Cultured thymus tissue implementation promotes donor-specific tolerance to allogeneic heart transplants.
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 genetically-recipient
T cells 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 Lewis x Dark Agouti (LWxDA) CTTI under the kidney capsule
and vascularized 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 naïve 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 10d;
n=5). Controls did not (n=5). 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.
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https://hdl.handle.net/10161/20658Published Version (Please cite this version)
10.1172/jci.insight.129983Publication Info
Kwun, Jean; Li, Jie; Rouse, Clay; Park, Jae Berm; Farris, Alton B; Kuchibhatla, Maragatha;
... Markert, M Louise (2020). Cultured thymus tissue implementation promotes donor-specific tolerance to allogeneic
heart transplants. JCI insight. 10.1172/jci.insight.129983. Retrieved from https://hdl.handle.net/10161/20658.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Allan Douglas Kirk
David C. Sabiston, Jr. Distinguished Professor of Surgery
I am a surgeon with interest in immune management of transplant recipients. I am particularly
interested in therapies that influence T cell costimulation pathways and adjuvant
therapies that facilitate costimulation blockade to prevent the rejection of transplanted
organs without undue suppression of protective immunity. I am also interested in understanding
how injury, such as that occurring during trauma or in elective surgery, influences
immune responses and subsequent healing following injur
Stuart Johnston Knechtle
William R. Kenan, Jr. Distinguished Professor
During my career as an academic surgeon, I have had the privilege of leading and/or
participating in a diverse portfolio of hypothesis-driven research projects. These
projects have centered on the immunology of surgery and transplantation, including
both cellular and antibody-mediated immune responses. During my training I studied
the response of hyper-sensitized recipients to allogeneic liver transplantation, and
am currently studying means of reducing immunologic memory that might
Maragatha Kuchibhatla
Professor of Biostatistics & Bioinformatics
Statistical research methodology, analysis of repeated measurements, latent growth
curve models, latent class growth models, classification and regression trees, designing
clinical trials, designing clinical trials in psychiatry -- both treatment and non-treatment
trials in various comorbid populations.
Jean Kwun
Associate Professor in Surgery
Research interests include humoral tolerance to organ transplants in animal model
and humans, developing a clinically relevant animal model to study the mechanisms
of antibody-mediated rejection (AMR), and establishing a conceptual basis that will
translate into therapeutic intervention of AMR.
Mary Louise Markert
Professor Emeritus of Pediatrics
Dr. Markert is currently investigating cultured thymus tissue implantatoin in children
with congenital athymia. Congenital athymia is a fatal disease as the patients have
no T cells to defend against infection. There are several etiologies of congenital
athymia including 22q11.2 deletion syndrome, CHARGE (coloboma, heart defects, choanal
atresia, growth or mental retardation, genital abnormalities and ear anomalies and
or deafness. Complete DiGeorge anomaly is a des
Joseph W Turek
Associate Professor of Surgery
Joseph W. Turek, MD, PhD, MBA is an academic pediatric cardiac surgeon at Duke University
in Durham, North Carolina. Since 2017, Dr. Turek has served as chief of pediatric
cardiac surgery and executive co-director of Duke Children’s Pediatric & Congenital
Heart Center. Prior to Duke, he served in a similar leadership role at the University
of Iowa Stead Family Children’s Hospital from 2012-2017.
Dr. Turek attended the Illinois Mathematics and Science Academy for second
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