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Regulatory B cell in transplantation

Jesus Duque-Afonso, Chiou-Hong Lin, Kyuho Han, Michael C Wei, Jue Feng, Jason Kurzer, Corina Schneidawind, Stephen H K Wong, Michael C Bassik, Michael L Cleary
There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL which result in hyperactivation of the key oncogenic effector enzyme PLCγ2...
October 7, 2016: Cancer Research
M Marchetti, G Barosi, F Cervantes, G Birgegård, M Griesshammer, C Harrison, R Hehlmann, J-J Kiladjian, N Kröger, M F McMullin, F Passamonti, A Vannucchi, T Barbui
Ruxolitinib is an oral JAK1/JAK2 inhibitor approved for the treatment of patients with myelofibrosis (MF) based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of three clinical outcomes: a) splenomegaly, b) disease-related symptoms, and c) survival...
October 14, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Xin-Guang Liu, Yu Liu, Feng Chen
Soluble fibrinogen-like protein 2 (sFGL2) is the soluble form of fibrinogen-like protein 2 belonging to the fibrinogen-related protein superfamily. It is now well characterized that sFGL2 is mainly secreted by regulatory T cell (Treg) populations, and exerts potently immunosuppressive activities. By repressing not only the differentiation and proliferation of T cells but also the maturation of dendritic cells (DCs), sFGL2 acts largely as an immunosuppressant. Moreover, sFGL2 also induces apoptosis of B cells, tubular epithelial cells (TECs), sinusoidal endothelial cells (SECs), and hepatocytes...
October 8, 2016: Oncotarget
Geothy Chakupurakal, María Alejandra Garcia-Marquez, Alexander Shimabukuro-Vornhagen, Sandra Kluth, Hans Schlosser, Sebastian Theurich, Christof Scheid, Michael Hallek, Udo Holtick, Michael von Bergwelt-Baildon
OBJECTIVE: The role of B-cells and the subgroup of IL-10 producing B-cells, known to have a regulatory function, in patients following a haematopoetic stem cell transplant (alloSCT) has not been clearly understood to date. METHODS: We prospectively recruited 95 patients following an alloSCT and studied the B-cell reconstitution on days 30, 90 and 150. Regulatory B10-cells could be analysed in 22 consecutively recruited patients on day 30 post transplant. RESULTS: The total B-cell percentages in transplant recipients (median 0...
September 26, 2016: European Journal of Haematology
Yao Qin, Mei Zhang, Rui-Mei Jiang, Qian Wu, Xin-Yu Xu, Heng Chen, Tao Yang
Recently, pancreatic islet transplantation has been shown to be a viable option for the treatment of type 1 diabetes mellitus. However, immune destruction becomes the major impediment to the clinical application of islet transplantation. Here, we evaluated changes affecting multiple types of immune cells and cytokines in allogeneic islet transplantation immunity after the administration of B10 cells alone and explored the regulatory mechanisms of B10 cells in T cell-mediated allograft rejection. In vitro assays, B10 cells significantly decreased the proliferative capacity of CD4(+)CD25(-) T cells (13...
September 19, 2016: Cellular Immunology
Sindhu Chandran, Sandy Feng
PURPOSE OF REVIEW: The attainment of tolerance remains a highly desirable goal in recipients of kidney transplants. Achievement of this goal would extend graft survival and eradicate toxicities related to long-term immunosuppression. Understanding mechanisms of tolerance and strategies to induce tolerance - their risk/benefit profiles - is essential for future success. RECENT FINDINGS: Mechanistic studies of spontaneously tolerant kidney transplant recipients have uncovered potential roles for B or regulatory T cells, or both, in the maintenance of tolerance...
November 2016: Current Opinion in Nephrology and Hypertension
Rie Sano, Tamiko Nakajima, Yoichiro Takahashi, Rieko Kubo, Momoko Kobayashi, Keiko Takahashi, Haruo Takeshita, Kenichi Ogasawara, Yoshihiko Kominato
The human ABO blood group system is of great importance in blood transfusion and organ transplantation. The ABO system is composed of complex carbohydrate structures that are biosynthesized by A- and B-transferases encoded by the ABO gene. However, the mechanisms regulating ABO gene expression in epithelial cells remain obscure. On the basis of DNase I-hypersensitive sites in and around ABO in epithelial cells, we prepared reporter plasmid constructs including these sites. Subsequent luciferase assays and histone modifications indicated a novel positive regulatory element, designated the +22...
