Matthew D Griffin

National University of Ireland, Galway, Gaillimh, Connaught, Ireland

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Publications (132)721.23 Total impact

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    ABSTRACT: Objective: Allogeneic cell therapies, such as mesenchymal stromal cells (MSC), which have potent regenerative and anti-inflammatory potential are being investigated as a therapy for osteoarthritis and cartilage injury. Here we describe another potential source of regenerative and anti-inflammatory allogeneic cells, culture expanded primary chondrocytes (CEPC). In direct comparison to allogeneic MSC, we extensively assess the immunological interactions of CEPC in an allogeneic setting. Methods: Chondrocytes were isolated from rat articular cartilage and cultured in normoxic or hypoxic conditions. In vitro co-culture assays with allogeneic lymphocytes and macrophages were used to assess the immunomodulatory capacities of the chondrocytes, followed by immune response analysis by flow cytometry, ELISA and qPCR. Results: CEPC showed reduced induction of proliferation, activation and cytotoxic granzyme-B expression in allogeneic T cells. Importantly, exposure to pro-inflammatory cytokines did not increase CEPC immunogenicity despite increases in MHC-I. Furthermore, CEPC had a potent ability to suppress allogeneic T cell proliferation, which was dependent on nitric oxide production. This suppression was contact independent in hypoxia cultured CEPC. Finally, chondrocytes were shown to have the capacity to modulate pro-inflammatory macrophage activity by reducing MHC-II expression and TNF-α secretion. Conclusion: These data indicate the potential use of allogeneic chondrocytes in osteoarthritis and cartilage defects. The lack of evident immunogenicity, despite exposure to a pro-inflammatory environment, coupled with the immunomodulatory ability indicates that these cells have the potential to evade the host immune system and suppress inflammation, thus potentially facilitating the resolution of OA induced inflammation and cartilage regeneration.
    No preview · Article · Oct 2015 · Osteoarthritis and Cartilage
  • P. Lohan · O. Treacy · K. Lynch · M. Griffin · T. Ritter · A.E. Ryan

    No preview · Article · Apr 2015 · Osteoarthritis and Cartilage
  • Sweta Rani · Aideen E Ryan · Matthew D Griffin · Thomas Ritter
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    ABSTRACT: 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.
    No preview · Article · Mar 2015 · Molecular Therapy
  • A. Ribeiro · T. Ritter · M. Griffin · R. Ceredig

