Publications by authors named "Thomas Ritter"

94 Publications

Cyclophosphamide alters the tumor cell secretome to potentiate the anti-myeloma activity of daratumumab through augmentation of macrophage-mediated antibody dependent cellular phagocytosis.

Oncoimmunology 2021 Jan 25;10(1):1859263. Epub 2021 Jan 25.

Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, NUI Galway, Galway, Ireland.

Multiple Myeloma (MM) is a malignant disorder of plasma cells which, despite significant advances in treatment, remains incurable. Daratumumab, the first CD38 directed monoclonal antibody, has shown promising activity alone and in combination with other agents for MM treatment. Daratumumab is thought to have pleiotropic mechanisms of activity including natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). With the knowledge that CD38-expressing NK cells are depleted by daratumumab, we sought to investigate a potential mechanism of enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) by combining daratumumab with cyclophosphamide (CTX). Cyclophosphamide's immunomodulatory function was investigated by conditioning macrophages with tumor cell secretome collected from cyclophosphamide treated MM cell lines (CTX-TCS). Flow cytometry analysis revealed that CTX-TCS conditioning augmented the migratory capacity of macrophages and increased CD32 and CD64 Fcγ receptor expression on their cell surface. Daratumumab-specific tumor clearance was increased by conditioning macrophages with CTX-TCS in a dose-dependent manner. This effect was impeded by pre-incubating macrophages with Cytochalasin D (CytoD), an inhibitor of actin polymerization, indicating macrophage-mediated ADCP as the mechanism of clearance. CD64 expression on macrophages directly correlated with MM cell clearance and was essential to the observed synergy between cyclophosphamide and daratumumab, as tumor clearance was attenuated in the presence of a FcγRI/CD64 blocking agent. Cyclophosphamide independently enhances daratumumab-mediated killing of MM cells by altering the tumor microenvironment to promote macrophage recruitment, polarization to a pro-inflammatory phenotype, and directing ADCP. These findings support the addition of cyclophosphamide to existing or novel monoclonal antibody-containing MM regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1859263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849715PMC
January 2021

Disseminated Infection and Vertebral Osteomyelitis following Immunotherapy for Bladder Cancer.

Case Rep Infect Dis 2020 28;2020:6676163. Epub 2020 Dec 28.

Department of Internal Medicine, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA.

The use of BCG in immunotherapy for bladder cancer has been in practice for over 40 years. However, uncommon, serious complications can occur with the therapy. Here, we present a case of vertebral osteomyelitis secondary to dissemination of BCG following immunotherapy, an exceedingly rare presentation of an already rare complication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/6676163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785387PMC
December 2020

The duration, dynamics and determinants of SARS-CoV-2 antibody responses in individual healthcare workers.

Clin Infect Dis 2021 Jan 6. Epub 2021 Jan 6.

Big Data Institute, University of Oxford, Oxford, UK.

Background: SARS-CoV-2 IgG antibody measurements can be used to estimate the proportion of a population exposed or infected and may be informative about the risk of future infection. Previous estimates of the duration of antibody responses vary.

Methods: We present 6 months of data from a longitudinal seroprevalence study of 3276 UK healthcare workers (HCWs). Serial measurements of SARS-CoV-2 anti-nucleocapsid and anti-spike IgG were obtained. Interval censored survival analysis was used to investigate the duration of detectable responses. Additionally, Bayesian mixed linear models were used to investigate anti-nucleocapsid waning.

Results: Anti-spike IgG levels remained stably detected after a positive result, e.g., in 94% (95% credibility interval, CrI, 91-96%) of HCWs at 180 days. Anti-nucleocapsid IgG levels rose to a peak at 24 (95% credibility interval, CrI 19-31) days post first PCR-positive test, before beginning to fall. Considering 452 anti-nucleocapsid seropositive HCWs over a median of 121 days from their maximum positive IgG titre, the mean estimated antibody half-life was 85 (95%CrI, 81-90) days. Higher maximum observed anti-nucleocapsid titres were associated with longer estimated antibody half-lives. Increasing age, Asian ethnicity and prior self-reported symptoms were independently associated with higher maximum anti-nucleocapsid levels and increasing age and a positive PCR test undertaken for symptoms with longer anti-nucleocapsid half-lives.

Conclusion: SARS-CoV-2 anti-nucleocapsid antibodies wane within months, and faster in younger adults and those without symptoms. However, anti-spike IgG remains stably detected. Ongoing longitudinal studies are required to track the long-term duration of antibody levels and their association with immunity to SARS-CoV-2 reinfection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciab004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929225PMC
January 2021

Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers.

N Engl J Med 2021 02 23;384(6):533-540. Epub 2020 Dec 23.

From Oxford University Hospitals NHS Foundation Trust (S.F.L., N.E.S., P.C.M., S.C., T.J., F.W., L.W., D.A., A.-M.O., K.J.), Nuffield Department of Medicine (S.F.L., D.O., N.E.S., P.C.M., A.H., S.B.H., B.D.M., R.J.C., E.Y.J., D.I.S., G.S., D.E., S. Hoosdally, D.W.C., C.P.C., A.S.W., T.E.A.P., T.M.W.), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (N.E.S., P.C.M., S. Hoosdally, D.W.C., A.S.W., T.E.A.P., D.W.E.), the Kennedy Institute of Rheumatology Research (B.D.M.), the Medical School, University of Oxford (L.J.P., T.G.R., Z.T.), Target Discovery Institute (D.E.), Nuffield Department of Population Health (A.-M.O., K.B.P., D.W.E.), and the Big Data Institute (D.W.E.), University of Oxford, and the NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England (N.E.S., P.C.M., S. Hoosdally, D.W.C., K.B.P., A.S.W., T.E.A.P., D.W.E.), Oxford, and the National Infection Service, Public Health England at Colindale, London (M.C., S. Hopkins) - all in the United Kingdom; and the Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam (T.M.W.).

