22 results on '"Haroon, Shaikh"'
Search Results
2. ROCKETS – a novel one-for-all toolbox for light sheet microscopy in drug discovery
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Joerg P. J. Mueller, Michael Dobosz, Nils O’Brien, Nassri Abdoush, Anna Maria Giusti, Martin Lechmann, Franz Osl, Ann-Katrin Wolf, Estibaliz Arellano-Viera, Haroon Shaikh, Markus Sauer, Andreas Rosenwald, Frank Herting, Pablo Umaña, Sara Colombetti, Thomas Pöschinger, and Andreas Beilhack
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imaging ,immunotherapy ,preclinical drug development ,biodistribution ,cancer ,light sheet fluorescence microscopy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Advancing novel immunotherapy strategies requires refined tools in preclinical research to thoroughly assess drug targets, biodistribution, safety, and efficacy. Light sheet fluorescence microscopy (LSFM) offers unprecedented fast volumetric ex vivo imaging of large tissue samples in high resolution. Yet, to date laborious and unstandardized tissue processing procedures have limited throughput and broader applications in immunological research. Therefore, we developed a simple and harmonized protocol for processing, clearing and imaging of all mouse organs and even entire mouse bodies. Applying this Rapid Optical Clearing Kit for Enhanced Tissue Scanning (ROCKETS) in combination with LSFM allowed us to comprehensively study the in vivo biodistribution of an antibody targeting Epithelial Cell Adhesion Molecule (EpCAM) in 3D. Quantitative high-resolution scans of whole organs did not only reveal known EpCAM expression patterns but, importantly, uncovered several new EpCAM-binding sites. We identified gustatory papillae of the tongue, choroid plexi in the brain and duodenal papillae as previously unanticipated locations of high EpCAM expression. Subsequently, we confirmed high EpCAM expression also in human tongue and duodenal specimens. Choroid plexi and duodenal papillae may be considered as particularly sensitive sites due to their importance for liquor production or as critical junctions draining bile and digestive pancreatic enzymes into the small bowel, respectively. These newly gained insights appear highly relevant for clinical translation of EpCAM-addressing immunotherapies. Thus, ROCKETS in combination with LSFM may help to set new standards for preclinical evaluation of immunotherapeutic strategies. In conclusion, we propose ROCKETS as an ideal platform for a broader application of LSFM in immunological research optimally suited for quantitative co-localization studies of immunotherapeutic drugs and defined cell populations in the microanatomical context of organs or even whole mice.
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- 2023
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3. Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells
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Haroon Shaikh, Joern Pezoldt, Zeinab Mokhtari, Juan Gamboa Vargas, Duc-Dung Le, Josefina Peña Mosca, Estibaliz Arellano Viera, Michael A.G. Kern, Caroline Graf, Niklas Beyersdorf, Manfred B. Lutz, Angela Riedel, Maike Büttner-Herold, Alma Zernecke, Hermann Einsele, Antoine-Emmanuel Saliba, Burkhard Ludewig, Jochen Huehn, and Andreas Beilhack
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Hematology ,Transplantation ,Medicine - Abstract
Acute graft versus host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) inflicted by alloreactive T cells primed in secondary lymphoid organs (SLOs) and subsequent damage to aGvHD target tissues. In recent years, Treg transfer and/or expansion has emerged as a promising therapy to modulate aGvHD. However, cellular niches essential for fostering Tregs to prevent aGvHD have not been explored. Here, we tested whether and to what extent MHC class II (MHCII) expressed on Ccl19+ fibroblastic reticular cells (FRCs) shape the donor CD4+ T cell response during aGvHD. Animals lacking MHCII expression on Ccl19-Cre–expressing FRCs (MHCIIΔCcl19) showed aberrant CD4+ T cell activation in the effector phase, resulting in exacerbated aGvHD that was associated with significantly reduced expansion of Foxp3+ Tregs and invariant NK T (iNKT) cells. Skewed Treg maintenance in MHCIIΔCcl19 mice resulted in loss of protection from aGvHD provided by adoptively transferred donor Tregs. In contrast, although FRCs upregulated costimulatory surface receptors, and although they degraded and processed exogenous antigens after myeloablative irradiation, FRCs were dispensable to activate alloreactive CD4+ T cells in 2 mouse models of aGvHD. In summary, these data reveal an immunoprotective, MHCII-mediated function of FRC niches in secondary lymphoid organs (SLOs) after allo-HCT and highlight a framework of cellular and molecular interactions that regulate CD4+ T cell alloimmunity.
