The initiation of organ graft rejection in human transplantation differs from that in rodent transplantation in two important ways: (a) humans, but not rodents, have alloreactive memory T cells in large numbers that correlate with rejection and (b) human but not rodent endothelial cells (EC) are able to activate alloreactive memory T cells. This project will explore two novel features of human EC presentation of alloantigens to human memory T cells. First, the investigators will characterize the process by which graft EC may present alloantigens to effector memory T cells in a manner that triggers both transendothelial migration and in situ activation and then compare this process to transendothelial migration of effector memory T cells initiated by inflammatory chemokines. The effects of the second population of cells in the walls of microvessels, namely pericytes (PC), will also be examined as preliminary data suggest that these cells, like EC, may present alloantigen to memory T cells but tolerize after they activate T cells. These experiments will be performed both in vitro using cultured cells and in vivo using immunodeficient mice engrafted with human skin and receiving adoptively transferred allogeneic T cells. The assays used to characterize transendothelial migration and T cell activation are well established in the investigators'laboratory. The recovery of T cells post transmigration for such analyses involve the application of new technologies to this problem. Second, the investigators will characterize signals that cause cultured human EC release membrane-bound vesicles, such as exosomes or plasma membrane-derived microparticles, determine the composition of such particles, and determine if these particles are capable of activating central memory T cells, initiating rejection at a distance. The systemic release of such particles by human EC within grafted skin on immunodeficient mice will also be examined. The initial characterization of EC-derived exosomes was made by the investigators and the tools for such analyses are well established. This characterization of EC presentation of alloantigen can lead to new strategies to reduce organ rejection in the clinic which remains as a major cause of allograft failure.
Organ transplantation is a life saving therapy for end stage heart, kidney, liver, and lung failure, but success is still limited by immune-mediated rejection. Rodent models have had only limited success in leading to further improvements in large part because the interactions of host memory T cells with graft endothelial cells is very different in humans. This project will further characterize such interactions between human cells and, if successful, will suggest new approaches to reduce organ graft rejection.
|Lim, Sangho; Kirkiles-Smith, Nancy C; Pober, Jordan S et al. (2018) Regulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection. Biomaterials 183:128-138|
|Liu, Rebecca; Merola, Jonathan; Manes, Thomas D et al. (2018) Interferon-? converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1. JCI Insight 3:|
|Manes, Thomas D; Wang, Vivian; Pober, Jordan S (2018) Divergent TCR-Initiated Calcium Signals Govern Recruitment versus Activation of Human Alloreactive Effector Memory T Cells by Endothelial Cells. J Immunol 201:3167-3174|
|Pellowe, Amanda S; Sauler, Maor; Hou, Yue et al. (2018) Endothelial cell-secreted MIF reduces pericyte contractility and enhances neutrophil extravasation. FASEB J :fj201800480R|
|Pober, Jordan S; Merola, Jonathan; Liu, Rebecca et al. (2017) Antigen Presentation by Vascular Cells. Front Immunol 8:1907|
|Merola, Jonathan; Jane-Wit, Daniel D; Pober, Jordan S (2017) Recent advances in allograft vasculopathy. Curr Opin Organ Transplant 22:1-7|
|Lauridsen, Holly M; Pellowe, Amanda S; Ramanathan, Anand et al. (2017) Tumor Necrosis Factor-? and IL-17A Activation Induces Pericyte-Mediated Basement Membrane Remodeling in Human Neutrophilic Dermatoses. Am J Pathol 187:1893-1906|
|Abrahimi, Parwiz; Qin, Lingfeng; Chang, William G et al. (2016) Blocking MHC class II on human endothelium mitigates acute rejection. JCI Insight 1:|
|Liu, Rebecca; Lauridsen, Holly M; Amezquita, Robert A et al. (2016) IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium. J Immunol 197:2400-8|
|Manes, Thomas D; Pober, Jordan S (2016) Significant Differences in Antigen-Induced Transendothelial Migration of Human CD8 and CD4 T Effector Memory Cells. Arterioscler Thromb Vasc Biol 36:1910-8|
Showing the most recent 10 out of 67 publications