Andrew D Clouston

University of Queensland, Brisbane, Queensland, Australia

Are you Andrew D Clouston?

Claim your profile

Publications (195)1252.99 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Up to 10% of CF children develop cirrhosis by the first decade. We evaluated the utility of 2 simple biomarkers, APRi and FIB-4 in predicting the degree of fibrosis in pediatric cystic fibrosis liver disease (CFLD) validated by liver biopsy. In this retrospective cross-sectional study, 67 children with CFLD had dual pass liver biopsies and 104 age and gender matched CF children without liver disease (CFnoLD) had serum to calculate APRi and FIB-4 collected at enrollment. CFLD was defined as having 2 of the following: 1) hepatomegaly ± splenomegaly, 2) >6 months elevation of ALT (>1.5x ULN), or 3) abnormal liver ultrasound findings. Biopsies were staged according to Metavir classification by two blinded pathologists. ROC analysis and continuation ratio logistic regression were performed to assess the predictability of these biomarkers to distinguish CFLD from CFnoLD and determine fibrosis stage specific cutoff values. The AUC for APRi was better than FIB-4 (0.75 vs 0.60, p=0.005) for predicting CFLD and severe CFLD (F3-4) (0.81). An APRi score > 0.264 demonstrated a sensitivity (95% CI) of 73.1% (60.9,83.2) and specificity of 70.2% (60.4, 78.8) in predicting CFLD. A 50% increase in APRi was associated with a 2.4 fold (95% CI: 1.7,3.3) increased odds of having CFLD. APRi demonstrated full agreement with histology staging 37% of the time, but was within 1 stage 73% of the time. Only FIB-4 predicted portal hypertension at diagnosis (AUC=0.91, p<0.001). This is the first liver biopsy validated study of APRi and FIB-4 in pediatric CFLD. APRi appears superior to FIB-4 in differentiating CFLD vs CFnoLD. APRi also exhibited a high AUC in predicting severe liver fibrosis with specific cut-offs for lower stages. This article is protected by copyright. All rights reserved. © 2015 by the American Association for the Study of Liver Diseases.
    Hepatology 07/2015; DOI:10.1002/hep.28016 · 11.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Most colorectal polyps are readily classified, but a subset of tubulovillous adenomas (TVA) with prominent serrated architecture cause diagnostic confusion. We aimed to 1) identify histological features that separate serrated TVAs from both conventional TVAs and traditional serrated adenomas (TSA) and 2) perform a clinicopathological and molecular analysis to determine if the serrated TVA has unique features. We collected 48 serrated TVAs, 50 conventional TVAs and 66 BRAF wild-type TSAs for analysis. For each polyp we performed a clinicopathological assessment, BRAF and KRAS mutation profiling, CpG island methylator phenotype status, MGMT methylation and immunohistochemical assessment of seven markers (MLH1, p16, p53, β-catenin, Ki67, CK7 and CK20). We found that serrated TVAs can be reliably diagnosed and have features distinct from both conventional TVAs and TSAs. Compared to conventional TVAs, serrated TVAs are larger, more often proximal, more histologically advanced, show more CpG island methylation and more frequent KRAS mutation. Compared to TSAs, they are more often proximal, show less CpG island methylation, more frequent MGMT methylation and more frequent nuclear staining for β-catenin. The serrated TVA can be reliably diagnosed and has unique features. It represents a precursor of KRAS mutated, microsatellite stable colorectal carcinoma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Histopathology 07/2015; DOI:10.1111/his.12788 · 3.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8(+) Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host-DC together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (e.g. RORγt, T-bet) and cytokines (e.g. IL-17A, IL-22, IFNγ, GM-CSF, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD, however Tc17 cells are non-cytolytic and fail to mediate graft-versus-leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyper-inflammatory, poorly-cytolytic effector population which we term inflammatory Tc17 (iTc17). Since iTc17 mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL. Copyright © 2015 American Society of Hematology.
    Blood 07/2015; DOI:10.1182/blood-2015-01-622662 · 10.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Viral infection is a common, life-threatening complication after allogeneic bone marrow transplantation (BMT), particularly in the presence of graft-versus-host disease (GVHD). Using cytomegalovirus (CMV) as the prototypic pathogen, we have delineated the mechanisms responsible for the inability to mount protective anti-viral responses in this setting. While CMV infection was self-limiting after syngeneic BMT, in the presence of GVHD after allogeneic BMT, CMV induced a striking cytopathy resulting in universal mortality in conjunction with a fulminant necrotizing hepatitis. Critically, GVHD induced a profound DC defect that led to a failure in the generation of CMV-specific CD8(+) T cell responses. This was accompanied by a defect in anti-viral CD8(+) T cells. In combination, these defects dramatically limited anti-viral T cell responses. The transfer of virus-specific cells circumvented the DC defects and provided protective immunity, despite concurrent GVHD. These data demonstrate the importance of avoiding GVHD when reconstructing anti-viral immunity after BMT, and highlight the mechanisms by which the adoptive transfer of virus-specific T cells overcome the endogenous defects in priming invoked by GVHD. Copyright © 2015 American Society of Hematology.
