Person: Ueno, Takuya
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Ueno
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Takuya
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Ueno, Takuya
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Publication Live Images of Donor Dendritic Cells Trafficking via CX3CR1 Pathway(Frontiers Media S.A., 2016) Ueno, Takuya; Kim, Pilhan; McGrath, Martina; Yeung, Melissa; Shimizu, Tetsunosuke; Jung, Keehoon; Sayegh, Mohamed; Chandraker, Anil; Abdi, Reza; Yun, Seok H.Background: A number of studies have demonstrated the role of CX3CR1 in regulating the migration of monocytes into peripheral tissue and their transformation into dendritic cell (DC). No data are yet available on the importance of chemokine pathways in regulating homeostasis of DC in heart transplants. Recently, we showed that recipients of heart allografts from CX3CR1−/− donors show longer survival. To assess the trafficking of dDC, we have developed and tested a novel in vivo imaging tool in CX3CR1GFP/+ DC (B6 background) heart graft into BALB/c recipient model. Results: Majority of GFP+ cells were noted in the middle of cardiac myocyte. However few hours post transplant, they experienced morphological changes including stretching their extensions (3 and 24 h). However, images from 72 h at cardiac graft showed many of GFP+ cells moved to vessel areas. GFP+ cells were detected in near vessel wall. Only one GFP+ cell was observed in three lymph nodes (two mesenteric and one inguinal) (72 h). Conclusion: Our data indicate that immediately post transplant dDC undergo morphological changes and traffic out of the organs via systemic circulation. While, we still noted presence of dDC in the transplanted organs, their trafficking to lymphoid tissue remains to be fully explored.Publication The Limits of Linked Suppression for Regulatory T Cells(Frontiers Media S.A., 2016) Ito, Toshiro; Yamada, Akira; Batal, Ibrahim; Yeung, Melissa; McGrath, Martina; Sayegh, Mohamed; Chandraker, Anil; Ueno, TakuyaBackground: We have previously found that CD4+CD25+ regulatory T cells (Tregs) can adoptively transfer tolerance after its induction with costimulatory blockade in a mouse model of murine cardiac allograft transplantation. In these experiments, we tested an hypothesis with three components: (1) the Tregs that transfer tolerance have the capacity for linked suppression, (2) the determinants that stimulate the Tregs are expressed by the indirect pathway, and (3) the donor peptides contributing to these indirect determinants are derived from donor major histocompatibility complex (MHC) antigens (Ags). Methods: First heart transplants were performed from the indicated donor strain to B10.D2 recipients along with costimulatory blockade treatment (250 μg i.p. injection of MR1 on day 0 and 250 μg i.p. injection of CTLA-4 Ig on day 2). At least 8 weeks later, a second heart transplant was performed to a new B10.D2 recipient who had been irradiated with 450 cGy. This recipient was given 40 × 106 naive B10.D2 spleen cells + 40 × 106 B10.D2 spleen cells from the first (tolerant) recipient. We performed three different types of heart transplants using various donors. Results: (1) Tregs suppress the graft rejection in an Ag-specific manner. (2) Tregs generated in the face of MHC disparities suppress the rejection of grafts expressing third party MHC along with tolerant MHC. Conclusion: The limits of linkage appear to be quantitative and not universally determined by either the indirect pathway or by peptides of donor MHC Ags.Publication Ligation of the Jugular Veins Does Not Result in Brain Inflammation or Demyelination in Mice(Public Library of Science, 2012) Atkinson, Wendy; Forghani, Reza; Wojtkiewicz, Gregory R.; Pulli, Benjamin; Iwamoto, Yoshiko; Ueno, Takuya; Waterman, Peter; Truelove, Jessica; Oklu, Rahmi; Chen, JohnAn alternative hypothesis has been proposed implicating chronic cerebrospinal venous insufficiency (CCSVI) as a potential cause of multiple sclerosis (MS). We aimed to evaluate the validity of this hypothesis in a controlled animal model. Animal experiments were approved by the institutional animal care committee. The jugular veins in SJL mice were ligated bilaterally (n = 20), and the mice were observed for up to six months after ligation. Sham-operated mice (n = 15) and mice induced with experimental autoimmune encephalomyelitis (n = 8) were used as negative and positive controls, respectively. The animals were evaluated using CT venography and 99mTc-exametazime to assess for structural and hemodynamic changes. Imaging was performed to evaluate for signs of blood-brain barrier (BBB) breakdown and neuroinflammation. Flow cytometry and histopathology were performed to assess inflammatory cell populations and demyelination. There were both structural changes (stenosis, collaterals) in the jugular venous drainage and hemodynamic disturbances in the brain on \(^{99m}\)Tc-exametazime scintigraphy (p = 0.024). In the JVL mice, gadolinium MRI and immunofluorescence imaging for barrier molecules did not reveal evidence of BBB breakdown (p = 0.58). Myeloperoxidase, matrix metalloproteinase, and protease molecular imaging did not reveal signs of increased neuroinflammation (all p>0.05). Flow cytometry and histopathology also did not reveal increase in inflammatory cell infiltration or population shifts. No evidence of demyelination was found, and the mice remained without clinical signs. Despite the structural and hemodynamic changes, we did not identify changes in the BBB permeability, neuroinflammation, demyelination, or clinical signs in the JVL group compared to the sham group. Therefore, our murine model does not support CCSVI as a cause of demyelinating diseases such as multiple sclerosis.Publication CD160Ig Fusion Protein Targets a Novel Costimulatory Pathway and Prolongs Allograft Survival(Public Library of Science, 2013) D’Addio, Francesca; Ueno, Takuya; Clarkson, Michael; Zhu, Baogong; Vergani, Andrea; Freeman, Gordon; Sayegh, Mohamed; Ansari, Mohammed Javeed I.; Fiorina, Paolo; Habicht, AntjeCD160 is a cell surface molecule expressed by most NK cells and approximately 50% of CD8+ cytotoxic T lymphocytes. Engagement of CD160 by MHC class-I directly triggers a costimulatory signal to TCR-induced proliferation, cytokine production and cytotoxic effector functions. The role of CD160 in alloimmunity is unknown. Using a newly generated CD160 fusion protein (CD160Ig) we examined the role of the novel costimulatory molecule CD160 in mediating CD4+ or CD8+ T cell driven allograft rejection. CD160Ig inhibits alloreactive CD8+ T cell proliferation and IFN-γ production in vitro, in particular in the absence of CD28 costimulation. Consequently CD160Ig prolongs fully mismatched cardiac allograft survival in CD4−/−, CD28−/− knockout and CTLA4Ig treated WT recipients, but not in WT or CD8−/− knockout recipients. The prolonged cardiac allograft survival is associated with reduced alloreactive CD8+ T cell proliferation, effector/memory responses and alloreactive IFN-γ production. Thus, CD160 signaling is particularly important in CD28-independent effector/memory CD8+ alloreactive T cell activation in vivo and therefore may serve as a novel target for prevention of allograft rejection.Publication Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis(The Rockefeller University Press, 2012) Leuschner, Florian; Rauch, Philipp J.; Ueno, Takuya; Gorbatov, Rostic; Marinelli, Brett; Lee, Won Woo; Dutta, Partha; Wei, Ying; Robbins, Clinton; Iwamoto, Yoshiko; Sena, Brena; Chudnovskiy, Aleksey; Panizzi, Peter; Higgins, John; Libby, Peter; Moskowitz, Michael; Pittet, Mikael; Swirski, Filip; Weissleder, Ralph; Nahrendorf, MatthiasIL-1b signaling augments continued splenic monocyte supply during acute inflammation.