Immune System; Transplantation Immunology; Cytokines; Endothelial Cells; Translational Medical Research
Stem Cell Center, Yale: Stem Cells and Tissue Repair | Tissue Specific Stem Cells
Our research addresses three interrelated problems in immunobiology and vascular biology. First, we examine and analyze the consequences that ensue when human T lymphocytes recognize specific antigens presented by human vascular cells compared to recognition of antigens presented by professional antigen presenting cells or by tissue cells. Second, we examine signaling pathways and transcriptional regulation of inducible molecules, such as leukocyte adhesion molecules, in vascular cells activated by T cells or their products (e.g., cytokines). Third, we analyze pathways of cell injury in vascular cells caused by leukocytes and their products as well as responses to resist such injuries. These studies may lead to novel, vascular cell-directed therapies for modifying immune and inflammatory diseases and for improved outcomes in transplantation of organs or tissue-engineered grafts.
Specialized Terms: Immunobiology of vascular endothelial cells; Cytokine actions and mechanisms; Transplantation immunology
Extensive Research Description
Our research addresses three interrelated problems in the immunobiology and pathology of vascular endothelial cells. First, we examine and analyze the consequences that ensue when human T lymphocytes recognize specific antigens presented by human vascular endothelial cells, pericytes or smooth muscle cells in comparison to recognition of antigens presented by professional antigen presenting cells or by tissue cells (e.g., fibroblasts).
Second, we examine the signaling pathways activated by T cells or their products (e.g., cytokines) or by B cell products (e.g., antibodies) and the transcriptional regulation of cytokine-induced molecules, such as leukocyte adhesion molecules, within vascular endothelial cells. We also study how these signals differentially affect various segements of the vascular tree such as arteries, capillaries or post-capillary venules. Third, we analyze the pathways of cell injury (e.g., apoptosis) in vascular endothelial cells induced by leukocytes and their products as well as responses made by endothelial cells to resist such injury.
Our experimental approaches involve use of normal and genetically-modified (i.e., transfected) cell populations in culture, use of chimeric animals, (e.g., immunodeficient mice doubly engrafted with human blood vessels and with human lymphocytes), and use of discarded human tissues from control and disease settings. These studies may lead to novel, vascular cell-directed therapies for modifying immune and inflammatory diseases. A particular focus of our work is on modifying the behavior of endothelial cells to improve outcomes of clinical transplantation and tissue engineering.
- Zhou J, Qin L, Yi T, Ali R, Qingle L, Yang J, Li G, Tobiasova Z, Yan H, Zhang J, Yun JL, Sadeghi M, Giordano FJ, Pober JS, Tellides G. Interferon-γ-mediated allograft rejection exacerbates cardiovascular disease of hyperlipidemic murin transplant recipients. Circ Res. 2015; (Epub ahead of print)
- Jane-wit D, Surovtseva YV, Qin l, Li G, Liu R, Clark P, Manes TD, Wang C, Kashgarian M, Kirkiles-Smith NC, Tellides G, Pober JS. Complement membrane attack complexes activate noncanonical NF-B by forming an Akt+NIK+ signalosome on Rab5+ endosomes. Proc Natl Acad Sci (USA) 2015; 112:9686-9691
- Abrahimi P, Chang WG, Kluger MS, Qyang Y, Tellides G, Saltzman WM, Pober JS. Efficient gene disruption in cultured primary human endothelial cells by CRISPR/Cas9. Circ Res. 2015;117:121-128.
- Clark P, Kim RK, Pober JS, Kluger MS. Tumor necrosis factor disrupts claudin-5 endothelial tight junction barriers in two distinct NF-kappa B-dependent phases. PLoSOne 2015;10:e0120075.
- Yao Y, Liu R, Shin MS, Trentalange M, Allore H, Nassar A, Kang I, Pober JS, Montgomery RR. CyTOF supports efficient detection of immune cell subsets from small samples. J Immunol Methods 2014; 415:1-5.
- Wang J, Al-Lamki RS, Zhu X, Liu H, Pober JS, Bradley JR. TL1-A can engage death receptor-3 and activate NF-kappa B in endothelial cells. BMC Nephrol 2014; 15:178.
- Chang WG, Fornoni A, Tietjen G, Mendez JJ, Nicklason LE, Saltzman WM, Pober JS. Tissue- engineered microvasculature to perfuse isolated renal glomeruli. Tissue Eng Part A 2015; (Epub ahead of print)
- Manes T, Pober JS. Polarized granzyme release is required for antigen-driven transendothelial migration of human effector memory CD4 T cells. J Immunol. 2014; 193:5809-5815.
- Wang C, Qin L, Manes TD, Kirkiles-Smith NC, Tellides G, Pober JS. Rapamycin antagonizesTNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2. J Exp Med. 2014;211:395-404.
- Spock CL, Tom LK, Canadas K, Sue GR, Sawh-Martinez R, Maier CL, Pober JS, Galan A, Schultz B, Waner M, Narayan D, Licinio J, Wong ML. Infantile hemangiomas exhibit neural crest and pericyte markers. Annals of Plastic Surgery 2015; 74:230-236.
- Lauridsen H, Pober JS, Gonzalez AL. A composite model of the human postcapillary venule for investigation of microvascular leukocyte recruitment. FASEB J. 2014; 28:1166-1180.
- Devalliere J, Chang WG, Andrejecsk JW, Abrahimi P, Cheng CJ, Jane-wit D, Saltzman WM, Pober, JS. Sustained delivery of proangiogenic microRNA-132 by nanoparticle transfection improves endothelial cell transplantation. FASEB J. 2014: 28:908-922.
- Chang WG, Andrejecsk JW, Saltzman WM, Pober JS. Pericytes modulate endothelial sprouting. Cardiovasc Res. 2013; 100:492-500.
- Jane-wit D, Manes TD, Yi T, Qin L, Clark P, Kirkiles-Smith NC, Abrahimi P, Devalliere J, Moeckel G, Kulkarni S, Tellides G, Pober JS. Alloantibody and complement promote T cell-Mediated cardiac allograft vasculopathy through non-canonical NF-κB signaling in endothelial Cells. Circulation 2013; 128:2504-2516.
- Andrejecsk JW, Cui J, Chang WG, Devalliere J, Pober JS, Saltzman WM. Exchanges of molecular signals between alginate-encapsulated pericytes and freely suspended endothelial cells within a 3D protein gel. Biomaterials 2013; 34:8699-8908.