    Blood 06/2015; DOI:10.1182/blood-2015-01-622837 · 10.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. 300 patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n=16) and evidence of progression to advanced fibrosis (n=18), by review of medical records and clinical data. Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only 2 of 227 (<1%) patients with ELF score <9.8. By contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in 6 and 4 patients, respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 61% (11/18) with an ELF score ≥9.8 showed evidence of progression to advanced fibrosis (after an average 6 years), whereas only 13.5% of those with an ELF score <9.8 (28/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression. Conclusions The ELF score is a valuable tool for risk stratification of patients with chronic liver disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 06/2015; DOI:10.1111/liv.12896 · 4.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are increasing clinical problems for which effective treatments are required. The polyphenol resveratrol prevents the development of fatty liver disease in a number of experimental studies. We hypothesized that it could revert steatohepatitis, including hepatic inflammation and fibrosis, in an experimental NASH model. To induce hepatic steatohepatitis, a 65% fat, 2% cholesterol and 0.5% cholate (HFC) diet was fed to rats for 1 or 16 weeks, prior to treatment. Subsequently, the diet was supplemented with resveratrol (approx. 100mg/rat/day) to three intervention groups; week 2-4, 2-7 or 17-22. Treated animals were sacrificed at the end of each intervention period with appropriate control and HFC diet controls. Blood and liver were harvested for analysis. When commenced early, resveratrol treatment partially mitigated transaminase elevations, hepatic enlargement and TNFα induced protein-3 protein expression, but generally resveratrol treatment had no effect on elevated hepatic triglyceride levels, histological steatohepatitis or fibrosis. We observed a slight reduction in Collagen1α1 mRNA expression and no reduction in the mRNA expression of other markers of fibrosis, inflammation or steatosis (TGFβ, TNFα, α2-MG, or SREBP-1c). Resveratrol metabolites were detected in serum, including trans-resveratrol-3-O-sulphate/trans-resveratrol-4'-O-sulphate (mean concentration 7.9μg/ml). Contrary to the findings in experimental steatosis, resveratrol treatment had no consistent therapeutic effect in alleviating manifest experimental steatohepatitis. Copyright © 2015. Published by Elsevier Ltd.
    Pharmacological Research 03/2015; 95. DOI:10.1016/j.phrs.2015.03.005 · 4.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Idiopathic Pneumonia Syndrome (IPS) is a relatively common, frequently fatal clinical entity characterized by non-infectious acute lung inflammation following allogeneic stem cell transplantation (SCT), the mechanisms of which are unclear. Here we demonstrate that immune suppression with cyclosporin after SCT limits Th1 differentiation and IFNγ secretion by donor T cells which is critical for inhibiting IL-6 generation from lung parenchyma during an alloimmune response. Thereafter, local IL-6 secretion induces donor alloantigen-specific Th17 cells to preferentially expand within the lung and blockade of IL-17A or transplantation of grafts lacking the IL-17 receptor prevents disease. Studies using IL-6(-/-) recipients or IL-6 blockade demonstrate that IL-6 is the critical driver of donor Th17 differentiation within the lung. Importantly, IL-6 is also dysregulated in patients undergoing clinical SCT and was present at very high levels in the plasma of patients with IPS compared to SCT recipients without complications. Furthermore, at the time of diagnosis, plasma IL-6 levels were higher in a subset of IPS patients who were non-responsive to steroids and anti-TNF therapy. In sum, pulmonary-derived IL-6 promotes IPS via the induction of Th17 differentiation and strategies that target these cytokines represent logical therapeutic approaches for IPS. Copyright © 2015 American Society of Hematology.
    Blood 02/2015; 125(15). DOI:10.1182/blood-2014-07-590232 · 10.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocyte clone size was measured in liver samples of 21 patients in various stages of chronic hepatitis B virus (HBV) infection and from 21 to 76 years of age. Hepatocyte clones containing unique virus–cell DNA junctions formed by the integration of HBV DNA were detected using inverse nested PCR. The maximum hepatocyte clone size tended to increase with age, although there was considerable patient-to-patient variation in each age group. There was an upward trend in maximum clone size with increasing fibrosis, inflammatory activity and with seroconversion from HBV e-antigen (HBeAg)-positive to HBeAg-negative, but these differences did not reach statistical significance. Maximum hepatocyte clone size did not differ between patients with and without a coexisting hepatocellular carcinoma. Thus, large hepatocyte clones containing integrated HBV DNA were detected during all stages of chronic HBV infection. Using laser microdissection, no significant difference in clone size was observed between foci of HBV surface antigen (HBsAg)-positive and HBsAg-negative hepatocytes, suggesting that expression of HBsAg is not a significant factor in clonal expansion. Laser microdissection also revealed that hepatocytes with normal-appearing histology make up a major fraction of the cells undergoing clonal expansion. Thus, preneoplasia does not appear to be a factor in the clonal expansion detected in our assays. Computer simulations suggest that the large hepatocyte clones are not produced by random hepatocyte turnover but have an as-yet-unknown selective advantage that drives increased clonal expansion in the HBV-infected liver.