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- 2022
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4. A decentralized multi agent ANN based control technique for operation cost optimization of isolated microgrid systems
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Ullah, Asad, Amin, Salman, Haroon, Shaikh Saaqib, Sajjad, Intisar Ali, and Shaukat, Hammad
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- 2021
5. A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity
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Juan Gamboa Vargas, Jennifer Wagner, Haroon Shaikh, Isabell Lang, Juliane Medler, Mohamed Anany, Tim Steinfatt, Josefina Peña Mosca, Stephanie Haack, Julia Dahlhoff, Maike Büttner-Herold, Carolin Graf, Estibaliz Arellano Viera, Hermann Einsele, Harald Wajant, and Andreas Beilhack
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agonist ,GvHD ,regulatory T cells ,serum retention ,TNF ,TNFR2 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity.MethodsSingle-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems.ResultsSTAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD.ConclusionsNewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD.
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- 2022
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6. Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract
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Haroon Shaikh, Juan Gamboa Vargas, Zeinab Mokhtari, Katja J. Jarick, Maria Ulbrich, Josefina Peña Mosca, Estibaliz Arellano Viera, Caroline Graf, Duc-Dung Le, Katrin G. Heinze, Maike Büttner-Herold, Andreas Rosenwald, Joern Pezoldt, Jochen Huehn, and Andreas Beilhack
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acute graft-versus host disease ,alloreactive T cells ,mesenteric lymph node ,lymph node transplantation ,mouse models ,lymph node stromal cells ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.
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- 2021
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7. Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells
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Satish Ranjan, Alexander Goihl, Shrey Kohli, Ihsan Gadi, Mandy Pierau, Khurrum Shahzad, Dheerendra Gupta, Fabian Bock, Hongjie Wang, Haroon Shaikh, Thilo Kähne, Dirk Reinhold, Ute Bank, Ana C. Zenclussen, Jana Niemz, Tina M. Schnöder, Monika Brunner-Weinzierl, Thomas Fischer, Thomas Kalinski, Burkhart Schraven, Thomas Luft, Jochen Huehn, Michael Naumann, Florian H. Heidel, and Berend Isermann
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Science - Abstract
Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.
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- 2017
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8. Photoconversion of Alloreactive T Cells in Murine Peyer’s Patches During Acute Graft-Versus-Host Disease: Tracking the Homing Route of Highly Proliferative Cells In Vivo
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Katja J. Jarick, Zeinab Mokhtari, Lukas Scheller, Julia Hartweg, Sina Thusek, Duc-Dung Le, Maria Ranecky, Haroon Shaikh, Musga Qureischi, Katrin G. Heinze, and Andreas Beilhack
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T cell migration ,acute graft-versus-host disease ,mouse models ,photoconversion ,Dendra2 ,Peyer’s patch ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The regulation of immune cell migration throughout the body is essential to warrant immunosurveillance and to maintain immune homeostasis. Marking and tracking of these cells has proven important to study mechanisms of immune cell trafficking and cell interaction in vivo. Photoconversion is a well-suited technique for intravital application because it enables contactless time- and location-specific marking of cells in the tissue without surgically manipulating the microenvironment of the cells in question. However, in dividing cells the converted fluorescent protein may decline quickly. Here, we provide a detailed description of the photoconversion technique and its applicability to tracking highly proliferating T cells from the priming site of T cell activation to peripheral target organs of effector function in a preclinical model. Dendra2+ T cells were photoconverted in the Peyer’s patches during the initiation phase of acute graft-versus-host disease (GvHD) and tracked through the mesenteric lymph nodes and the peripheral blood to the small intestine with flow cytometry and intravital two-photon microscopy. Photoconverted alloreactive T cells preserved the full proliferative capacity, homing, and migration of alloreactive T cells in the intestinal lamina propria. We conclusively proved that photoconversion of highly proliferative alloreactive T cells in the Peyer’s patches is an effective tool to study trafficking of alloreactive T cells under physiologic conditions and to GvHD target tissues. This technique can also be applied to the study of immune cell tracking under inflammatory and non-inflammatory conditions.