    No preview · Conference Paper · Dec 2014
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    ABSTRACT: Mesenchymal stem cells (MSCs) suppress T-helper (Th)-17 cell differentiation and are being pursued clinically for the treatment of conditions associated with aberrant Th17 responses. Whether such immunomodulatory effects are enhanced by co-administration of MSCs with other agents is not well known. In this study, the individual and combined effects of MSCs and the vitamin D receptor (VDR) agonist paricalcitol on Th17 induction were investigated in vitro and in a mouse model of sterile kidney inflammation (unilateral ureteral obstruction). In-vitro, MSCs and paricalcitol additively suppressed Th17 differentiation although only MSCs suppressed expression of Th17-associated transcriptions factors. The combined administration of MSCs and paricalcitol resulted in early (day 3) reduction of intra-renal CD4(+) and CD8(+) T-cells, CD11b(+)/Ly6G(+) neutrophils and inflammatory (Ly6C(hi)) monocytes as well as reduced transcript for IL-17. Later (day 8), obstructed kidneys of MSC and paricalcitol double-treated, but not single-treated, mice had reduced tubular injury and interstitial fibrosis as well as lower numbers of neutrophils and inflammatory monocytes and an increase in the ratio between M2 (CD206(+)) and M1 (CD206(-)) macrophages compared to controls. Adjunctive therapy with VDR agonists may represent a strategy for enhancing the immunosuppressive properties of MSCs in the setting of pathogenic Th17-type immune responses and related inflammatory responses.
    No preview · Article · Oct 2014 · American journal of physiology. Renal physiology
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    Michelle M Duffy · Matthew D Griffin
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    ABSTRACT: Systemic administration of mesenchymal stem (stromal) cells (MSCs) has shown benefit in a range of experimental models of acute kidney injury, although the reported mechanisms of action and requirement for MSC localization to the kidney have varied. Geng and colleagues now demonstrate that a single intravenous infusion of MSCs given 6 hours after induction of acute muscle necrosis (rhabdomyolysis) robustly ameliorates the resulting acute kidney injury and promotes early intra-renal accumulation of CD206+ (M2) macrophages. The benefit occurred in the absence of MSC localization to the kidney and could be reproduced by adoptive transfer of ex vivo-programmed M2 macrophages.
    Preview · Article · Sep 2014 · Stem Cell Research & Therapy
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    ABSTRACT: 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
    Full-text · Article · Aug 2014 · Stem Cell Research & Therapy
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    ABSTRACT: Mesenchymal stem cells (MSCs) are being investigated extensively due to their ability to dampen immune responses. Here, we tested the ability of MSCs from three distinct sources to prolong rat corneal allograft survival. A fully allogeneic rat cornea transplant model (DA to LEW) was used. Recipient rats received 1 × 106 MSCs (syn [LEW], allo [DA] or third-party [Wistar Furth]) intravenously 7 days before transplantation and again on the day of transplantation (day 0). A high percentage of untreated and syn-MSC treated allografts were rejected (80% and 100%, respectively). Preactivation of syn-MSCs with interferon gamma also failed to prolong allograft survival. Conversely, corneal allograft survival was significantly prolonged in allo-MSC treated (90%) and third-party MSC treated (80%) allograft recipients. Flow cytometric analysis revealed less infiltrating natural killer T cells in corneas of both allo- and third-party MSC treated animals, coupled with a higher proportion of splenic CD4+Foxp3+ regulatory T cells, compared to controls. In the case of allo- and third-party MSCs, results from a delayed-type hypersensitivity assay clearly showed that hypo-responsiveness was specific for corneal donor-associated allo-antigens. Thus, allo- and third-party MSC treatment prolongs corneal allograft survival by suppressing peripheral immune responses and promoting an intragraft immunoregulatory milieu.
    Full-text · Article · Aug 2014 · American Journal of Transplantation
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    ABSTRACT: Multipotent mesenchymal stromal cells are multipotent cells capable of differentiating into different mesodermal cell types. Enigmatically, mesenchymal stromal cells present in the bone marrow support early lymphopoiesis yet can inhibit mature lymphocyte growth. Critical features of the bone marrow microenvironment, such as the level of oxygen, play an important role in mesenchymal stromal cell biology. Herein, we show that a panel of continuously growing mouse mesenchymal stromal cell lines, namely OP9, MS5, PA6, ST2 and B16-14, exhibit mesenchymal stromal cell characteristic phenotypes and respond physiologically to oxygen deprivation. Culturing freshly isolated bone marrow-derived mesenchymal stromal cells or cell lines at 5% O2 resulted in a dramatic increase in expression of hypoxia-inducible factor family members and of key genes involved in their differentiation. Phenotypically, their osteogenic and adipogenic differentiation capacity was generally improved in hypoxia, whereas their inhibitory effects on in vitro T-cell proliferation were preserved. Taken together, we conclude that these continuously growing mouse cell lines behave as canonical mesenchymal stromal cells and respond physiologically to hypoxia, thereby providing a potent tool for the study of different aspects of mesenchymal stromal cell biology.Immunology and Cell Biology advance online publication, 29 April 2014; doi:10.1038/icb.2014.30.
    No preview · Article · Apr 2014 · Immunology and Cell Biology
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    Senthilkumar Alagesan · Matthew D Griffin