Background: The relationship between the presence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the risk of subsequent reinfection remains unclear.

Methods: We investigated the incidence of SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) in seropositive and seronegative health care workers attending testing of asymptomatic and symptomatic staff at Oxford University Hospitals in the United Kingdom. Baseline antibody status was determined by anti-spike (primary analysis) and anti-nucleocapsid IgG assays, and staff members were followed for up to 31 weeks. We estimated the relative incidence of PCR-positive test results and new symptomatic infection according to antibody status, adjusting for age, participant-reported gender, and changes in incidence over time.

Results: A total of 12,541 health care workers participated and had anti-spike IgG measured; 11,364 were followed up after negative antibody results and 1265 after positive results, including 88 in whom seroconversion occurred during follow-up. A total of 223 anti-spike-seronegative health care workers had a positive PCR test (1.09 per 10,000 days at risk), 100 during screening while they were asymptomatic and 123 while symptomatic, whereas 2 anti-spike-seropositive health care workers had a positive PCR test (0.13 per 10,000 days at risk), and both workers were asymptomatic when tested (adjusted incidence rate ratio, 0.11; 95% confidence interval, 0.03 to 0.44; P = 0.002). There were no symptomatic infections in workers with anti-spike antibodies. Rate ratios were similar when the anti-nucleocapsid IgG assay was used alone or in combination with the anti-spike IgG assay to determine baseline status.

Conclusions: The presence of anti-spike or anti-nucleocapsid IgG antibodies was associated with a substantially reduced risk of SARS-CoV-2 reinfection in the ensuing 6 months. (Funded by the U.K. Government Department of Health and Social Care and others.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2034545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781098PMC
February 2021

Nanosensitive optical coherence tomography to assess wound healing within the cornea.

Biomed Opt Express 2020 Jul 2;11(7):3407-3422. Epub 2020 Jun 2.

Tissue Optics and Microcirculation Imaging Facility, National Biophotonics and Imaging Platform, School of Physics, National University of Ireland, Galway, Ireland.

Optical coherence tomography (OCT) is a non-invasive depth resolved optical imaging modality, that enables high resolution, cross-sectional imaging in biological tissues and materials at clinically relevant depths. Though OCT offers high resolution imaging, the best ultra-high-resolution OCT systems are limited to imaging structural changes with a resolution of one micron within very limited depth. Nanosensitive OCT (nsOCT) is a recently developed technique that is capable of providing enhanced sensitivity of OCT to structural changes. Improving the sensitivity of OCT to detect structural changes at the nanoscale level, to a depth typical for conventional OCT, could potentially improve the diagnostic capability of OCT in medical applications. In this paper, we demonstrate the capability of nsOCT to detect structural changes deep in the rat cornea following superficial corneal injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/BOE.389342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510923PMC
July 2020

TGF-β1-Licensed Murine MSCs Show Superior Therapeutic Efficacy in Modulating Corneal Allograft Immune Rejection In Vivo.

Mol Ther 2020 09 30;28(9):2023-2043. Epub 2020 May 30.

Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland. Electronic address:

Mesenchymal stromal cells (MSCs) are a promising therapeutic option for multiple immune diseases/disorders; however, efficacy of MSC treatments can vary significantly. We present a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with transforming growth factor-β1 (TGF-β MSCs) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes following co-culture assays. These TGF-β MSC-expanded regulatory T lymphocytes also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably elevated prostaglandin E2 (PGE2). Furthermore, TGF-β MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for unlicensed MSC-treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (1) therapeutic efficacy of TGF-β MSCs is Smad2/3-dependent, (2) the enhanced immunosuppressive capacity of TGF-β MSCs is contact-dependent, and (3) enhanced secretion of PGE2 (via prostaglandin EP4 [E-type prostanoid 4] receptor) by TGF-β MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-β1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymthe.2020.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474271PMC
September 2020

Investigating the Potential and Pitfalls of EV-Encapsulated MicroRNAs as Circulating Biomarkers of Breast Cancer.

Cells 2020 01 7;9(1). Epub 2020 Jan 7.

Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, H91 YR71, Ireland.

Extracellular vesicles (EVs) shuttle microRNA (miRNA) throughout the circulation and are believed to represent a fingerprint of the releasing cell. We isolated and characterized serum EVs of breast tumour-bearing animals, breast cancer (BC) patients, and healthy controls. EVs were characterized using transmission electron microscopy (TEM), protein quantification, western blotting, and nanoparticle tracking analysis (NTA). Absolute quantitative (AQ)-PCR was employed to analyse EV-miR-451a expression. Isolated EVs had the appropriate morphology and size. Patient sera contained significantly more EVs than did healthy controls. In tumour-bearing animals, a correlation between serum EV number and tumour burden was observed. There was no significant relationship between EV protein yield and EV quantity determined by NTA, highlighting the requirement for direct quantification. Using AQ-PCR to relate miRNA copy number to EV yield, a significant increase in miRNA-451a copies/EV was detected in BC patient sera, suggesting potential as a novel biomarker of breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9010141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016709PMC
January 2020

High-risk Corneal Transplantation: Recent Developments and Future Possibilities.

