221 results found
Trento C, Bernardo ME, Nagler A, et al., 2018, Manufacturing mesenchymal stromal cells for the treatment of graft-versus-host disease: a survey among centers affiliated with the European Society for Blood and Marrow Transplantation, Biology of Blood and Marrow Transplantation, Vol: 24, Pages: 2365-2370, ISSN: 1083-8791
The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease and improve survival. However, clinical studies have not yet provided conclusive evidence of their efficacy largely because of lack of patients' stratification criteria. The heterogeneity of MSC preparations is also a major contributing factor, as manufacturing of therapeutic MSC is performed according to different protocols among different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting among different centers. In order to acquire information on MSC manufacturing we sent a questionnaire to the European Society for Blood and Marrow Transplantation centers registered as producing MSC. Data from 17 centers were obtained and analyzed by means of a 2-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex vivo expansion, and data on MSC product specification for clinical release. The majority of centers manufactured MSC from bone marrow (88%), whilst only 2 centers produced MSC from umbilical cord blood or cord tissue. One of the major changes in the manufacturing process has been the replacement of fetal bovine serum with human platelet lysate as medium supplement. 59% of centers used only third-party MSC, whilst only 1 center manufactured exclusively autologous MSC. The large majority of these facilities (71%) administered MSC exclusively from frozen batches. Aside from variations in the culture method, we found large heterogeneity also regarding product specification, particularly in the markers used for phenotypical characterization and their threshold of expression, use of potency assays to test MSC functionality, and karyotyping. The initial data collected from this survey highlight the variability in MSC manufact
Trento C, Bernardo ME, Nagler A, et al., 2018, Manufacturing Mesenchymal Stromal Cells for the Treatment of Graft-versus-Host Disease: A Survey among Centers Affiliated with the European Society for Blood and Marrow Transplantation, BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, Vol: 24, Pages: 2365-2370, ISSN: 1083-8791
Galleu A, Riffo-Vasquez Y, Trento C, et al., 2017, Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation, Science Translational Medicine, Vol: 9, ISSN: 1946-6234
The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSCs, we found a striking parallel, whereby only those with high cytotoxic activity against MSCs responded to MSC infusion, whereas those with low activity did not. The need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSCs and produce indoleamine 2,3-dioxygenase, which is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSCs or that all patients could be treated with ex vivo apoptotic MSCs.
Vallant N, Sandhu B, Trento C, et al., 2017, INVESTIGATION OF MESENCHYMAL STEM CELLS FOR PRECONDITIONING OF KIDNEY GRAFTS IN AN EX-VIVO PORCINE MODEL OF HYPOTHERMIC MACHINE PERFUSION, Publisher: WILEY, Pages: 501-501, ISSN: 0934-0874
Galleu A, Deplano S, Szydlo R, et al., 2017, MESENCHYMAL STROMAL CELLS FOR THE TREATMENT OF STEROID-RESISTANT ACUTE GRAFT VERSUS HOST DISEASE: FACTORS INFLUENCING CLINICAL RESPONSES, 22nd Congress of the European-Hematology-Association, Publisher: FERRATA STORTI FOUNDATION, Pages: 336-337, ISSN: 0390-6078
Trento C, Marigo I, Pievani A, et al., 2017, Bone marrow mesenchymal stromal cells induce nitric oxide synthase-dependent differentiation of CD11b(+) cells that expedite hematopoietic recovery, HAEMATOLOGICA, Vol: 102, Pages: 818-825, ISSN: 0390-6078
Tamaddon M, Burrows M, Ferreira SA, et al., 2017, Monomeric, porous type II collagen scaffolds promote chondrogenic differentiation of human bone marrow mesenchymal stem cells in vitro, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Osteoarthritis (OA) is a common cause of pain and disability and is often associated with the degeneration of articular cartilage. Lesions to the articular surface, which are thought to progress to OA, have the potential to be repaired using tissue engineering strategies; however, it remains challenging to instruct cell differentiation within a scaffold to produce tissue with appropriate structural, chemical and mechanical properties. We aimed to address this by driving progenitor cells to adopt a chondrogenic phenotype through the tailoring of scaffold composition and physical properties. Monomeric type-I and type-II collagen scaffolds, which avoid potential immunogenicity associated with fibrillar collagens, were fabricated with and without chondroitin sulfate (CS) and their ability to stimulate the chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells was assessed. Immunohistochemical analyses showed that cells produced abundant collagen type-II on type-II scaffolds and collagen type-I on type-I scaffolds. Gene expression analyses indicated that the addition of CS – which was released from scaffolds quickly – significantly upregulated expression of type II collagen, compared to type-I and pure type-II scaffolds. We conclude that collagen type-II and CS can be used to promote a more chondrogenic phenotype in the absence of growth factors, potentially providing an eventual therapy to prevent OA.
