Vascularized thymic lobe transplantation in miniature swine: Thymopoiesis and tolerance induction across fully MHC-mismatched barriers

Abstract

As the major site of self-nonself discrimination in the immune system, the thymus, if successfully transplanted, could potentially carry with it the induction of central tolerance to any other organ or tissue from the same donor. We have recently developed a technique for transplantation of an intact, vascularized thymic lobe (VTL) in miniature swine. In the present study, we have examined the ability of such VTL allografts to support thymopoiesis and induce transplantation tolerance across fully MHC-mismatched barriers. Six miniature swine recipients received fully MHC-mismatched VTL grafts with a 12-day course of tacrolimus. Three of these recipients were thymectomized before transplantation and accepted their VTL allografts long-term, with evidence of normal thymopoiesis. In contrast, three euthymic recipients rejected their VTL allografts. Donor renal allografts, matched to the donor VTL grafts, were transplanted without immunosuppression into two of the three thymectomized recipients, and one of the three euthymic recipients. These renal allografts were accepted by thymectomized recipients, but rejected by the euthymic recipient in an accelerated fashion. This study thus demonstrates that successful transplantation of a vascularized thymus across a fully MHC-mismatched barrier induces tolerance in this preclinical, large-animal model. This procedure should enable studies on the role of the thymus in transplantation immunology as well as offer a potential strategy for tolerance induction in clinical transplantation.thymus transplantation ͉ vascularization

Thymic rejuvenation and the induction of tolerance by adult thymic grafts

“…FK506 has been found previously not to have measurable effects on thymus structure or involution in miniature swine (13). The morphometric analysis of aged thymus grafts transplanted into juvenile recipients revealed marked rejuvenation of these grafts within two months of transplantation (Fig.…”

“…2 and 3 and SI Fig. 7) or juvenile MHC-mismatched VTLs (13). Aged MHC-mismatched VTL grafts were still hypocellular on day 60, but thymic stromal cells were present without vasculitis ( Fig.…”

“…We subsequently assessed the ability of older thymus grafts to induce tolerance across MHC disparate barriers with the same 28-day course of FK506 that was used across MHC-matched barriers. Based on our previous experience with mouse and porcine thymic transplantations (13,14), recipients (recipients 4-6) were completely thymectomized before the transplantation of two haplotype, class I-mismatched VTL grafts. Frequent VTL biopsies were performed on recipient 4 to examine the development of thymopoiesis in the VTL graft.…”

Generation of Thymic Epithelial Cell Progenitors by Mouse Embryonic Stem Cells

“…For example, keratinocyte growth factor and sex steroid ablation have been reported to improve thymopoiesis by restoration of the functions of thymic epithelial cells [8][9][10][11][12][13]. Transplantation of cultured thymus fragments has been used to provide the thymic microenvironment for T-cell regeneration in patients and experimental animals with T-cell deficiencies or as a method for the induction of tolerance in organ transplantation [7,[14][15][16][17]. Studies on thymus organogenesis in the murine embryo have indicated that both the cortical and medullary epithelial cells arise from a common progenitor population [18,19].…”

Rejuvenation of the Thymic Microenvironment by ESC-derived Thymic Epithelial Progenitors

“…Administration of keratinocyte growth factor or sex steroid ablation has been shown to increase the number of TECs, resulting in enhanced thymopoiesis (Kelly et al, 2008;Min et al, 2002;Min et al, 2007;Alpdogan et al, 2006). Additionally, transplantation of cultured thymus fragments has been used to provide the thymic microenvironment for T-cell regeneration in patients and experimental animals with T-cell deficiencies or as a method for the induction of tolerance in organ transplantation (Markert et al, 2003;Hong et al, 1979;Yamada et al, 2000;Kamano et al 2004). However, the applications of cultured thymus fragments are limited by tissue availability.…”