Transplantation 2019 12;103(12):2468-2478

Department of Ophthalmology, CHU de Nantes, France.

Human corneal transplantation (keratoplasty) is typically considered to have superior short- and long-term outcomes and lower requirement for immunosuppression compared to solid organ transplants because of the inherent immune privilege and tolerogenic mechanisms associated with the anterior segment of the eye. However, in a substantial proportion of corneal transplants, the rates of acute rejection and/or graft failure are comparable to or greater than those of the commonly transplanted solid organs. Critically, while registry data and observational studies have helped to identify factors that are associated with increased risk of corneal transplant failure, the extent to which these risk factors operate through enhancing immune-mediated rejection is less clear. In this overview, we summarize a range of important recent clinical and basic insights related to high-risk corneal transplantation, the factors associated with graft failure, and the immunological basis of corneal allograft rejection. We highlight critical research areas from which continued progress is likely to drive improvements in the long-term survival of high-risk corneal transplants. These include further development and clinical testing of predictive risk scores and assays; greater use of multicenter clinical trials to optimize immunosuppressive therapy in high-risk recipients and robust clinical translation of novel, mechanistically-targeted immunomodulatory and regenerative therapies that are emerging from basic science laboratories. We also emphasize the relative lack of knowledge regarding transplant outcomes for infection-related corneal diseases that are common in the developing world and the potential for greater cross-pollination and synergy between corneal and solid organ transplant research communities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000002938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867666PMC
December 2019

TNF-α/IL-1β-licensed mesenchymal stromal cells promote corneal allograft survival myeloid cell-mediated induction of Foxp3 regulatory T cells in the lung.

FASEB J 2019 08 20;33(8):9404-9421. Epub 2019 May 20.

Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing, and Health Sciences, National University of Ireland-Galway, Galway, Ireland.

Mesenchymal stromal cells (MSCs) have shown promise as a therapy for immune-mediated disorders, including transplant rejection. Our group previously demonstrated the efficacy of pretransplant, systemic administration of allogeneic but not syngeneic MSCs in a rat cornea transplant model. The aim of this study was to enhance the immunomodulatory capacity of syngeneic MSCs. , MSCs licensed with TNF-α/IL-1β (MSCs) suppress syngeneic lymphocyte proliferation NO production. , when administered post-transplantation, nonlicensed syngeneic MSCs improved graft survival from 0 to 50% and MSCs, in an NO-dependent manner, improved survival to 70%. Improved survival was associated with increased CD4CD25forkhead box P3 regulatory T (T) cells and decreased proinflammatory cytokine expression in the draining lymph node. MSCs demonstrated a more potent immunomodulatory capacity compared with nonlicensed MSCs, promoting an immune-regulatory CD11bB220 monocyte/macrophage population and significantly expanding T cells in the lungs and spleen. , we observed that lung-derived myeloid cells act as intermediaries of MSC immunomodulatory function. MSC-conditioned myeloid cells suppressed stimulated lymphocyte proliferation and promoted expansion of T cells from naive lymphocytes. This work illustrates how syngeneic MSC therapy can be enhanced by licensing and optimization of timing strategies and further highlights the important role of myeloid cells in mediating MSC immunomodulatory capacity.-Murphy, N., Treacy, O., Lynch, K., Morcos, M., Lohan, P., Howard, L., Fahy, G., Griffin, M. D., Ryan, A. E., Ritter, T. TNF-α/IL-1β-licensed mesenchymal stromal cells promote corneal allograft survival myeloid cell-mediated induction of Foxp3 regulatory T cells in the lung.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201900047RDOI Listing
August 2019

Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation.

Front Immunol 2018 20;9:2666. Epub 2018 Nov 20.

Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.

High-risk cornea transplant recipients represent a patient population with significant un-met medical need for more effective therapies to prevent immunological graft rejection due to heightened anti-donor immune response. In this study, a rat model of pre-existing anti-donor immunity was developed in which corneal allografts were rejected earlier than in non-pre-sensitized recipients. In this model, third-party (non-donor, non-recipient strain) allogeneic mesenchymal stromal cells (allo-MSC) were administered intravenously 7 and 1 days prior to transplantation. Rejection-free graft survival to 30 days post-transplant improved from 0 to 63.6% in MSC-treated compared to vehicle-treated control animals ( = < 0.0001). Pre-sensitized animals that received third-party allo-MSC prior to transplantation had significantly higher proportions of CD45CD11b B220 monocytes in the lungs 24 h after the second MSC injection and significantly higher proportions of CD4 FoxP3 regulatory T cells in the graft-draining lymph nodes at the average day of rejection of control animals. In experiments, third-party allo-MSC polarized primary lung-derived CD11b/c myeloid cells to a more anti-inflammatory phenotype, as determined by cytokine profile and conferred them with the capacity to suppress T cell activation via prostaglandin E and TGFβ1. In experiments designed to further validate the clinical potential of the protocol, thawed cryopreserved, third-party allo-MSC were shown to be similarly potent at prolonging rejection-free corneal allograft survival as their freshly-cultured counterparts in the pre-sensitized high-risk model. Furthermore, thawed cryopreserved third-party allo-MSC could be co-administered with mycophenolate mofetil without adversely affecting their immunomodulatory function. In conclusion, a clinically-relevant protocol consisting of two intravenous infusions of third-party allo-MSC during the week prior to transplantation, exerts a potent anti-rejection effect in a pre-sensitized rat model of high-risk corneal allo-transplantation. This immune regulatory effect is likely to be mediated in the immediate post-transplant period through the promotion, by allo-MSC, of alternatively-activated macrophages in the lung and, later, by enhanced regulatory T-cell numbers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.02666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255848PMC
October 2019

Stromal Cell PD-L1 Inhibits CD8 T-cell Antitumor Immune Responses and Promotes Colon Cancer.

