimerism and tolerance, we combined recipient preconditioning and VBM in a NHP model of face transplantation.
Five cynomolgus macaques received anti-thymocyte immunoglobulin (Atgam), 7 Gy thymic irradiation, and 1.5 Gy total body irradiation (TBI). The 2 first animals received an additional 1.5 Gy TBI. Splenectomy was performed and heterotopic facial segment including VBM was transplanted from an MHC mismatched donor. Animals received tacrolimus and mycophenolate mofetil. Rejection episodes were not treated.
Absolute CD3 and CD4 count fell to nadirs of 27.5 and 25.3 by post-operative days (POD) 0-7. Pancytopenia developed with 48% decrease in Hct, 79% reduction in platelet counts, and 92% depletion of WBC by PODs 14-21. Cell counts demonstrated recovery by POD 20-28. After double dose TBI, cell counts fell more sharply and did not recover. Although grafts displayed no Banff grade II rejection, all had early endpoints from technical failure, weight loss, or infection. Macrochimerism was augmented: sustained up to 22.6% in one animal after single dose TBI, and transient in 3 others (to 5.9% in single dose TBI, with 23.2% and 24.1% after double dose TBI).
Recipient preconditioning with irradiation, T cell depletion, and splenectomy was associated with significant morbidity and mortality secondary to pancytopenia, even with reduced TBI. While increased chimerism may increase the potential to develop immunologic tolerance, depletional conditioning will require careful titration to achieve good clinical outcomes.
To cite this abstract in AMA style:Brazio P, Ha J, Munivenkatappa R, Mohan R, Rodriguez E, Bartlett S, Barth R. Irradiation and T Cell Depletion Augment Bone Marrow-Derived Chimerism at the Cost of Morbidity and Mortality in a Non-Human Primate Model of Vascularized Composite Allotransplantation [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/irradiation-and-t-cell-depletion-augment-bone-marrow-derived-chimerism-at-the-cost-of-morbidity-and-mortality-in-a-non-human-primate-model-of-vascularized-composite-allotransplantation/. Accessed May 27, 2020.
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