September 1, 2016: Journal of Biological Chemistry
Tobias Alexander, Renate Arnold, Falk Hiepe, Andreas Radbruch
Over the past 20 years, immunoablation followed by transplantation of autologous haematopoietic stem cells (ASCT) has emerged as a promising treatment option for patients with severe forms of autoimmune diseases (ADs) that insufficiently respond to standard immunosuppressive or novel biologic treatment. Meanwhile, mechanistic studies have provided the proof-of-concept that the long-term, treatment-free remissions achieved by ASCT are associated with the eradication of the autoreactive immunologic memory and a fundamental reconfiguration of the immune system...
July 2016: Clinical and Experimental Rheumatology
Jiyan Su, Qingfeng Xie, Yang Xu, Xian C Li, Zhenhua Dai
CD8(+) T cells are regulatory T cells (Tregs) that suppress both alloimmunity and autoimmunity in many animal models. This class of regulatory cells includes the CD8(+)CD28(-), CD8(+)CD103(+), CD8(+)FoxP3(+) and CD8(+)CD122(+) subsets. The mechanisms of action of these regulatory cells are not fully understood; however, the secretion of immunosuppressive cytokines, such as interleukin (IL)-4, IL-10 and transforming growth factor beta (TGF-β) as well as the direct killing of target cells via Fas L/Fas and the perforin/granzyme B pathways have been demonstrated in various models...
2014: Burns and trauma
Daniel N Mori, Hua Shen, Anjela Galan, Daniel R Goldstein
Organ transplantation in older people is increasing, but how aging impacts B-cell responses to organ transplantation is still unknown. Here, we show that the depletion of B-cells with anti-CD20 antibodies has disparate effects depending on recipient age. In young murine recipients, anti-CD20 treatment impaired the ability of immune modulation to extend skin allograft survival. In contrast, anti-CD20 treatment extended allograft survival in aged recipients treated with immune modulation. Although regulatory B-cell function and the numbers of marginal and follicular B cells were similar between age groups, a subpopulation of B cells, termed age-associated B cells (ABCs), accumulated upon aging...
August 22, 2016: European Journal of Immunology
Hai-Ying Zhang, Qiang Zhao, Tao Wu
Graft versus host disease (GVHD) is the major complication of allogenic hematopoietic stem cell transplantation (allo-HSCT), and is a mainly responsible result for the non-recurrence-related mortality of long-term survived patient after transplantation. Studies indicated that regulatory T (Treg) cells can inhibit early-GVHD. Since the transcriptional factor NF-κB has been implicated in the regulation of Treg cell proliferation and activation, it becomes a potential target of GVHD therapy. Thus, in this review the function and signaling pathway of NF-κB, as well as the relationship between GVHD and NF-κB, are discussed and summarized...
August 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
Martin Chopra, Marlene Biehl, Tim Steinfatt, Andreas Brandl, Juliane Kums, Jorge Amich, Martin Vaeth, Janina Kuen, Rafaela Holtappels, Jürgen Podlech, Anja Mottok, Sabrina Kraus, Ana-Laura Jordán-Garrote, Carina A Bäuerlein, Christian Brede, Eliana Ribechini, Andrea Fick, Axel Seher, Johannes Polz, Katja J Ottmüller, Jeanette Baker, Hidekazu Nishikii, Miriam Ritz, Katharina Mattenheimer, Stefanie Schwinn, Thorsten Winter, Viktoria Schäfer, Sven Krappmann, Hermann Einsele, Thomas D Müller, Matthias J Reddehase, Manfred B Lutz, Daniela N Männel, Friederike Berberich-Siebelt, Harald Wajant, Andreas Beilhack
Donor CD4(+)Foxp3(+) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT [allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology...
August 22, 2016: Journal of Experimental Medicine
M Kouwenberg, C W M Jacobs, J van der Vlag, L B Hilbrands
INTRODUCTION: Tolerogenic dendritic cells (DCs) have the potential to prolong graft survival after transplantation. Tolerogenic DCs are in general characterized by a low expression of co-stimulatory molecule and a high IL-10:IL-12 production ratio. Based on promising results with earlier used alternatively activated DCs, we aimed to generate in culture potentially tolerogenic DC by simultaneously blocking GSK3 by lithium chloride (LiCl) and stimulating TLR2 by PAM3CysSerLys4. MATERIALS AND METHODS: Bone marrow-derived LiClPAM3 DCs were generated by the addition of LiCl 24 hours before harvesting, and one hour later PAM3CysSerLys4...
2016: PloS One
William J Burlingham, Ewa Jankowska-Gan, Steve Kempton, Lynn Haynes, Dixon B Kaufman
UNLABELLED: Naturally acquired immune regulation amongst family members can result in mutual regulation between living related renal transplant donor and recipients. Pretransplant bidirectional regulation predisposed to superior renal allograft outcome in a CAMPATH-1H protocol. We tested whether Rhesus macaques, a large animal model of choice for preclinical transplant studies, share these immunoregulatory properties. METHODS: Antigen-specific linked suppression was measured by trans vivo delayed-type hypersensitivity [tvDTH] response...
