Addressing Chronic Rejection in Heart Transplants
The hypothesis is that reparative damage-associated molecular patterns signals initiating the repair of tissue damage early after surgery become dysregulated around the vasculature due to a sustained inflammatory response by alloreactive immune cells.
McGowan Institute for Regenerative Medicine affiliated faculty member Hēth Turnquist, PhD (pictured), Associate Professor in the University of Pittsburgh School of Medicine, Department of Surgery, T.E. Starzl Transplantation Institute, with a secondary appointment in the Department of Immunology, is the principal investigator of the newly funded National Institutes of Health/National Heart, Lung, and Blood Institute 5-year grant entitled, “Immunoregulatory Mechanisms of IL-33 in Heart Transplantation.”
The project will address chronic allograft vasculopathy and fibrosis, also called chronic rejection. This is an immunosuppressant-resistant disease that develops in almost half of heart transplants after ten years and remains a leading cause of recipient death one-year post-transplant. The blockage of graft blood vessels and progressive graft scarring causing chronic rejection may reflect failed tissue repair by the recipient's immune system. These studies will pair precise transgenic mice transplant models with cutting-edge technologies to provide previously unattainable insights into how innate and adaptive alloresponses may dysregulate repair processes to cause chronic heart transplant rejection.
The project abstract reads:
Early graft injury is the consequence of unavoidable transplant-associated events, such as donor brain death, ischemia/reperfusion injury, and surgical trauma. Recipient responses to graft alloantigens will also produce graft damage throughout the life of the graft. These injuries and stresses cause the release of self-molecules containing damage-associated molecular patterns (DAMPs). It is well appreciated that DAMPs support pro-inflammatory responses when they are sensed by cells of the innate immune system, particularly monocytes and macrophages. Preclinical rodent heart transplant studies reveal that these released DAMPs initiate and propagate alloresponses and targeting inflammatory DAMPs, or the signaling cascades they activate, reduce alloimmunity and improve outcomes after transplantation. Yet, our recent research has provided compelling evidence that these graft injuries also release reparative DAMPs (rDAMPs), such as Interleukin-33 (IL-33), which limits local inflammation and initiates immune-mediated tissue repair after heart transplant. By assessing pediatric heart transplant recipient samples and using a preclinical mouse heart transplant model, we identified that IL-33 is upregulated in graft stromal cells and limits the development of allograft vasculopathy and graft fibrosis that later culminates in chronic rejection (CR). Our published and preliminary data suggest that IL-33 mediates this protection by targeting infiltrating monocytes and macrophages, as well as regulatory T cells (Tregs), to limit the generation of pro-inflammatory macrophages and then coordinate a Treg and reparative macrophage-mediated response to injury. While these data are encouraging, our studies also suggest that the processes that initiate repair of early tissue damage may become dysregulated over the graft's life. In preliminary data, we show that vessel-associated Tregs become pathologic when their sustained secretion of repair factors in response to IL-33 promotes the proliferation of local fibroblasts contributing to CR. In addition to having their functions programmed by local rDAMPs, graft infiltrating recipient monocytes recognize allogenic molecules causing them to mature into pro-inflammatory myeloid cells that stimulate T cell proliferation and IFNγ production in the graft. We have established that monocytes and macrophages recognize and develop allospecific cytotoxicity and memory to MHCI antigens via paired immunoglobulin-like receptors-A. These data lead us to HYPOTHESIZE that rDAMP signals initiating the repair of tissue damage early after heart transplantation become dysregulated around the vasculature due to a sustained inflammatory response by alloreactive immune cells. We will test this hypothesis in two aims: In AIM 1, we will define how rDAMP and immune cell interactions evolve in heart transplant microenvironments during CR development. In AIM 2, we will establish if innate alloimmunity prevents effective injury resolution and repair after heart transplantation.
Congratulations, Dr. Turnquist!
Illustration: McGowan Institute for Regenerative Medicine.
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NIH Reporter: Immunoregulatory Mechanisms of IL-33 in Heart Transplantation
Bio: Dr. Hēth Turnquist
The project will address chronic allograft vasculopathy and fibrosis, also called chronic rejection. This is an immunosuppressant-resistant disease that develops in almost half of heart transplants after ten years and remains a leading cause of recipient death one-year post-transplant. The blockage of graft blood vessels and progressive graft scarring causing chronic rejection may reflect failed tissue repair by the recipient's immune system. These studies will pair precise transgenic mice transplant models with cutting-edge technologies to provide previously unattainable insights into how innate and adaptive alloresponses may dysregulate repair processes to cause chronic heart transplant rejection.
The project abstract reads:
Early graft injury is the consequence of unavoidable transplant-associated events, such as donor brain death, ischemia/reperfusion injury, and surgical trauma. Recipient responses to graft alloantigens will also produce graft damage throughout the life of the graft. These injuries and stresses cause the release of self-molecules containing damage-associated molecular patterns (DAMPs). It is well appreciated that DAMPs support pro-inflammatory responses when they are sensed by cells of the innate immune system, particularly monocytes and macrophages. Preclinical rodent heart transplant studies reveal that these released DAMPs initiate and propagate alloresponses and targeting inflammatory DAMPs, or the signaling cascades they activate, reduce alloimmunity and improve outcomes after transplantation. Yet, our recent research has provided compelling evidence that these graft injuries also release reparative DAMPs (rDAMPs), such as Interleukin-33 (IL-33), which limits local inflammation and initiates immune-mediated tissue repair after heart transplant. By assessing pediatric heart transplant recipient samples and using a preclinical mouse heart transplant model, we identified that IL-33 is upregulated in graft stromal cells and limits the development of allograft vasculopathy and graft fibrosis that later culminates in chronic rejection (CR). Our published and preliminary data suggest that IL-33 mediates this protection by targeting infiltrating monocytes and macrophages, as well as regulatory T cells (Tregs), to limit the generation of pro-inflammatory macrophages and then coordinate a Treg and reparative macrophage-mediated response to injury. While these data are encouraging, our studies also suggest that the processes that initiate repair of early tissue damage may become dysregulated over the graft's life. In preliminary data, we show that vessel-associated Tregs become pathologic when their sustained secretion of repair factors in response to IL-33 promotes the proliferation of local fibroblasts contributing to CR. In addition to having their functions programmed by local rDAMPs, graft infiltrating recipient monocytes recognize allogenic molecules causing them to mature into pro-inflammatory myeloid cells that stimulate T cell proliferation and IFNγ production in the graft. We have established that monocytes and macrophages recognize and develop allospecific cytotoxicity and memory to MHCI antigens via paired immunoglobulin-like receptors-A. These data lead us to HYPOTHESIZE that rDAMP signals initiating the repair of tissue damage early after heart transplantation become dysregulated around the vasculature due to a sustained inflammatory response by alloreactive immune cells. We will test this hypothesis in two aims: In AIM 1, we will define how rDAMP and immune cell interactions evolve in heart transplant microenvironments during CR development. In AIM 2, we will establish if innate alloimmunity prevents effective injury resolution and repair after heart transplantation.
Congratulations, Dr. Turnquist!
Illustration: McGowan Institute for Regenerative Medicine.
Read more...
NIH Reporter: Immunoregulatory Mechanisms of IL-33 in Heart Transplantation
Bio: Dr. Hēth Turnquist