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Cultured thymus tissue implantation promotes donor-specific tolerance to allogeneic heart transplants
Jean Kwun, … , Allan D. Kirk, M. Louise Markert
Jean Kwun, … , Allan D. Kirk, M. Louise Markert
Published April 30, 2020
Citation Information: JCI Insight. 2020;5(11):e129983. https://doi.org/10.1172/jci.insight.129983.
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Research Article Immunology Transplantation

Cultured thymus tissue implantation promotes donor-specific tolerance to allogeneic heart transplants

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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.

Authors

Jean Kwun, Jie Li, Clay Rouse, Jae Berm Park, Alton B. Farris, Maragatha Kuchibhatla, Joseph W. Turek, Stuart J. Knechtle, Allan D. Kirk, M. Louise Markert

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Figure 3

Donor-specific tolerance in animals with CTTI versus general hyporesponsiveness in animals without CTTI.

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Donor-specific tolerance in animals with CTTI versus general hyporespons...
(A) Graft survival of BN (cervical) heart in recipients with or without CTTI. Recipients with CTTI rejected the BN heart rapidly (median survival time = 10 ± 1.0 days), whereas recipients without CTTI did not reject the third-party BN hearts. The BN control (no immunosuppression/thymectomy) shows rejection of BN hearts by LW rats. The syngeneic control shows lack of rejection of LW hearts by LW rats. Kaplan-Meier survival curve showed significant differences in the graft survival. (B) ISHLT grading showed a severe rejection of BN heart in animals with CTTI, whereas there was a significant reduction of rejection in recipients without CTTI compared with BN controls with no immunosuppression (n = 3–5 per group). Turkey test, ***P < 0.001; NS, not significant (P > 0.05). (C) Representative scanned image of explanted BN heart graft at the time of rejection or designated time points posttransplantation. Both BN heart grafts from animals with CTTI (third panel) and allogeneic (second panel) showed severe mononuclear cell infiltration, whereas BN heart grafts from animals without CTTI (fourth panel) or animals with syngeneic CTTI (first panel) showed no sign of rejection. Images were adapted from whole slide scan. CTTI, cultured thymus tissue implantation; BN, Brown Norway; LW, Lewis; ISHLT, International Society for Heart and Lung Transplantation.

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