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- 2018
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9. Endothelial Cells Activate Alloreactive CD4+ T Cells to Initiate Acute Graft-Versus-Host Disease
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Haroon Shaikh, Juan Gamboa Vargas, Zeinab Mokhtari, Josefina Peña Mosca, Joern Pezoldt, Hermann Einsele, Jochen Huehn, and Andreas Beilhack
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
10. Harnessing the Expression of TNFR2 on Tregs to Prevent Agvhd
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Juan Gamboa Vargas, Carla Kanzler, Lukas Scheller, Jennifer Kreckel, Haroon Shaikh, Isabell Lang, Juliane Medler, Mohamed Anany, Tim Steinfatt, Julia Hartweg, Stefanie Haack, Ernst Holler, Maike Büttner-Herold, Paula Tabares Gaviria, Harald Wajant, Andreas Beilhack, and Hermann Einsele
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
11. GVHD: pDCs providing VIP protection
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Haroon Shaikh and Andreas Beilhack
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Immunology ,Graft vs Host Disease ,Humans ,Transplantation, Homologous ,Dendritic Cells ,Cell Biology ,Hematology ,Biochemistry ,Tissue Donors ,Vasoactive Intestinal Peptide - Published
- 2022
12. Optimal Solution of Reactive Power Dispatch in Transmission System to Minimize Power Losses Using Sine-Cosine Algorithm
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Saddique, Muhammad Shahzar, primary, Habib, Salman, additional, Haroon, Shaikh Saaqib, additional, Bhatti, Abdul Rauf, additional, Amin, Salman, additional, and Ahmed, Emad M., additional
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- 2022
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13. Lymphatic migration of unconventional T cells promotes site-specific immunity in distinct lymph nodes
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Marco A. Ataide, Konrad Knöpper, Paulina Cruz de Casas, Milas Ugur, Sarah Eickhoff, Mangge Zou, Haroon Shaikh, Apurwa Trivedi, Anika Grafen, Tao Yang, Immo Prinz, Knut Ohlsen, Mercedes Gomez de Agüero, Andreas Beilhack, Jochen Huehn, Mauro Gaya, Antoine-Emmanuel Saliba, Georg Gasteiger, Wolfgang Kastenmüller, Centre d'Immunologie de Marseille - Luminy (CIML), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Mice, Inbred C57BL ,Disease Models, Animal ,Mice ,Infectious Diseases ,T-Lymphocytes ,[SDV]Life Sciences [q-bio] ,Immunology ,Immunity ,Receptors, Antigen, T-Cell ,Animals ,Immunology and Allergy ,Mice, Transgenic ,Lymph Nodes - Abstract
Lymphatic transport of molecules and migration of myeloid cells to lymph nodes (LNs) continuously inform lymphocytes on changes in drained tissues. Here, using LN transplantation, single-cell RNA-seq, spectral flow cytometry, and a transgenic mouse model for photolabeling, we showed that tissue-derived unconventional T cells (UTCs) migrate via the lymphatic route to locally draining LNs. As each tissue harbored a distinct spectrum of UTCs with locally adapted differentiation states and distinct T cell receptor repertoires, every draining LN was thus populated by a distinctive tissue-determined mix of these lymphocytes. By making use of single UTC lineage-deficient mouse models, we found that UTCs functionally cooperated in interconnected units and generated and shaped characteristic innate and adaptive immune responses that differed between LNs that drained distinct tissues. Lymphatic migration of UTCs is, therefore, a key determinant of site-specific immunity initiated in distinct LNs with potential implications for vaccination strategies and immunotherapeutic approaches.