Cancer Immunol Res 2018 11 18;6(11):1426-1441. Epub 2018 Sep 18.

Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Republic of Ireland.

Stromal cells of mesenchymal origin reside below the epithelial compartment and provide structural support in the intestine. These intestinal stromal cells interact with both the epithelial cell compartments, as well as infiltrating hematopoietic immune cells. The importance of these cells in regulating immune homeostasis during inflammation is well recognized. However, little is known about their function and phenotype in the inflammatory tumor microenvironment. Using a syngeneic, immunogenic model of colorectal cancer, we showed that TNFα-initiated inflammatory signaling in CT26 colorectal cancer cells selectively induced PD-L1 expression in stromal cells. Using shRNA and antibody-mediated approaches, we showed that stromal cell PD-L1 potentiated enhanced immunosuppression, characterized by inhibition of activated CD8 granzyme B-secreting T cells , and the inhibition of CD8 effector cells was associated with enhanced tumor progression. Stromal cell immunosuppressive and tumor-promoting effects could be reversed with administration of anti-PD-1 We validated our findings of stromal cell expression in two cohorts of clinical samples and also observed PD-L1 induction on human stromal cells in response to exposure to the inflammatory secretome from human colon cancer cells, irrespective of microsatellite instability. Collectively, our data showed that tumor-associated stromal cells support T-cell suppression by PD-L1 induction, which is dependent on colon cancer inflammatory signaling. Our findings reveal a key role of mesenchymal stromal cells PD-L1 in suppression of CD8 antitumor immune responses and potentiation of colorectal cancer progression. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-17-0443DOI Listing
November 2018

Interspecies Incompatibilities Limit the Immunomodulatory Effect of Human Mesenchymal Stromal Cells in the Rat.

Stem Cells 2018 08 16;36(8):1210-1215. Epub 2018 May 16.

Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland.

Mesenchymal stem/stromal cells (MSC) are an immunomodulatory cell population which are under preclinical and clinical investigation for a number of inflammatory conditions including transplantation. In this study, a well-established rat corneal transplantation model was used to test the ability of human MSC to prolong corneal allograft rejection-free survival using a pre-transplant intravenous infusion protocol previously shown to be efficacious with allogeneic rat MSC. Surprisingly, pre-transplant administration of human MSC had no effect on corneal allograft survival. In vitro, human MSC failed to produce nitric oxide and upregulate IDO and, as a consequence, could not suppress rat T-cell proliferation. Furthermore, human MSC were not activated by rat pro-inflammatory cytokines. Thus, interspecies incompatibility in cytokine signaling leading to failure of MSC licensing may explain the lack of in vivo efficacy of human MSC in a rat tissue allotransplant model. Interspecies incompatibilities should be taken into consideration when interpreting preclinical data efficacy data in the context of translation to clinical trial. Stem Cells 2018;36:1210-1215.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/stem.2840DOI Listing
August 2018

Anti-donor antibody induction following intramuscular injections of allogeneic mesenchymal stromal cells.

Immunol Cell Biol 2018 05 23;96(5):536-548. Epub 2018 Mar 23.

Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland.

Allogeneic mesenchymal stromal cells (allo-MSC) are a promising "off-the-shelf" therapy with anti-inflammatory and pro-repair properties. This study investigated humoral immune responses to intramuscular (IM) injections of allo-MSC. Total and isotype-specific anti-donor IgG and donor-specific complement-mediated lysis were determined in sera from healthy mice 2 weeks after single or repeated IM injections of fully mismatched-MHC allo-MSC with comparison to mice receiving syngeneic MSC, allogeneic splenocytes or saline. In mice subjected to hind limb ischemia (HLI), anti-donor IgG was analyzed following IM allo-MSC injection with and without administration of the T-cell immunosuppressant tacrolimus. Recipients of single and repeated IM allo-MSC developed readily-detectable anti-donor IgG. Serum anti-donor IgG levels were similar to those of allo-splenocyte recipients but had higher IgG1/IgG2a ratio and variable capacity for complement-mediated lysis of donor cells. The induced anti-donor IgG bound readily to allo-MSC and this binding was increased following allo-MSC pretreatment with interferon gamma. In mice with HLI, IM injection of allo-MSC into the ischemic limb was also associated with induction of anti-donor IgG but this was abrogated by tacrolimus (FK-506). The results indicate that allo-MSC are inherently immunogenic when delivered intramuscularly to healthy and ischemic mouse hind limb, but induce an IgG1-skewed humoral response that is suppressed by tacrolimus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imcb.12024DOI Listing
May 2018

Extracellular vesicles as modulators of wound healing.

Adv Drug Deliv Rev 2018 04 31;129:394-406. Epub 2018 Jan 31.

Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland; CÚRAM Centre for Research in Medical Devices, National University of Ireland, Galway, Ireland. Electronic address:

Impaired healing of cutaneous wounds and ulcers continues to have a major impact on the quality of life of millions of people. In recent years, the capacity for stem and progenitor cells to promote wound repair has been investigated with evidence that secreted factors are responsible for the observed therapeutic benefits. This review addresses current evidence in support of stem/progenitor cell-derived extracellular vesicles (EVs) as a regenerative therapy for acceleration of wound healing. Encouraging results for local or systemic administration of EVs have been reported in a range of clinically-relevant animal models of cutaneous wounds. Furthermore, a number of plausible mechanisms involving EV-mediated transfer of proteins and RNAs that trigger pro-repair pathways in target cells have been demonstrated experimentally. However, for successful clinical translation in the coming years, further emphasis on standardized experimental protocols, detailed methodological reporting and clear definition of EV-based therapeutic products will be required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.addr.2018.01.018DOI Listing
April 2018

Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization.

Front Immunol 2017 15;8:1844. Epub 2018 Jan 15.

Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland.

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.01844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775516PMC
January 2018

Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?

Front Immunol 2017 24;8:1626. Epub 2017 Nov 24.

Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.

Mesenchymal stromal cells (MSC) have been used to treat a broad range of disease indications such as acute and chronic inflammatory disorders, autoimmune diseases, and transplant rejection due to their potent immunosuppressive/anti-inflammatory properties. The breadth of their usage is due in no small part to the vast quantity of published studies showing their ability to modulate multiple immune cell types of both the innate and adaptive immune response. While patient-derived (autologous) MSC may be the safer choice in terms of avoiding unwanted immune responses, factors including donor comorbidities may preclude these cells from use. In these situations, allogeneic MSC derived from genetically unrelated individuals must be used. While allogeneic MSC were initially believed to be immune-privileged, substantial evidence now exists to prove otherwise with multiple studies documenting specific cellular and humoral immune responses against donor antigens following administration of these cells. In this article, we will review recent published studies using non-manipulated, inflammatory molecule-activated (licensed) and differentiated allogeneic MSC, as well as MSC extracellular vesicles focusing on the immune responses to these cells and whether or not such responses have an impact on allogeneic MSC-mediated safety and efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.01626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705547PMC
November 2017

Regulating Immunogenicity and Tolerogenicity of Bone Marrow-Derived Dendritic Cells through Modulation of Cell Surface Glycosylation by Dexamethasone Treatment.

Front Immunol 2017 30;8:1427. Epub 2017 Oct 30.

School of Medicine, Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland.

Dendritic cellular therapies and dendritic cell vaccines show promise for the treatment of autoimmune diseases, the prolongation of graft survival in transplantation, and in educating the immune system to fight cancers. Cell surface glycosylation plays a crucial role in the cell-cell interaction, uptake of antigens, migration, and homing of DCs. Glycosylation is known to change with environment and the functional state of DCs. Tolerogenic DCs (tDCs) are commonly generated using corticosteroids including dexamethasone, however, to date, little is known on how corticosteroid treatment alters glycosylation and what functional consequences this may have. Here, we present a comprehensive profile of rat bone marrow-derived dendritic cells, examining their cell surface glycosylation profile before and after Dexa treatment as resolved by both lectin microarrays and lectin-coupled flow cytometry. We further examine the functional consequences of altering cell surface glycosylation on immunogenicity and tolerogenicity of DCs. Dexa treatment of rat DCs leads to profoundly reduced expression of markers of immunogenicity (MHC I/II, CD80, CD86) and pro-inflammatory molecules (IL-6, IL-12p40, inducible nitric oxide synthase) indicating a tolerogenic phenotype. Moreover, by comprehensive lectin microarray profiling and flow cytometry analysis, we show that sialic acid (Sia) is significantly upregulated on tDCs after Dexa treatment, and that this may play a vital role in the therapeutic attributes of these cells. Interestingly, removal of Sia by neuraminidase treatment increases the immunogenicity of immature DCs and also leads to increased expression of pro-inflammatory cytokines while tDCs are moderately protected from this increase in immunogenicity. These findings may have important implications in strategies aimed at increasing tolerogenicity where it is advantageous to reduce immune activation over prolonged periods. These findings are also relevant in therapeutic strategies aimed at increasing the immunogenicity of cells, for example, in the context of tumor specific immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.01427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670353PMC
October 2017

Distinctive Surface Glycosylation Patterns Associated With Mouse and Human CD4 Regulatory T Cells and Their Suppressive Function.

Front Immunol 2017 21;8:987. Epub 2017 Aug 21.

Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland.

Regulatory T-cells (Treg) are essential for maintaining immune homeostasis and tolerance. Surface glycosylation is ubiquitous on mammalian cells and regulates diverse biological processes. While it is currently well accepted that surface glycan expression influences multiple aspects of T-cell function, little is known about the relevance of glycosylation to Treg biology. This study aimed to profile the surface glycosylation characteristics of Treg in various lymphoid compartments of mouse and in human peripheral blood with comparison to non-regulatory, conventional CD4 T-cells (Tconv). It also sought to determine the relationship between the surface glycosylation characteristics and suppressive potency of Treg. Lectin-based flow cytometric profiling demonstrated that Treg surface glycosylation differs significantly from that of Tconv in the resting state and is further modified by activation stimuli. In mouse, the surface glycosylation profiles of FoxP3 Treg from spleen and lymph nodes were closely comparable but greater variability was observed for Treg in thymus, bone marrow, and blood. Surface levels of tri/tetra-antennary glycans correlated with expression of proteins known to be involved in Treg suppressive functions, including GITR, PD-1, PD-L1, CD73, CTLA-4, and ICOS. In coculture experiments involving purified Treg subpopulations and CD4 or CD8 Tconv, higher surface tri/tetra-antennary glycans was associated with greater Treg suppressive potency. Enzymatic manipulation of mouse Treg surface glycosylation resulting in a temporary reduction of surface -glycans significantly reduced Treg capacity to suppress Tconv activation through contact-dependent mechanisms. Overall, these findings demonstrate that Treg have distinctive surface glycan characteristics that show variability across anatomical locations and are modulated by activation events. They also provide evidence of an important role for surface glycosylation in determining Treg phenotype and suppressive potency. These insights may prove relevant to the analysis of Treg in disease settings and to the further development of Treg-based immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.00987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566562PMC
August 2017

Corrigendum to: "Development of a flow cytometry-based potency assay for measuring the in vitro immunomodulatory properties of mesenchymal stromal cells" [J. Immunol. Lett. 177 (2016) 38-46].