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    ABSTRACT: Infusing ex vivo-generated alternatively activated macrophages (AAM) has shown promise in experimental systems as a therapeutic strategy for inflammatory kidney disease. In the mouse Adriamycin nephropathy model, however, Cao et al. report that AAM derived from bone marrow precursors fail to ameliorate disease severity. Absence of the anticipated protective effect resulted from a loss of macrophage anti-inflammatory (M2) phenotype following trafficking to injured kidney-an effect that was mediated by localized colony-stimulating factor-1-dependent macrophage proliferation.
    Preview · Article · Apr 2014 · Kidney International
  • Hatem Amer · Matthew D Griffin
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    ABSTRACT: In follow-up to a recently published randomized controlled clinical trial, Issa et al. provide evidence that systemic activity and physiological responsiveness of the renin aldosterone angiotensin system (RAAS) are well within normal limits in most kidney recipients during the first 5 years post-transplant. Implications of the results include the need to better understand intra-renal RAAS activity in transplanted kidneys and to identify patients in which the graft-protective effects of RAAS blockade are most relevant.
    No preview · Article · Feb 2014 · Kidney International
  • Senthilkumar Alagesan · Matthew D Griffin
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    ABSTRACT: Recent developments toward the successful clinical application of autologous and allogeneic mesenchymal stem cells (MSCs) to organ transplantation are summarized with a focus on safety and efficacy. Clinical trials in organ transplantation and other conditions indicate that infusion of autologous or allogeneic MSCs is generally well tolerated. However, new studies also suggest that efficacy may be curtailed by sequestration in the lungs and early elimination. Safety concerns regarding autologous and/or allogeneic MSCs that have recently been investigated include transient proinflammatory effects, influences on opportunistic infections and cancers and alloantibody induction. Animal models indicate that autologous MSCs are likely to be efficacious in preventing or treating early intragraft inflammation and may reduce the risk of acute rejection - observations that have been borne out in a randomized controlled trial of living-donor kidney transplantation. The potential for donor-specific or third-party allogeneic MSCs to promote allograft tolerance is suggested by animal model studies but has not yet been proven in humans. Recent reports on the safety and efficacy of autologous MSCs for early posttransplant outcomes give cause for optimism. Benefits of allogeneic MSCs for long-term allograft survival and of MSCs for chronic transplant injury await clinical validation.
    No preview · Article · Dec 2013 · Current opinion in organ transplantation
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    ABSTRACT: Allogeneic mesenchymal stem cells (MSC) have potent regenerative and immunosuppressive potential and are being investigated as a therapy for osteoarthritis, however little is known about the immunological changes that occur in allogeneic MSC after ex vivo induced or in vivo differentiation. 3D chondrogenic differentiation was induced in an alginate matrix, which served to immobilize and potentially protect MSC at the site of implantation. We show that allogeneic differentiated MSC lost the ability to inhibit T-cell proliferation in vitro, in association with reduced nitric oxide & prostaglandin E2 secretion. Differentiation altered immunogenicity as evidenced by induced proliferation of allogeneic T cells, and increased susceptibility to cytotoxic lysis by allo-specific T cells. Undifferentiated or differentiated allogeneic MSC were implanted subcutaneously, with and without alginate encapsulation. Increased CD3(+) and CD68(+) infiltration was evident in differentiated and splenocyte encapsulated implants only. Without encapsulation, increased local memory T-cell responses were detectable in recipients of undifferentiated and differentiated MSC; however only differentiated MSC induced systemic memory T-cell responses. In recipients of encapsulated allogeneic cells, only differentiated allogeneic MSC induced memory T-cell responses locally and systemically. Systemic allo-immune responses to differentiated MSC indicate immunogenicity regardless of alginate encapsulation and may require immunosuppressive therapy for therapeutic use.Molecular Therapy (2013); doi:10.1038/mt.2013.261.
    Full-text · Article · Nov 2013 · Molecular Therapy
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    ABSTRACT: Mesenchymal stromal (stem) cells (MSCs) continue to be a strong area of focus for academic- and industry-based researchers who share the goal of expanding their therapeutic use for diverse inflammatory and immune-mediated diseases. Recently, there has been an accelerated rate of scientific publication, clinical trial activity and commercialisation in the field. This has included the reporting of exciting new developments in four areas that will be of key importance to future successful use of MSC-based therapies in large numbers of patients: (a) Fundamental biology of the primary cells in bone marrow and other tissues that give rise to MSCs in culture. (b) Mechanisms by which MSCs modulate immune and inflammatory responses in vivo. (c) Insights into MSC kinetics, safety and efficacy in relevant animal disease models. (d) Isolation, definition and clinical trial-based testing of human MSCs by biomedical companies and academic medical centres. Despite this progress, it remains unclear whether MSCs will enter mainstream therapeutic practice as a frequently-used alternative to pharmacotherapy or surgical/radiological procedures in the foreseeable future. In this review we summarise some of the most significant new developments for each of the four areas that contribute to the process of translating MSC research to the clinical arena. In the context of this recent progress, we discuss key challenges and specific knowledge gaps which, if not addressed in a coordinated fashion, may hinder the creation of robust "translational pipelines" for consolidating the status of MSC-based therapies.