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- 2022
14. Probabilistic Generation Model of Solar Irradiance for Grid Connected Photovoltaic Systems Using Weibull Distribution
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Afzaal, Muhammad Umar, primary, Sajjad, Intisar Ali, additional, Awan, Ahmed Bilal, additional, Paracha, Kashif Nisar, additional, Khan, Muhammad Faisal Nadeem, additional, Bhatti, Abdul Rauf, additional, Zubair, Muhammad, additional, Rehman, Waqas ur, additional, Amin, Salman, additional, Haroon, Shaikh Saaqib, additional, Liaqat, Rehan, additional, Hdidi, Walid, additional, and Tlili, Iskander, additional
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- 2020
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15. The Penetration of Renewable and Sustainable Energy in Asia: A State-of-the-Art Review on Net-Metering
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Rehman, Waqas Ur, primary, Bhatti, Abdul Rauf, additional, Awan, Ahmed Bilal, additional, Sajjad, Intisar Ali, additional, Khan, Asad Ali, additional, Bo, Rui, additional, Haroon, Shaikh Saaqib, additional, Amin, Salman, additional, Tlili, Iskander, additional, and Oboreh-Snapps, Oroghene, additional
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- 2020
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16. Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells
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Dheerendra Gupta, Tina M. Schnöder, Thilo Kähne, Satish Ranjan, Thomas Luft, Jana Niemz, Dirk Reinhold, Shrey Kohli, Haroon Shaikh, Jochen Huehn, Berend Isermann, Hongjie Wang, Alexander Goihl, Florian H. Heidel, Burkhart Schraven, Ihsan Gadi, Thomas Kalinski, Ute Bank, Fabian Bock, Mandy Pierau, Khurrum Shahzad, Michael Naumann, Ana Claudia Zenclussen, Thomas Fischer, Monika C. Brunner-Weinzierl, and Helmholtz Centre for infection research GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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0301 basic medicine ,medicine.medical_treatment ,Graft vs Host Disease ,General Physics and Astronomy ,Kaplan-Meier Estimate ,Mice, SCID ,Hematopoietic stem cell transplantation ,T-Lymphocytes, Regulatory ,0302 clinical medicine ,immune system diseases ,Mice, Inbred NOD ,Mice, Knockout ,Mice, Inbred BALB C ,Mice, Inbred C3H ,Multidisciplinary ,Hematopoietic Stem Cell Transplantation ,FOXP3 ,Acquired immune system ,Haematopoiesis ,Graft-versus-host disease ,Allotransplantation ,CD4-positive T cells ,surgical procedures, operative ,Signal Transduction ,medicine.drug ,Science ,Receptors, Proteinase-Activated ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Thrombomodulin ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,medicine ,Animals ,Humans ,Receptor, PAR-2 ,Transplantation, Homologous ,business.industry ,General Chemistry ,Mice, Inbred C57BL ,Transplantation ,030104 developmental biology ,Immunology ,Receptors, Thrombin ,Protein Multimerization ,business ,Ex vivo ,Protein C ,030215 immunology - Abstract
Graft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4+FOXP3+). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4−CD4+) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD., Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.
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- 2017
17. MHC Class II on Ccl19+ Reticular Cells Mitigates Graft-Versus-Host Disease Via Maintenance of Regulatory T Cells
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Duc Dung Le, Juan Gamboa Vargas, Muhammad Haroon Shaikh, Josefina Peña Mosca, Andreas Beilhack, Burkhard Ludewig, and Hermann Einsele
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MHC class II ,Graft-versus-host disease ,biology ,Reticular cell ,Immunology ,CCL19 ,biology.protein ,medicine ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Cell biology - Abstract