Immunol Lett 2016 12 9;180:81. Epub 2016 Nov 9.

Regenerative Medicine Institute, National Centre for Biomedical Engineering Science and School of Medicine, National University of Ireland, Galway, Ireland. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imlet.2016.09.002DOI Listing
December 2016

Mesenchymal stem cell therapy to promote corneal allograft survival: current status and pathway to clinical translation.

Curr Opin Organ Transplant 2016 Dec;21(6):559-567

aCollege of Medicine, Nursing and Health Sciences, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland *Both authors contributed equally to this manuscript.

Purpose Of Review: This article reviews the literature on the therapeutic potential of mesenchymal stem cells (MSCs) to prolong corneal allograft survival.

Recent Findings: To date, only small numbers studies have investigated the MSC ability to modulate corneal allograft survival. Most reports have shown positive results, which is encouraging, however as different MSC-application strategies (time point of injection, cell number/number of injections, route of injection, MSC source, MSC licensing) have been employed in various animal models it is difficult to compare and validate the results. The MSC ability to promote graft survival has been attributed to their modulation of the recipient immune system, altering the Th1/Th2 balance, expanding Foxp3 regulatory T cells, polarizing macrophages and inhibiting intra-graft infiltration of antigen presenting cells. More in depth analysis is required to elucidate the mechanism of MSC-immunomodulation in vivo.

Summary: MSCs have shown the potential to modulate corneal allograft rejection in various models using MSCs from different species. In particular for high-risk patients with poor prognosis MSC therapy might be a promising approach to promote corneal allograft survival. First-in-man clinical trials with MSC will hopefully shed new light on MSC-mediated immunomodulation in vivo and contribute to the restoration of vision in patients receiving corneal allografts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MOT.0000000000000360DOI Listing
December 2016

Minimum information about tolerogenic antigen-presenting cells (MITAP): a first step towards reproducibility and standardisation of cellular therapies.

PeerJ 2016 30;4:e2300. Epub 2016 Aug 30.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Cellular therapies with tolerogenic antigen-presenting cells (tolAPC) show great promise for the treatment of autoimmune diseases and for the prevention of destructive immune responses after transplantation. The methodologies for generating tolAPC vary greatly between different laboratories, making it difficult to compare data from different studies; thus constituting a major hurdle for the development of standardised tolAPC therapeutic products. Here we describe an initiative by members of the tolAPC field to generate a minimum information model for tolAPC (MITAP), providing a reporting framework that will make differences and similarities between tolAPC products transparent. In this way, MITAP constitutes a first but important step towards the production of standardised and reproducible tolAPC for clinical application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7717/peerj.2300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012269PMC
September 2016

Mesenchymal stromal cells (MSCs) and colorectal cancer: a troublesome twosome for the anti-tumour immune response?

Oncotarget 2016 Sep;7(37):60752-60774

Regenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Science (NCBES) NUI, Galway, Ireland.

The tumour microenvironment (TME) is an important factor in determining the growth and metastasis of colorectal cancer, and can aid tumours by both establishing an immunosuppressive milieu, allowing the tumour avoid immune clearance, and by hampering the efficacy of various therapeutic regimens. The tumour microenvironment is composed of many cell types including tumour, stromal, endothelial and immune cell populations. It is widely accepted that cells present in the TME acquire distinct functional phenotypes that promote tumorigenesis. One such cell type is the mesenchymal stromal cell (MSC). Evidence suggests that MSCs exert effects in the colorectal tumour microenvironment including the promotion of angiogenesis, invasion and metastasis. MSCs immunomodulatory capacity may represent another largely unexplored central feature of MSCs tumour promoting capacity. There is considerable evidence to suggest that MSCs and their secreted factors can influence the innate and adaptive immune responses. MSC-immune cell interactions can skew the proliferation and functional activity of T-cells, dendritic cells, natural killer cells and macrophages, which could favour tumour growth and enable tumours to evade immune cell clearance. A better understanding of the interactions between the malignant cancer cell and stromal components of the TME is key to the development of more specific and efficacious therapies for colorectal cancer. Here, we review and explore MSC- mediated mechanisms of suppressing anti-tumour immune responses in the colon tumour microenvironment. Elucidation of the precise mechanism of immunomodulation exerted by tumour-educated MSCs is critical to inhibiting immunosuppression and immune evasion established by the TME, thus providing an opportunity for targeted and efficacious immunotherapy for colorectal cancer growth and metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.11354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312417PMC
September 2016

Development of a flow cytometry-based potency assay for measuring the in vitro immunomodulatory properties of mesenchymal stromal cells.

Immunol Lett 2016 09 20;177:38-46. Epub 2016 Jul 20.

