Primary Investigators: Dr. M Sleiman
Institution: Medical University of South Carolina
Funding began in 2018.
1. What is the major problem being addressed by this study?
Heart transplant patients need continuous medication to prevent transplant rejection and these medications can be very toxic. Our aim from this study is to test, using mouse models, new therapies that can limit transplant injury and prevent rejection without being toxic to the body. This is established by designing the therapies in a way that make them target mainly transplant tissue and not the whole body. Moreover, the transplanted organs are usually obtained from brain dead donors which increases their damage. Our study will help us understand how a certain component of the immune system called the “complement system” contribute to this damage.
2. What specific questions are you asking and how will you attempt to answer them?
To study how the ‘complement system’ affects damage caused by brain death we will use a drug that inhibits it ‘complement system’. We have a mouse model where we induce brain death in a mouse and then transplant its heart in another mouse. We will treat the mice with the drug and see how this affects heart transplant damage. This same drug is also studied as a therapy for heart transplant injury. Another therapy we are testing uses immune cells (called Tregs) that inhibit the immune system. We will take these cell from the mice and modify them so that they go specifically to the heart transplant, after they are injected in recipients, and test if they can prevent rejection.
3. 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? For instance, new drug(s), a surgical technique/procedure, a diagnostic tool/test, a previously undetected risk factor, etc:
A heart transplant can be the only available treatment for a lot of patients who suffer from heart failure due to coronary artery disease or several hereditary diseases. This treatment needs constant medication to prevent the transplanted heart from being rejected by the body. Although they did increase survival, these medications are toxic and still half of the patients die with the first 10 years after transplant. Our long-term goal is to translate these novel and innovative therapies to the clinic to enhance long-term survival of heart transplant recipients while having no to low toxicities. This is in line with the AHA mission to reduce t
Cardiac transplant (Tx) patients need immunosuppressants (IMS) to maintain graft survival. These IMS can be highly toxic and have failed to control long term tolerance. Therefore, we need to better understand mechanisms of graft injury and design better and less toxic therapies. Brain death (BD) injury (BDI) and ischemia reperfusion (IR) injury (IRI) are two unavoidable factors that exacerbate graft injury and there is currently no intervention to control them. Our lab has previously shown that the complement system (C) plays an important role in both types of injury making C inhibition a promising therapeutic strategy. Given the several homeostatic functions of C, it is important to limit its inhibition to graft tissue. We have characterized several C inhibitors (inhs) that target heart grafts by means of single chain antibodies (scFv) that recognize neoepitopes expressed on grafts after BD and IR. Another approach is the use of regulatory T-cells (Treg) where injecting mice with graft specific Tregs can establish long term survival. An emerging method to confer specificity is the use of chimeric antigen receptor (CAR): a membrane receptor (usually a graft alloantigen-specific scFv) linked to T-cell intracellular signaling domains.
Aim 1: Determine the role of C-dependent BDI & IRI on alloimmune response & cardiac graft rejection.
Aim 2: Characterize graft targeted CAR Tregs & investigate their ability to induce tolerance.
Heart transplant recipients need to receive life-long treatment with certain drugs to prevent graft loss.
Although these drugs can successfully prevent graft loss early on, most grafts are eventually lost. Also,
these drugs can lead to serious side effects from kidney damage to a higher risk of infections and cancer.
The main goal of this study is to test new therapies that can lower the level of injury or enhance heart
transplant survival while lowering the use of currently used drugs. Our first treatment approach is to inhibit
a component of the immune system called the “complement system” (or CS). CS heightens damage to
grafts early after transplantation. However, it has important functions within the body. Therefore, it would
be optimal to only inhibit it within the graft. For that reason, we created a protein (C2-CR1) made of two
components. The first component (C2) makes the protein localize into the graft tissue by binding to
markers present on the graft due to damage. The other component is called CR1, which suppresses the
complement system. We show in our study that this protein can decrease injury in heart grafts after
transplantation using a mouse model.
Another proposed treatment is using cells called Tregs. Tregs are a type of immune cells that inhibit the
immune system. We will genetically modify T-cells to become Tregs that recognize and infiltrate heart
grafts where they could suppress the immune system locally. Our approach is unique because it uses a
common target available on grafts from any donor. We faced several hurdles creating these cells, but we
recently got promising data. We have now generated stable Treg cells and are in the process of testing
them in vitro then in a mouse model of heart transplantation.
Our studies may lead to new therapies that can suppress the immune system locally in heart grafts. This
may result in better graft survival and lower doses of currently used drugs to lessen toxic side effects.
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