Allogeneic T cell priming is considered as an essential event determining the outcome of allogeneic hematopoietic stem cell transplantation (allo-HCT), ideally triggering anti-leukemic responses (GvL effect) or, at worst, causing life-threatening acute graft-versus-host disease (aGvHD). During aGvHD initiation, alloreactive T cells are activated by host antigen presenting cells (APCs), rapidly expand and subsequently exert tissue damage. Recently, it was discovered that in absence of host hematopoietic APCs, aGvHD cannot be prevented, suggesting a crucial role of non-hematopoietic APCs for priming alloreactive T cells (Toubai et al., Blood 2012, Li et al., J Immunol. 2012, Koyama et al., Nat Med 2012). However, the exact location and identity of host non-hematopoietic APCs triggering alloreactive T cell responses remains controversial and needs to be proven in vivo. Fibroblastic reticular cells (FRCs) have shown to provide the crucial delta-like notch ligand to alloreactive T cells (Chung et al., JCI 2017) in aGvHD, therefore we investigated the role of FRCs MHC class II in aGvHD and their potential role as non-hematopoietic APCs in MHC class II dependent manner. In vitro cultured FRCs cell line as well as FRCs from lethally irradiated mice upregulate MHCII and co-stimulatory molecules. Moreover, FACS sorted FRCs (CD45-CD24-CD31-gp38+) were able to process DQ-OVA via MHC class II machinery, indicating that FRCs have the potential to activate CD4+ T cells. Employing allo-HCT mouse models in combination with flow cytometry and advanced microscopy techniques, we explored early alloreactive T cells activation initially in a myeloablatively conditioned MHC major mismatch allo-HCT setting (FVB/NàC57Bl/6). We generated MHCIIΔCcl19 mice with a Ccl19-intrinsic deletion of MHC class II on all Ccl19 expressing reticular lineage cells by crossing mice with floxed H2-Ab1 gene (H2-Ab1fl) with a mouse expressing Cre recombinase under the control of the Ccl19 promoter (Ccl19Cre). On day+3 after allo-HCT, CD4+ T cells activation (CD44 and CD25 expression) and proliferation (Ki67 expression and CFSE dilution) did not differ in the MHCIIΔCcl19 mice from H2-Ab1fl wildtype littermates. To further elucidate FRCs MHC class II in aGvHD milieu, we utilized iFABP-tOVA transgenic model in which OVA is expressed by intestinal epithelial cells as well as ectopically by FRCs of the lymphoid organs. OT-II cells transferred from RagΔ background mice failed to proliferate in the mLNs of lethally irradiated iFABP-tOVA, whereas excessive proliferation was observed in CD11c.DOG mice (where OVA is presented by CD11c-expressing cells). Taken together these results indicate that MHCII on FRCs does not play a role in direct antigen presentation and CD4+ T cell activation. Next, we asked whether MHCII on FRCs influences alloreactivity of CD4+ T cells in the symptomatic phase of aGvHD. Indeed, in MHCIIΔCcl19 mice, CD4+ T cells expressed higher levels of effector molecules: CD44 and CD127 as well as the proliferation marker Ki67 on day +30 of allo-HCT. Furthermore, the proportion of donor CD90.1+CD4+FoxP3+ regulatory T cells (Tregs) were reduced in MHCIIΔCcl19 mice as compared to H2-Ab1fl wild-type littermates. This led to overall poor survival of MHCIIΔCcl19 mice by day+60 after allo-HCT. At this time point in MHCIIΔCcl19 mice CD4+ T cells displayed higher levels of CD44, CD127 and Ki67 and down-regulated PD-1 and Lag3. To further elucidate the effect of FRCs MHC class II on CD4+FoxP3+ donor Tregs, we transplanted CD90.1+CD4+CD25hi Tregs, TCD BM from FVB mice along with naïve luc+ CD90.1+CD4+ T cells from FVB.L2G85 mice. Tregs protected against aGvHD in H2-Ab1fl littermate controls whereas Tregs could not protect MHCIIΔCcl19 recipients rendering them susceptible to aGvHD and to poor overall survival. Conclusively, these results indicate for the first time that MHC class II on FRCs assists to maintain donor Tregs in the SLOs after allo-HCT. Conclusively, we propose a model in which FRCs promote T cell alloreactivity by providing notch ligands (Chung et al., JCI 2017) in the initiation phase and mitigate aGvHD by maintenance of Tregs via MHC class II in the aGvHD-effector phase. Disclosures Einsele: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau.