Regenerative Medicine Institute, National Centre for Biomedical Engineering Science and School of Medicine, National University of Ireland, Galway, Ireland. Electronic address:

Human bone marrow-derived mesenchymal stromal/stem cells (MSC) have well-documented modulatory effects on multiple immune cell types. Although these effects are linked to their therapeutic benefit in diverse diseases, a reliable, quantitative assay of the immunomodulatory potency of individual human MSC preparations is lacking. The aims of this study were to develop an optimised rapid turnaround, flow cytometry-based whole-blood assay to monitor MSC potency and to validate its application to MSC immunomodulation. A protocol for short-term LPS stimulation of anti-coagulated whole blood samples followed by combined surface CD45/CD14 and intracellular TNF-α staining was initially developed for analysis on a 4 colour desktop cytometer. Optimal monocyte activation was dependent on the presence of extracellular calcium ions thereby precluding the use of EDTA and sodium citrate as anticoagulants. Optimal assay conditions proved to be 1ng/mL ultrapure-LPS added to 10-fold diluted, heparin anti-coagulated whole blood incubated for 6h at 37°C. Under these conditions, addition of human bone marrow-derived MSC (hBM-MSC) from multiple donors resulted in a reproducible, dose-dependent inhibition of LPS-stimulated monocyte TNF-α expression. We conclude that this protocol represents a practical, quantitative assay of a clinically relevant functional effect of hBM-MSCs as well as other immunomodulatory agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imlet.2016.07.010DOI Listing
September 2016

vIL-10-overexpressing human MSCs modulate naïve and activated T lymphocytes following induction of collagenase-induced osteoarthritis.

Stem Cell Res Ther 2016 May 18;7(1):74. Epub 2016 May 18.

Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland.

Background: Recent efforts in osteoarthritis (OA) research have highlighted synovial inflammation and involvement of immune cells in disease onset and progression. We sought to establish the in-vivo immune response in collagenase-induced OA and investigate the ability of human mesenchymal stem cells (hMSCs) overexpressing viral interleukin 10 (vIL-10) to modulate immune populations and delay/prevent disease progression.

Methods: Eight-week-old male C57BL/6 mice were injected with 1 U type VII collagenase over two consecutive days. At day 7, 20,000 hMSCs overexpressing vIL-10 were injected into the affected knee. Control groups comprised of vehicle, 20,000 untransduced or adNull-transduced MSCs or virus alone. Six weeks later knees were harvested for histological analysis and popliteal and inguinal lymph nodes for flow cytometric analysis.

Results: At this time there was no significant difference in knee OA scores between any of the groups. A trend toward more damage in animals treated with hMSCs was observed. Interestingly there was a significant reduction in the amount of activated CD4 and CD8 T cells in the vIL-10-expressing hMSC group.

Conclusions: vIL-10-overexpressing hMSCs can induce long-term reduction in activated T cells in draining lymph nodes of mice with collagenase-induced OA. This could lead to reduced OA severity or disease progression over the long term.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13287-016-0331-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870800PMC
May 2016

The Exosome - A Naturally Secreted Nanoparticle and its Application to Wound Healing.

Adv Mater 2016 Jul 17;28(27):5542-52. Epub 2015 Dec 17.

Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, County Galway, Ireland.

Wound healing is a complex process and often delayed in patients with underlying chronic conditions. The cost of wound care is a significant burden to the society, warranting new techniques to prompt wound healing. Several studies have reported on the beneficial effects of mesenchymal stem cells (MSCs) function in recruiting host cells, releasing secretory factors and matrix proteins thereby increasing wound heal. These secrete bioactive trophic factors from MSCs also includes extracellular vesicles (EVs) or exosomes. Recent studies have shown that EVs are one of the key secretory products of MSCs mediating cell-to-cell communication to enhance wound healing. Current knowledge related to the potential use of EVs in wound healing is reviewed and the promising future for EVs - a naturally secreted nanoparticle - as an alternative to cell-based therapy is discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adma.201504009DOI Listing
July 2016

Corneal Immunosuppressive Mechanisms, Anterior Chamber-Associated Immune Deviation (ACAID) and Their Role in Allograft Rejection.

Methods Mol Biol 2016 ;1371:205-14

Orbsen Therapeutics Ltd, Galway, Ireland.

Corneal transplantation is the most frequently performed transplant procedure in humans. Human leukocyte antigen matching, while imperative for other types of organ transplants, is usually not performed before cornea transplantation. With the use of topical steroid immunosuppressants, which are subsequently tailed off to almost zero, most corneal transplants will not be rejected in recipients with low risk of graft rejection. This phenomenon has been described as immune privilege by Medawar many years ago. However, this immune privilege is relative and can be easily eroded, e.g. by postoperative nonspecific inflammation or other causes of corneal or ocular inflammation. Interestingly, corneas that are at high risk of rejection have a higher failure rate than other organs. Considerable progress has been made in recent years to provide a better understanding of corneal immune privilege. This chapter will review current knowledge on ocular immunosuppressive mechanisms including anterior chamber-associated immune deviation and discuss their role(s) in corneal allograft rejection. Ultimately, this evolving information will be of benefit in developing therapeutic strategies to prevent corneal transplant rejection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-3139-2_13DOI Listing
August 2016

Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-free Therapeutic Applications.

Mol Ther 2015 May 19;23(5):812-823. Epub 2015 Mar 19.

Regenerative Medicine Institute (REMEDI), College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland.