    Full-text · Article · Oct 2013 · Stem Cells
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    ABSTRACT: Urinary extracellular vesicles (uEVs) are released by cells throughout the nephron and contain biomolecules from their cells of origin. Although uEV-associated proteins and RNA have been studied in detail, little information exists regarding uEV glycosylation characteristics. Surface glycosylation profiling by flow cytometry and lectin microarray was applied to uEVs enriched from urine of healthy adults by ultracentrifugation and centrifugal filtration. The carbohydrate specificity of lectin microarray profiles was confirmed by competitive sugar inhibition and carbohydrate-specific enzyme hydrolysis. Glycosylation profiles of uEVs and purified Tamm Horsfall protein were compared. In both flow cytometry and lectin microarray assays, uEVs demonstrated surface binding, at low to moderate intensities, of a broad range of lectins whether prepared by ultracentrifugation or centrifugal filtration. In general, ultracentrifugation-prepared uEVs demonstrated higher lectin binding intensities than centrifugal filtration-prepared uEVs consistent with lesser amounts of co-purified non-vesicular proteins. The surface glycosylation profiles of uEVs showed little inter-individual variation and were distinct from those of Tamm Horsfall protein, which bound a limited number of lectins. In a pilot study, lectin microarray was used to compare uEVs from individuals with autosomal dominant polycystic kidney disease to those of age-matched controls. The lectin microarray profiles of polycystic kidney disease and healthy uEVs showed differences in binding intensity of 6/43 lectins. Our results reveal a complex surface glycosylation profile of uEVs that is accessible to lectin-based analysis following multiple uEV enrichment techniques, is distinct from co-purified Tamm Horsfall protein and may demonstrate disease-specific modifications.
    Full-text · Article · Sep 2013 · PLoS ONE
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    ABSTRACT: Postkidney transplant hyperparathyroidism is a significant problem. Vitamin D receptor agonists are known to suppress parathyroid hormone (PTH) secretion. We examined the effect of oral paricalcitol on posttransplant secondary hyperparathyroidism by conducting an open label randomized trial in which 100 incident kidney transplant recipients were randomized 1:1 to receive oral paricalcitol, 2 μg per day, for the first year posttransplant or no additional therapy. Serial measurements of serum PTH, calcium and bone alkaline phosphatase, 24-h urine calcium and bone density were performed. The primary endpoint was the frequency of hyperparathyroidism 1-year posttransplant. Eighty-seven patients completed the trial. One-year posttransplant, 29% of paricalcitol-treated subjects had hyperparathyroidism compared with 63% of untreated patients (p = 0.0005). Calcium supplementation was discontinued in two control and 15 treatment patients due to mild hypercalcemia or hypercalcuria. Paricalcitol was discontinued in four patients due to hypercalcuria/hypercalcemia and in one for preference. Two subjects required decreasing the dose of paricalcitol to 1 μg daily. Hypercalcemia was asymptomatic and reversible. Incidence of acute rejection, BK nephropathy and renal function at 1 year were similar between groups. Moderate renal allograft fibrosis was reduced in treated patients. Oral paricalcitol is effective in decreasing posttransplant hyperparathyroidism and may have beneficial effects on renal allograft histology.
    No preview · Article · Apr 2013 · American Journal of Transplantation
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    ABSTRACT: Background: The optimal approach to monitoring blood pressure (BP) in the peritoneal dialysis (PD) population is unclear. Ambulatory BP monitoring reliably predicts prognosis, but can be inconvenient. The accuracy of home BP monitoring in this population is unproven. The automated BpTRU device (BpTRU Medical Devices, Coquitlam, BC, Canada), which provides an average of up to 6 successive in-office BP measurements, has not been studied in this patient group. Methods: We studied 17 patients (average age: 54 ± 12 years; 12 men, 5 women; 94% on automated PD) attending a single center. All patients underwent office, home, BpTRU, and ambulatory BP measurement. The reference standard for analysis was daytime ambulatory BP. Correlation between the referent method and each comparator method was determined (Pearson correlation coefficient), and Bland-Altman scatter plots depicting the differences in the BP measurements were constructed. Results: Mean office BP (126.4 ± 16.9/78.8 ± 11.6 mmHg) and BpTRU BP (123.8 ± 13.7/80.7 ± 11.1 mmHg) closely approximated mean daytime ambulatory BP (129.3 ± 14.8/78.2 ± 7.9 mmHg). Mean home BP (143.8 ± 15.0/89.9 ± 28.1 mmHg) significantly overestimated mean daytime systolic BP by 14.2 mmHg (95% confidence interval: 4.3 mmHg to 24.1 mmHg; p = 0.008). Bland-Altman plots demonstrated poorest agreement between home BP and daytime ambulatory BP. No patient had "white-coat hypertension," and only 1 patient had false-resistant hypertension. Most patients showed abnormal nocturnal dipping patterns (non-dipping: n = 11; reverse-dipping: n = 5; normal dipping: n = 1). Conclusions: We report a novel finding that BP measurement using the BpTRU device is more accurate than home BP measurement in a PD population. Potential explanations for this observation include poor home BP measurement technique, use of poorly validated home BP measurement devices, or a reduced prevalence of white-coat effect among PD patients. Our study also confirms that, in the PD population, BP measurements vary considerably with patient location, time of day, and measurement technique.
    No preview · Article · Apr 2013
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    Jana Pindjakova · Matthew D Griffin