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- 2020
18. Non-Hematopoietic Lymphoid Stromal Cells Prime Alloreactive CD4+ T Cells in Acute Graft-Versus-Host Disease
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Muhammad Haroon Shaikh, Zeinab Mokthari, Katja J. Ottmüller, Maria Ulbrich, Andreas Beilhack, Burkhard Ludewig, Hermann Einsele, Duc Dung Le, Juan Gamboa Vargas, Joern Pezoldt, and Jochen Huehn
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MHC class II ,Lymphocyte ,T cell ,Immunology ,Antigen presentation ,Priming (immunology) ,Cell Biology ,Hematology ,Biology ,Biochemistry ,medicine.anatomical_structure ,medicine ,Lymph node stromal cell ,biology.protein ,Antigen-presenting cell ,CD8 - Abstract
Allogeneic T cell priming is considered as an essential event determining the outcome of allogeneic hematopoietic stem cell transplantation (allo-HCT), ideally triggering anti-leukemic responses (GvL effect) or, at worst, causing life-threatening acute graft-versus-host disease (aGvHD). During acute GvHD initiation, alloreactive T cells are activated by host antigen presenting cells (APCs), rapidly expand and subsequently exert tissue damage. Recently, it was discovered that absence of host hematopoietic APCs does not prevent acute GvHD, suggesting a crucial role of non-hematopoietic APCs for priming alloreactive T cells (Toubai et al., Blood 2012, Li et al., J Immunol. 2012). Furthermore, it was even suggested that in the absence of professional APCs allogeneic CD4+ T cells can be activated in the lamina propria by MHC class II expressing myofibroblasts (Koyama et al., Nat Med 2012). As exact location and identity of host non-hematopoietic APCs triggering alloreactive T cell responses are essential to dissect the priming of GvHD-inducing vs. GvL-mediating allogeneic T cells, we investigated the role of lymph node stromal cells (LNSCs) in the initiation phase of aGvHD and their potential role as non-hematopoietic APCs. Employing allo-HCT mouse models in combination with flow cytometry and advanced microscopy techniques, we explored early alloreactive T cells activation first in a myeloablatively conditioned MHC major mismatch allo-HCT setting (FVB→B6). Under these conditions, CD4+ and CD8+ T cells activation and proliferation occurred exclusively in secondary lymphoid organs (SLOs) and not in the intestinal lamina propria early after allo-HCT within the first three days after allo-HCT. To study non-hematopoietic antigen presentation early after allo-HCT, we generated bone marrow B6.MHCIIΔ/Δ→B6.WT chimeras that lacked MHC II expression in the host hematopoietic compartment. Subsequent allo-HCT of these chimeras revealed activation and expansion of allogenic donor CD4+ T-cells exclusively in SLOs and not the lamina propria in the first three days after transplantation. Next, we generated recipient mice that selectively lacked MHCII expression either in CD11c expressing cells or under the control of the Vav1-promoter in all hematopoietic cells. In both type of recipients, allogenic donor CD4+ T-cells were activated within 3 days after allo-HCT in SLOs and no other tissues. After irradiation of B6.WT mice we observed LNSCs upregulate co-stimulatory receptors early after irradiation (24 and 72 hours), in vitro and in vivo suggesting that they may act as active non-hematopoietic APCs. Next, we performed mixed lymphocyte reactions (MLRs) of irradiated APCs derived from TgVav1-Cre+MHCIIΔ/Δmice with alloreactive CD4+ T cells from FVB mice. Here, we observed in the total absence of hematopoietic MHCII antigen presentation reduced but still pronounced activation of alloreactive CD4+ T cells. Therefore, in these transgenic allo-HCT models, hematopoietic cells in the SLOs were dispensable for alloreactive CD4+ T cell activation in the initiation phase of aGvHD. To ascertain that SLOs are the exclusive priming sites of alloreactive CD4+ T cells, we transplanted mesenteric lymph nodes (mLNs) from a B6.CD11c.DTR mice, depleted of CD11c+ cells into B6.MHCIIΔ/Δmice. After successful engraftment of donor mLNs in these mice, allo-HCT revealed these as unique priming sites in MHCII deficient hosts for alloreactive CD4+ T cells, which differentiated into CD44hiCD62Llow effector T cells that were detectable in the transplanted mLNs. Conclusively, these results indicate that specialized non-hematopoietic lymph node stromal cells prime alloreactive CD4+ T cell within the SLOs early after allo-HCT. Pinpointing the molecular pathways in these non-hematopoietic APCs within SLOs that trigger alloreactive T cell responses may prove fruitful for selective therapeutic intervention after allo-HCT. Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