Mesenchymal stem (stromal) cells (MSCs) are multipotent cells with the ability to differentiate into several cell types, thus serving as a cell reservoir for regenerative medicine. Much of the current interest in therapeutic application of MSCs to various disease settings can be linked to their immunosuppressive and anti-inflammatory properties. One of the key mechanisms of MSC anti-inflammatory effects is the secretion of soluble factors with paracrine actions. Recently it has emerged that the paracrine functions of MSCs could, at least in part, be mediated by extracellular vesicles (EVs). EVs are predominantly released from the endosomal compartment and contain a cargo that includes miRNA, mRNA, and proteins from their cells of origin. Recent animal model-based studies suggest that EVs have significant potential as a novel alternative to whole cell therapies. Compared to their parent cells, EVs may have a superior safety profile and can be safely stored without losing function. In this article, we review current knowledge related to the potential use of MSC-derived EVs in various diseases and discuss the promising future for EVs as an alternative, cell-free therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/mt.2015.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427881PMC
May 2015

TNFα and IL-1β influence the differentiation and migration of murine MSCs independently of the NF-κB pathway.

Stem Cell Res Ther 2014 Aug 27;5(4):104. Epub 2014 Aug 27.

Introduction: Mesenchymal stem cells (MSCs) have the ability to repair and regenerate tissue, home to sites of inflammation, and evade the host immune system. As such, they represent an attractive therapy for the treatment of autoimmune inflammatory diseases. However, results from in vivo murine studies in inflammatory arthritis have been conflicting, and this may be due to the genetic background of the MSCs used. It is known that the inflammatory milieu may influence properties of MSCs and that, in the case of human bone marrow-derived MSCs, this may be mediated by the nuclear factor-kappa-B (NF-κB) pathway. We sought to determine whether pro-inflammatory cytokines altered the differentiation and migration capacity of murine MSCs from different mouse strains and whether this was mediated by NF-κB.

Methods: The differentiation and migration of FVB and BALB/c MSCs were carried out in the presence of varying concentrations of tumor necrosis factor-alpha (TNFα) and interleukin (IL)-1β, and the NF-κB pathway was inhibited in one of two ways: either by transduction of MSCs with an adenoviral vector expressing a super-repressor of NF-κB or by the addition of curcumin to culture media.

Results: Both BALB/c and FVB MSCs were sensitive to the effect of pro-inflammatory cytokines in vitro. TNFα and IL-1β suppressed BALB/c osteogenesis and adipogenesis and FVB osteogenesis. The migration of both cell types toward media containing fetal bovine serum was augmented by pre-stimulation with either cytokine. In neither cell type were the cytokine effects reversed by abrogation of the NF-κB pathway.

Conclusions: These data show that murine MSCs from different genetic backgrounds may be influenced by an inflammatory milieu in a manner that is not mediated by NF-κB, as is the case for human MSCs. This is not mediated by NF-κB. These findings are important and should influence how in vivo trials of murine MSCs are interpreted and the future development of pre-clinical studies in inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/scrt492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177434PMC
August 2014

Changes in immunological profile of allogeneic mesenchymal stem cells after differentiation: should we be concerned?

Stem Cell Res Ther 2014 Aug 19;5(4):99. Epub 2014 Aug 19.

Mesenchymal stem cells (MSCs) are an adult stromal cell population possessing potent differentiation capacity and a potential for use across major histocompatibility complex barriers. Although allogeneic MSCs have potent immunosuppressive properties, evidence also suggests that they elicit a weak allogeneic immune response. However, the effect of induced differentiation on the immunosuppressive ability and immunogenicity of allogeneic MSCs is a potential obstacle when applying MSCs in tissue replacement therapies. These concerns will be explored in this review, with particular emphasis on changes in the cell surface expression of immunogenic markers, changes in the secretion of immunosuppressive molecules and in vivo functional benefits of the cell therapy. We review the literature from a translational point of view, focusing on pre-clinical studies that have utilised and analysed the effects of allogeneic immune responses on the ability of allogeneic MSCs to regenerate damaged tissue in models of bone, heart and cartilage defects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/scrt488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282147PMC
August 2014

Immune modulation to improve tissue engineering outcomes for cartilage repair in the osteoarthritic joint.

Tissue Eng Part B Rev 2015 Feb 4;21(1):55-66. Epub 2014 Aug 4.

1 Regenerative Medicine Institute, National University of Ireland Galway , Galway, Ireland .

Osteoarthritis (OA), the most common form of arthritis, is a disabling degenerative joint disease affecting synovial joints and is associated with cartilage destruction, inflammation of the synovial membrane, and subchondral bone remodeling. Inflammation of the synovial membrane may arise secondary to degenerative processes in articular cartilage (AC), or may be a primary occurrence in OA pathogenesis. However, synovial inflammation plays a key role in the pathogenesis and disease progression of OA through the production of pro-inflammatory mediators, and is associated with cartilage destruction and pain. The triggers that initiate activation of the immune response in OA are unknown, but crosstalk between osteoarthritic chondrocytes, cartilage degradation products, and the synovium may act to perpetuate this response. Increasing evidence has emerged highlighting an important role for pro-inflammatory mediators and infiltrating inflammatory cell populations in the progression of the disease. Tissue engineering strategies hold great potential for the repair of damaged AC in an osteoarthritic joint. However, an in-depth understanding of how OA-associated inflammation impacts chondrocyte and progenitor cell behavior is required to achieve efficient cartilage regeneration in a catabolic osteoarthritic environment. In this review, we will discuss the role of inflammation in OA, and investigate novel immune modulation strategies that may prevent disease progression and facilitate successful cartilage regeneration for the treatment of OA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ten.TEB.2014.0098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321974PMC
February 2015