Giacomassi C, Buang N, Ling GS, et al., 2016, Complement C3 exacerbates imiquimod-induced skin inflammation and psoriasiform dermatitis, Journal of Investigative Dermatology, Vol: 137, Pages: 760-763, ISSN: 1523-1747
The complement system is pivotal in protection against pathogens, but also plays important roles in bridging innate and adaptive immune responses (Scott and Botto, 2015) and in modulating local and systemic inflammation (Markiewski and Lambris, 2007). Activation of complement occurs through three different pathways (classical, alternative and lectin), converges at C3 cleavage and culminates in the formation of the membrane attack complex. The anaphylotoxic fragments, C3a and C5a, generated during the proteolytic cascade, recruit immune cells that can promote the removal of debris and pathogens, but can also cause tissue damage (Markiewski and Lambris, 2007).
Sweeney NP, Regan C, Liu J, et al., 2016, Rapid and efficient stable gene transfer to mesenchymal stromal cells using a modified foamy virus vector, Molecular Therapy, Vol: 24, Pages: 1227-1236, ISSN: 1525-0024
Mesenchymal stromal cells (MSCs) hold great promise for regenerative medicine. Stable ex vivo gene transfer to MSCs could improve the outcome and scope of MSC therapy, but current vectors require multiple rounds of transduction, involve genotoxic viral promoters and/or the addition of cytotoxic cationic polymers in order to achieve efficient transduction. We describe a self-inactivating foamy virus vector (FVV), incorporating the simian macaque foamy virus envelope and using physiological promoters, which efficiently transduces murine MSCs (mMSCs) in a single-round. High and sustained expression of the transgene, whether GFP or the lysosomal enzyme, arylsulphatase A (ARSA), was achieved. Defining MSC characteristics (surface marker expression and differentiation potential), as well as long-term engraftment and distribution in the murine brain following intracerebroventricular delivery, are unaffected by FVV transduction. Similarly, greater than 95% of human MSCs (hMSCs) were stably transduced using the same vector, facilitating human application. This work describes the best stable gene transfer vector available for mMSCs and hMSCs.
Ali R, Nicholas R, Marley S, et al., 2015, Preliminary results of a phase 2 trial of autologous mesenchymal cell therapy in MS (STREAMS), 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 556-556, ISSN: 1352-4585
Mattoscio M, Nicholas R, Sormani MP, et al., 2015, Hematopoietic mobilization Potential biomarker of response to natalizumab in multiple sclerosis, NEUROLOGY, Vol: 84, Pages: 1473-1482, ISSN: 0028-3878
Giacomassi C, Ling GS, Strid J, et al., 2014, Complement C3 exacerbates skin inflammation in a murine model of imiquimod-induced psoriasis, IMMUNOLOGY, Vol: 143, Pages: 120-120, ISSN: 0019-2805
Lai P-C, Chiu L-Y, Srivastava P, et al., 2014, Unique Regulatory Properties of Mesangial Cells Are Genetically Determined in the Rat, PLOS One, Vol: 9, ISSN: 1932-6203
Mesangial cells are glomerular cells of stromal origin. During immune complex mediated crescentic glomerulonephritis (Crgn), infiltrating and proliferating pro-inflammatory macrophages lead to crescent formation. Here we have hypothesised that mesangial cells, given their mesenchymal stromal origin, show similar immunomodulatory properties as mesenchymal stem cells (MSCs), by regulating macrophage function associated with glomerular crescent formation. We show that rat mesangial cells suppress conA-stimulated splenocyte proliferation in vitro, as previously shown for MSCs. We then investigated mesangial cell-macrophage interaction by using mesangial cells isolated from nephrotoxic nephritis (NTN)-susceptible Wistar Kyoto (WKY) and NTN-resistant Lewis (LEW) rats. We first determined the mesangial cell transcriptome in WKY and LEW rats and showed that this is under marked genetic control. Supernatant transfer results show that WKY mesangial cells shift bone marrow derived macrophage (BMDM) phenotype to M1 or M2 according to the genetic background (WKY or LEW) of the BMDMs. Interestingly, these effects were different when compared to those of MSCs suggesting that mesangial cells can have unique immunomodulatory effects in the kidney. These results demonstrate the importance of the genetic background in the immunosuppressive effects of cells of stromal origin and specifically of mesangial cell-macrophage interactions in the pathophysiology of crescentic glomerulonephritis.