19. Tissue Derived Non-Classical Monocyte Derived Host Macrophages Protect Against Murine Intestinal Acute Graft-Versus-Host Disease
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Christian Brede, Natalio Garbi, Julia Hartweg, Antoine-Emmanuel Saliba, Lukas Scheller, Duc Dung Le, Amy J. Wagers, Ana-Laura Jordán Garrote, Ehsan Vafadarnejad, Andreas Beilhack, Tim Steinfatt, Haroon Shaikh, Carina A. Bäuerlein, Simone S. Riedel, Ranecky Maria, Andreas Brandl, Nageswara Rao Tata, Manfred B. Lutz, Katja J. Ottmüller, Musga Qureischi, Hermann Einsele, and Anja Mottok
- Subjects
Lamina propria ,Adoptive cell transfer ,medicine.medical_treatment ,T cell ,Immunology ,Priming (immunology) ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Haematopoiesis ,medicine.anatomical_structure ,Cytokine ,medicine ,Bone marrow ,Antigen-presenting cell - Abstract
Acute graft versus host disease (aGVHD) remains a major complication in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), the only curative treatment for many malignant hematologic diseases. After initial priming in secondary lymphoid organs, alloreactive donor T cells efficiently migrate to the intestinal tract, liver and skin. We observed that alloreactive effector T cells infiltrating and attacking the lamina propria of the small and large intestines closely interact with intestinal myeloid cells of host origin. Here we asked whether these intimate interactions regulate alloreactive effector T cell responses and how they impact intestinal aGvHD. To address these questions, we employed non-invasive bioluminescence imaging, fluorescence and confocal microscopy, clinical and histopathologic scoring, flow cytometry and single cell RNA sequencing in murine models of myeloablative, MHC-mismatched allo-HSCT. In the intestinal lamina propria, we observed that allogeneic T cells closely interacted with CD11b+CD11c+CD103- radio-resistant host type hematopoietic myeloid antigen presenting cells. Selective depletion of intestinal CD11chi or CX3CR1+CD11chi host cells 3 or 8 days after allo-HSCT accelerated alloreactive T cell infiltration, increased T cell mediated inflammatory cytokine production and exacerbated tissue damage resulting in hyperacute lethal aGvHD. These results suggested a strong immunoregulatory effect of these intestinal host-type myeloid cells. Single cell RNA-Seq analysis and flow cytometry (e.g. MHC II, CD11c, F4/80, CD26, CD64, CCR2, CX3CR1), lineage reporter- and defined knockout mice determined these cells as non-classical monocyte derived macrophages as the development and differentiation of these cells did not depend on Flt3, Zbtb46, and CCR2 but rather on CSF-1R and CX3CR1. Adoptive transfer, bone marrow chimeras and parabiosis experiments revealed that these non-classical monocyte derived macrophages differentiated from non-circulating non-classical monocytic precursors. Finally, PD-L1 expression on these intestinal host non-classical monocyte derived macrophages but not on stroma or other hematopoietic cells regulated alloreactive T cell responses in the intestinal tract. Based on these findings we postulate that a specialized and persistent subpopulation of host non-classical monocyte derived macrophages can potently suppress alloreactive T cells in the lamina propria of the intestinal tract. Fostering the differentiation and function of these tissue resident cells may represent an attractive therapeutic strategy to prevent intestinal aGvHD. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
20. Optimal Scheduling of Residential Home Appliances by Considering Energy Storage and Stochastically Modelled Photovoltaics in a Grid Exchange Environment Using Hybrid Grey Wolf Genetic Algorithm Optimizer.
