Abstract
Eighty-six infants born without a thymus have been treated with allogeneic cultured thymus tissue implantation (CTTI). These infants, who lack T cells and are profoundly immunodeficient at birth, after CTTI from an unmatched donor develop T cells similar to those of recipient that are tolerant to both their own major histocompatibility antigens and those of the donor. We tested use of CTTI with the goal of inducing tolerance to unmatched heart transplants in immunocompetent rats. We thymectomized and T cell-depleted Lewis rats. The rats were then given cultured thymus tissue from F1 (Lewis × Dark Agouti ) under the kidney capsule and vascularized Dark Agouti (DA) heart transplants in the abdomen. Cyclosporine was administered for 4 months. The control group did not receive CTTI. Recipients with CTTI showed repopulation of naive and recent thymic emigrant CD4 T cells; controls had none. Recipients of CTTI did not reject DA cardiac allografts. Control animals did not reject DA grafts, due to lack of functional T cells. To confirm donor-specific unresponsiveness, MHC-mismatched Brown Norway (BN) hearts were transplanted 6 months after the initial DA heart transplant. LW rats with LWxDA CTTI rejected the third-party BN hearts (mean survival time 10 days); controls did not. CTTI recipients produced antibody against third-party BN donor but not against the DA thymus donor, demonstrating humoral donor-specific tolerance. Taken together, F1(LWxDA) CTTI given to Lewis rats resulted in specific tolerance to the allogeneic DA MHC expressed in the donor thymus, with resulting long-term survival of DA heart transplants after withdrawal of all immunosuppression.
Highlights
Ray Owen first observed immune tolerance to other individuals’ blood in Freemartin calves [1], and later Peter Medawar was the first to induce transplant tolerance by injecting neonatal mice with adult donor tissue/cell suspension [2]
In order to perform allogeneic cultured thymus tissue implantation (CTTI) in a rat model with procedures used for the treatment of athymic infants with complete DiGeorge anomaly, thymus was harvested from 3-day-old F1(Lewis × Dark Agouti [LWxDA]) rat pups
As in cultured human thymus, the network of thymic epithelial cells (TECs) was preserved in the rat cultured thymus tissue based on cytokeratin (CK) staining (Supplemental Figure 2)
Summary
Ray Owen first observed immune tolerance to other individuals’ blood in Freemartin calves [1], and later Peter Medawar was the first to induce transplant tolerance by injecting neonatal mice with adult donor tissue/cell suspension [2]. These examples of tolerance induction were related to the immature nature of the neonatal immune system [3, 4]. The thymoheart was formed by injecting finely minced thymus tissue of the donor type into the atrial appendages of miniature swine Those hearts were able to survive in an allogeneic recipient for up to approximately 194 days [10]. Despite success for up to 300 days, data have not been published showing the long-term success needed for human transplantation
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