Past Funded Research Project 

Prevention of Homograft Induced Cardiac Allograft Vasculopathy in Pediatric Heart Transplantation

Primary Investigators: Dr. Jean Kwun

Institution: Duke University Medical Center

Funding began in 2015.

This study was funded in 2015, with a focus on research into one of the major factors limiting long-term survival after a heart transplant. The main goal of the study is to develop a mouse model which mimics pediatric heart transplantation after homograft and to investigate the effect of MHC matching, short-term immunosuppression and desensitization methods to reduce pre-formed donor-specific alloantibody (DSA) and control de novo DSA after heart transplantation. The major goals remain unchanged from the initial competing award. 

 

Please read below to learn more about this research project.

What is the major problem being addressed by this study?
Transplanted heart goes through what seems to be an accelerated aging process. Although there are multiple variables, the average graft survival is short (10-15 years). Chronic allograft rejection is a major obstacle in achieving long-term graft survival after organ transplantation. This is definitely devastating stats for transplant recipients especially for pediatric patients considering that children with organ transplants have the greatest need for long-term graft function. Although the etiology of chronic rejection is multifactorial, antibody against the graft is considered to have a causal effect on development of chronic rejection.

What specific questions are you asking and how will you attempt to answer them?
Cryopreserved, cadaveric pulmonary artery and aortic tissue (homograft) is commonly used in the surgical approach to a variety of congenital heart defects. The common use of homograft in over 65% of pediatric cardiac surgeries to temporize cardiac pathology and permit growth before definitive cardiac surgery is particularly sensitizing. In this sense, the pediatric patients experience sensitization events such as homograft prior to their heart transplantations should be treated differently. In the proposed study, we will evaluate the effect of homograft in later antibody-mediated rejection and test possible interventions by using animal model mimics pediatric heart transplant patients with homograft.

What is the long-term biomedical significance of your work, particularly as it pertains to the cardiovascular area?
What major therapeutic advance(s) do you anticipate that it will lead to? The proposed study will provide a proof of concept for homograft sensitization in pediatric patients and provide possible treatment regimens (Bortezomib, Retuximab and Belatacept), which are readily available for human patients. Novel strategies to reduce alloantibodies and humoral response via MHC matching or short-term immunosuppression can positively impact the short and long term survival of transplanted hearts in pediatric patients

Specific Aim 1: To develop a murine model of cardiac allograft antibody-mediated rejection (AMR) that emulates the clinical problem seen in children of sensitization by prior surgery with homograft before cardiac transplantation.

Specific Aim 2: To investigate the effects of desensitization in aortic transplantation induced cardiac allograft AMR model.

Cardiac Allograft vasculopathy (also known as chronic rejection) is a major obstacle in achieving long-term graft survival after heart transplantation. Although the etiology of chronic rejection is multifactorial, antibody against to the graft is considered to have a causal effect on the development of chronic rejection. In this sense, the pediatric patients who experience sensitization events such as homograft prior to their heart transplantations should be treated differently. There are few treatments available to the clinician to either prevent the induction of alloantibody or to eliminate it once its produced. We propose to investigate a novel animal model that mimics sensitized pediatric patients by sequential transplantation of the aorta and heart to study the effect of matching homograft sensitization and immunosuppression with clinically relevant desensitization treatment regimens. The potential significance of this proposed study is to provide translatable potential interventions in this pathological process. The proposed studies are based on preliminary data that has been thoroughly substantiated. We also have the ability to perform the proposed studies using methods and materials that are commonly used in our laboratory.

SIGN UP FOR OUR NEWSLETTER

Save Lives as an
Organ Donor

Enduring Hearts Inc.
is a Registered 501(c)(3)
Charity EIN 46-2665745

info@enduringhearts.org
(240) EHEART-1
3600 Dallas Highway, Suite 230-350
Marietta, GA 30064