- Author
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Iqbal, Muhammad Muzaffar, Sajjad, Malik Intisar Ali, Amin, Salman, Haroon, Shaikh Saaqib, Liaqat, Rehan, Khan, Muhammad Faisal Nadeem, Waseem, Muhammad, and Shah, Muhammad Athar
- Subjects
GENETIC algorithms ,HOUSEHOLD appliances ,ENERGY storage ,RENEWABLE energy sources ,SMART power grids ,PHOTOVOLTAIC power systems - Abstract
The transformation of a conventional power system to a smart grid has been underway over the last few decades. A smart grid provides opportunities to integrate smart homes with renewable energy resources (RERs). Moreover, it encourages the residential consumers to regulate their home energy consumption in an effective way that suits their lifestyle and it also helps to preserve the environment. Keeping in mind the techno-economic reasons for household energy management, active participation of consumers in grid operations is necessary for peak reduction, valley filling, strategic load conservation, and growth. In this context, this paper presents an efficient home energy management system (HEMS) for consumer appliance scheduling in the presence of an energy storage system and photovoltaic generation with the intention to reduce the energy consumption cost determined by the service provider. To study the benefits of a home-to-grid (H2G) energy exchange in HEMS, photovoltaic generation is stochastically modelled by considering an energy storage system. The prime consideration of this paper is to propose a hybrid optimization approach based on heuristic techniques, grey wolf optimization, and a genetic algorithm termed a hybrid grey wolf genetic algorithm to model HEMS for residential consumers with the objectives to reduce energy consumption cost and the peak-to-average ratio. The effectiveness of the proposed scheme is validated through simulations performed for a residential consumer with several domestic appliances and their scheduling preferences by considering real-time pricing and critical peak-pricing tariff signals. Results related to the reduction in the peak-to-average ratio and energy cost demonstrate that the proposed hybrid optimization technique performs well in comparison with different meta-heuristic techniques available in the literature. The findings of the proposed methodology can further be used to calculate the impact of different demand response signals on the operation and reliability of a power system. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
21. Short Term Economic Emission Power Scheduling of Hydrothermal Energy Systems Using Improved Water Cycle Algorithm.
- Author
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HAROON, SHAIKH SAAQIB and MALIK, TAHIR NADEEM
- Subjects
HYDROTHERMAL electric power systems ,HYDROLOGIC cycle ,SCHEDULING ,CLEAN energy ,EMISSIONS (Air pollution) ,WASTE gases ,WASTE products & the environment - Abstract
Due to the increasing environmental concerns, the demand of clean and green energy and concern of atmospheric pollution is increasing. Hence, the power utilities are forced to limit their emissions within the prescribed limits. Therefore, the minimization of fuel cost as well as exhaust gas emissions is becoming an important and challenging task in the short-term scheduling of hydro-thermal energy systems. This paper proposes a novel algorithm known as WCA-ER (Water Cycle Algorithm with Evaporation Rate) to inspect the short term EEPSHES (Economic Emission Power Scheduling of Hydrothermal Energy Systems). WCA has its ancestries from the natural hydrologic cycle i.e. the raining process forms streams and these streams start flowing towards the rivers which finally flow towards the sea. The worth of WCA-ER has been tested on the standard economic emission power scheduling of hydrothermal energy test system consisting of four hydropower and three thermal plants. The problem has been investigated for the three case studies (i) ECS (Economic Cost Scheduling), (ii) ES (Economic Emission Scheduling) and (iii) ECES (Economic Cost & Emission Scheduling). The results obtained show that WCA-ER is superior to many other methods in the literature in bringing lower fuel cost and emissions. [ABSTRACT FROM AUTHOR]
- Published
- 2017
22. Multiple Fuel Machines Power Economic Dispatch Using Stud Differential Evolution.
- Author
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Naila, Haroon, Shaikh Saaqib, Hassan, Shahzad, Amin, Salman, Sajjad, Intisar Ali, Waqar, Asad, Aamir, Muhammad, Yaqoob, Muneeb, and Alam, Imtiaz
- Subjects
- *
DIFFERENTIAL evolution , *MATHEMATICAL optimization , *HEURISTIC programming , *HYDROTHERMAL electric power systems , *ELECTRIC power production - Abstract
This paper presents an optimization method for solving the Power Economic Dispatch (PED) problem of thermal generation units with multiple fuels and valve point loadings. The proposed optimizer is a variant of Differential Evolution (DE) characterized as a Stud Differential Evolution (SDE), which has been proposed earlier and implemented on a hydrothermal energy system. In SDE, an operator named Stud Crossover (SC) is introduced in the conventional DE during the trial vector updating process. In SC operator, a best vector gives its optimal information to all other population members through mating. The proposed algorithm’s effectiveness to solve Multiple Fuel PED problem, with and without Valve Point Loading Effects (VPLEs), has been validated by testing it on 10 machine multiple fuel standard test systems having 2400 MW, 2500 MW, 2600 MW, and 2700 MW load demands. The results depict the strength of SDE over various other methods in the literature. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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