    Preview · Article · Mar 2013 · Journal of the American Society of Nephrology
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    ABSTRACT: Mesenchymal stem (stromal) cells (MSCs) have potent anti-inflammatory/ immunosuppressive properties which underlie much of their therapeutic potential. This fact has led to the widely accepted belief that MSCs from genetically unrelated individuals (allogeneic (allo)-MSCs) can be used therapeutically with equal efficacy to autologous MSCs and without triggering the donor-specific immune responses that are typically associated with allo-transplants. In this article, we critically review available experimental data to determine whether good in vivo evidence exists in support of the 'immune privileged' status of allo-MSCs. We also examine published studies regarding the immunogenicity of allo-MSCs following activation ('licensing') by inflammatory stimuli or following differentiation. Among the identified studies which have addressed in vivo immunogenicity of allo-MSCs, there was substantial variability as regards experimental species, disease model, route of MSC administration, cell dose and stringency of the immunological assays employed. Nonetheless, the majority of these studies has documented specific cellular (T-cell) and humoral (B-cell/antibody) immune responses against donor antigens following administration of non-manipulated, interferon-γ-activated and differentiated allo-MSCs. The consequences of such anti-donor immune responses were also variable and ranged from reduced in vivo survival of allo-MSCs with accelerated rejection of subsequent allogeneic transplants to apparent promotion of donor-specific tolerance. On the basis of these findings and on existing knowledge of allo-antigen recognition from the field of transplant immunology, we propose that the concept of the immune privileged nature of allo-MSCs should be reconsidered and that the range and clinical implications of anti-donor immune responses elicited by allo-MSCs be more precisely studied in human and animal recipients. © 2013 Australasian Society for Immunology Inc. All rights reserved.
    Full-text · Article · Dec 2012 · Immunology and Cell Biology
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    ABSTRACT: Conjugated linoleic acid (CLA) induces regression of preestablished atherosclerosis in the ApoE(-/-) mouse. Understanding the mechanisms involved may help in identifying novel pathways associated with the regression of human disease. Animals were administered a 1% cholesterol diet for 12 wk, with 1% CLA supplementation from wk 8 to 12. ApoE(-/-) mice fed only the 1% cholesterol diet for 12 wk were employed as controls. Transcriptomic analysis of mouse aorta showed that many of the components of the IL-10 signaling pathway were modified during CLA-induced regression. Real-time PCR and Western blot analysis showed increased IL-10 receptor expression, phosphorylation of STAT3, and downstream target gene expression in the aorta, alongside an increase in serum IL-10 (79.8±22.4 vs. 41.9±5.5 pg/ml, n=10; P<0.01). CLA -supplementation also increased IL-10 production in bone marrow-derived macrophages (143.6±28.6 vs. 94±5.6 pg/ml, n=5; P<0.05). To explore the mechanisms for altered IL-10 production, we examined the profile of monocyte/macrophage phenotype in the vessel wall, bone marrow, and spleen. CLA increased macrophage polarization toward an anti-inflammatory M2 phenotype in vivo, increasing the population of Ly6C(lo) monocytes (29 vs. 77±14, n=5, P < 0.05) in the aorta. CLA had similar effects on monocytes/macrophages differentiated from marrow-derived progenitor cells and on splenocytes. The induction of IL-10 on CLA supplementation in this model may reflect a systemic alteration toward an anti-inflammatory phenotype, which, in turn promotes increased vascular infiltration by Ly6C(lo) monocytes. These cells may contribute to CLA-induced disease regression.-McCarthy, C., Duffy, M. M., Mooney, D., James, W. G., Griffin, M. D., Fitzgerald, D. J., Belton, O. IL-10 mediates the immunoregulatory response in conjugated linoleic acid-induced regression of atherosclerosis.
    Full-text · Article · Oct 2012 · The FASEB Journal

Publication Stats

6k Citations
721.23 Total Impact Points


  • 2008-2015
    • National University of Ireland, Galway
      • Regenerative Medicine Institute
      Gaillimh, Connaught, Ireland
  • 1996-2010
    • Mayo Clinic - Rochester
      • • Department of Nephrology
      • • Department of Internal Medicine
      Rochester, Minnesota, United States
  • 2007
    • Mayo Foundation for Medical Education and Research
      • Division of Nephrology and Hypertension
      Scottsdale, AZ, United States
  • 2001-2006
    • University of California, San Francisco
      San Francisco, California, United States
  • 2005
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 1999-2001
    • University of Chicago
      • Committee on Immunology
      Chicago, IL, United States
  • 1997
    • Northwestern University
      Evanston, Illinois, United States