July 2015: Transplantation Direct
Ludovic Belle, Kimberle Agle, Vivian Zhou, Cheng Yin-Yuan, Richard Komorowski, Daniel Eastwood, Brent Logan, Jie Sun, Nico Ghilardi, Daniel Cua, Calvin B Williams, Melanie Gaignage, Reece Marillier, Jacques van Snick, William R Drobyski
Re-establishment of competent regulatory pathways has emerged as a strategy to reduce the severity of graft versus host disease (GVHD), and re-calibrate the effector and regulatory arms of the immune system. However, clinically feasible, cost effective strategies that do not require extensive ex vivo cellular manipulation have remained elusive. In the current study, we demonstrate that inhibition of the interleukin 27p28 (IL-27p28) signaling pathway through antibody blockade or genetic ablation prevented lethal GVHD in multiple murine transplant models...
August 3, 2016: Blood
Kiyohiko Hotta, Akihiro Aoyama, Tetsu Oura, Yohei Yamada, Makoto Tonsho, Kyu Ha Huh, Kento Kawai, David Schoenfeld, James S Allan, Joren C Madsen, Gilles Benichou, Rex-Neal Smith, Robert B Colvin, David H Sachs, A Benedict Cosimi, Tatsuo Kawai
Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen...
July 7, 2016: JCI Insight
Sun Hwa Kim, Amitabh Das, Jin Choul Chai, Bert Binas, Mi Ran Choi, Kyoung Sun Park, Young Seek Lee, Kyoung Hwa Jung, Young Gyu Chai
Due to their multipotentiality and immunomodulation, human mesenchymal stem cells (hMSCs) are widely studied for the treatment of degenerative and inflammatory diseases. Transplantation of hMSCs to damaged tissue is a promising approach for tissue regeneration. However, the physiological mechanisms and regulatory processes of MSC trafficking to injured tissue are largely unexplored. Here, we evaluated the gene expression profile and migratory potential of hMSCs upon stimulation with the TLR4 ligand lipopolysaccharide (LPS)...
2016: Scientific Reports
Anushruti Sarvaria, Rafet Basar, Rohtesh S Mehta, Hila Shaim, Muharrem Muftuoglu, Ahmad Khoder, Takuye Sekine, Elif Gokdemir, Kayo Kondo, David Marin, May Daher, Amin M Alousi, Abdullah Alsuliman, Enli Liu, Betul Oran, Amanda Olson, Roy B Jones, Uday Popat, Chitra Hosing, Richard Champlin, Elizabeth J Shpall, Katayoun Rezvani
Cord blood (CB) offers a number of advantages over other sources of hematopoietic stem cells, including a lower rate of chronic graft-versus-host disease (cGVHD) in the presence of increased HLA disparity. Recent research in experimental models of autoimmunity and in patients with autoimmune or alloimmune disorders has identified a functional group of interleukin-10 (IL-10)-producing regulatory B cells (Bregs) that negatively regulate T-cell immune responses. At present, however, there is no consensus on the phenotypic signature of Bregs, and their prevalence and functional characteristics in CB remain unclear...
September 8, 2016: Blood
Lei Gao, Yanqi Zhang, Baoyang Hu, Jia Liu, Peiyan Kong, Shifeng Lou, Yi Su, Tonghua Yang, Huimin Li, Yao Liu, Cheng Zhang, Li Gao, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, Xi Zhang
PURPOSE: Although mesenchymal stromal cells (MSCs) possess immunomodulatory properties and exhibit promising efficacy against chronic graft-versus-host disease (cGVHD), little is known about the efficacy of MSCs in the prophylaxis of cGVHD after HLA-haploidentical hematopoietic stem-cell transplantation (HLA-haplo HSCT). PATIENTS AND METHODS: In this multicenter, double-blind, randomized controlled trial, we investigated the incidence and severity of cGVHD among patients, and the changes in T, B, and natural killer (NK) cells after the repeated infusion of MSCs...
August 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Cameron McDonald-Hyman, Ryan Flynn, Angela Panoskaltsis-Mortari, Nicholas Peterson, Kelli P A MacDonald, Geoffrey R Hill, Leo Luznik, Jonathan S Serody, William J Murphy, Ivan Maillard, David H Munn, Laurence A Turka, John Koreth, Corey S Cutler, Robert J Soiffer, Joseph H Antin, Jerome Ritz, Bruce R Blazar
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions...
August 18, 2016: Blood
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