Ali R, Nicolas R, Marley S, et al., 2014, STREAMS: PRELIMINARY RESULTS FROM A PHASE II TRIAL, Meeting of the Associatiion-of-British-Neurologists, Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Bradshaw A, Dazzi F, Marley S, et al., 2014, MESENCHYMAL STROMAL CELLS FOR THE TREATMENT OF GRAFT VERSUS HOST DISEASE IN PATIENTS WITH CONCOMITANT INFECTION, 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation, Publisher: NATURE PUBLISHING GROUP, Pages: S535-S535, ISSN: 0268-3369
Ruutu T, Gratwohl A, De Witte T, et al., 2014, Erratum: Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice (Bone Marrow Transplantatio (2014) 49 (319) DOI:10.1038/bmt.2013.210), Bone Marrow Transplantation, Vol: 49, ISSN: 0268-3369
Ruutu T, Gratwohl A, de Witte T, et al., 2014, Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice, BONE MARROW TRANSPLANTATION, Vol: 49, Pages: 168-173, ISSN: 0268-3369
Ruutu T, Gratwohl A, de Witte T, et al., 2014, Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice., Bone Marrow Transplant, Vol: 49
Innes AJ, Beattie R, Sergeant R, et al., 2013, Escalating-dose HLA-mismatched DLI is safe for the treatment of leukaemia relapse following alemtuzumab-based myeloablative allo-SCT, BONE MARROW TRANSPLANTATION, Vol: 48, Pages: 1324-1328, ISSN: 0268-3369
Auner HW, Moody AM, Ward TH, et al., 2013, Combined Inhibition of p97 and the Proteasome Causes Lethal Disruption of the Secretory Apparatus in Multiple Myeloma Cells, PLOS One, Vol: 8, ISSN: 1932-6203
Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER)-associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non-redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma.
Vianello F, Cannella L, Coe D, et al., 2013, Enhanced and aberrant T cell trafficking following total body irradiation: a gateway to graft-versus-host disease?, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 162, Pages: 808-818, ISSN: 0007-1048
Dazzi F, 2013, Cancer makes new friends with old tricks, BLOOD, Vol: 122, Pages: 1093-1094, ISSN: 0006-4971
Mussai F, De Santo C, Abu-Dayyeh I, et al., 2013, Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment, BLOOD, Vol: 122, Pages: 749-758, ISSN: 0006-4971
Patel A, Laffan MA, Dazzi F, et al., 2013, Mesenchymal stromal stem cell therapy for septic shock, UK Critical Care Research Forum
Fibbe WE, Dazzi F, LeBlanc K, 2013, MSCs: science and trials, NATURE MEDICINE, Vol: 19, Pages: 812-813, ISSN: 1078-8956
Basak GW, de Wreede LC, van Biezen A, et al., 2013, Donor lymphocyte infusions for the treatment of chronic myeloid leukemia relapse following peripheral blood or bone marrow stem cell transplantation, BONE MARROW TRANSPLANTATION, Vol: 48, Pages: 837-842, ISSN: 0268-3369
Weng L, Marigo I, Karadimitris A, et al., 2013, Natural killer T-cells control the expansion of myeloid-derived suppressor cells during the haematopoietic reconstitution: a novel immunoregulatory network post-transplant, 39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S136-S136, ISSN: 0268-3369
Li YT, Weng L, Lopes L, et al., 2013, NF-kappa B pathway plays a key role in mesenchymal stromal cell-mediated immunomodulation, 39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S261-S261, ISSN: 0268-3369
Galleu A, Weng L, Marigo I, et al., 2013, A potency assay for clinical grade mesenchymal stromal cells, 39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S262-S263, ISSN: 0268-3369
Lopes LM, Coelho MB, Dazzi F, 2013, Mesenchymal stromal cells differently regulate acute and chronic inflammatory responses, 39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S260-S260, ISSN: 0268-3369
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