    Journal of Viral Hepatitis 01/2015; 22(9). DOI:10.1111/jvh.12380 · 3.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE, since most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision-making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histologic definitions of BE and early EAC; prevalence, incidence, natural history and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability. This article is protected by copyright. All rights reserved.
    Journal of Gastroenterology and Hepatology 01/2015; 30(5). DOI:10.1111/jgh.12913 · 3.50 Impact Factor
  • Human pathology 12/2014; 46(4). DOI:10.1016/j.humpath.2014.10.030 · 2.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To develop a model of stress-induced senescence to study the hepatocyte senescence associated secretory phenotype (SASP). Hydrogen peroxide treatment was used to induce senescence in the human HepG2 hepatocyte cell line. Senescence was confirmed by cytochemical staining for a panel of markers including Ki67, p21, heterochromatin protein 1β, and senescence-associated-β-galactosidase activity. Senescent hepatocytes were characterised by gene expression arrays and quantitative polymerase chain reaction (qPCR), and conditioned media was used in proteomic analyses, a human chemokine protein array, and cell migration assays to characterise the composition and function of the hepatocyte SASP. Senescent hepatocytes induced classical markers of senescence (p21, heterochromatin protein 1β, and senescence-associated-β-galactosidase activity); and downregulated the proliferation marker, Ki67. Hepatocyte senescence induced a 4.6-fold increase in total secreted protein (P = 0.06) without major alterations in the protein profile. Senescence-induced genes were identified by microarray (Benjamini Hochberg-corrected P < 0.05); and, consistent with the increase in secreted protein, gene ontology analysis revealed a significant enrichment of secreted proteins among inducible genes. The hepatocyte SASP included characteristic factors such as interleukin (IL)-8 and IL-6, as well as novel components such as SAA4, IL-32 and Fibrinogen, which were validated by qPCR and/or chemokine protein array. Senescent hepatocyte-conditioned medium elicited migration of inflammatory (granulocyte-macrophage colony stimulating factor, GM-CSF-derived), but not non-inflammatory (CSF-1-derived) human macrophages (P = 0.022), which could contribute to a pro-inflammatory microenvironment in vivo, or facilitate the clearance of senescent cells. Our novel model of hepatocyte senescence provides insights into mechanisms by which senescent hepatocytes may promote chronic liver disease pathogenesis.
    12/2014; 20(47):17851-62. DOI:10.3748/wjg.v20.i47.17851
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and AimsThere is increasing need to identify individuals with advanced liver fibrosis, who are at risk of complications such as hepatocellular carcinoma. The commercially available Enhanced Liver Fibrosis (ELF) test provides a non-invasive assessment of fibrosis severity. This study was designed to determine the diagnostic accuracy of the manufacturer's cut-off value (≥9.8) in identifying advanced fibrosis.Methods The relationship between ELF score and fibrosis was examined using serum collected at time of liver biopsy for investigation of liver disease, particularly viral hepatitis. Fibrosis was staged using a modified METAVIR score. If available, liver tissue was recut and stained with Sirius red to determine collagen proportional area and subsinusoidal fibrosis.ResultsELF score ≥9.8 had a sensitivity of 74.4% and specificity 92.4% for detecting advanced fibrosis. In the whole cohort (n=329), ELF score was more likely to incorrectly classify individuals if age was ≥45 years and METAVIR inflammatory grade was 2 or 3 (adjusted OR 3.71 and 2.62 respectively). In contrast, ELF score was less likely to misclassify individuals in the presence of steatosis (OR 0.37). Neither subsinusoidal fibrosis nor collagen proportional area explained the discordance in ELF score for patients with or without advanced fibrosis.Conclusion Although ELF score ≥9.8 reliably identifies advanced fibrosis in patients with chronic liver disease, both age and inflammatory activity need to be considered when interpreting the result. Importantly, ELF score performed well in the presence of steatosis and could thus be helpful in the assessment of fatty liver disease.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 12/2014; 35(6). DOI:10.1111/liv.12760 · 4.85 Impact Factor
  • Journal of Gastroenterology and Hepatology 10/2014; 29:18-18. · 3.50 Impact Factor
  • Journal of Gastroenterology and Hepatology 10/2014; 29:19-19. · 3.50 Impact Factor
  • Journal of Gastroenterology and Hepatology 10/2014; 29:8-9. · 3.50 Impact Factor
  • Journal of Gastroenterology and Hepatology 10/2014; 29:18-19. · 3.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The traditional serrated adenoma is the least common colorectal serrated polyp. The clinicopathological features and molecular drivers of these polyps require further investigation. We have prospectively collected a cohort of 200 ordinary and advanced traditional serrated adenomas and performed BRAF and KRAS mutational profiling, CpG island methylator phenotype analysis, and immunohistochemistry for a panel of 7 antibodies (MLH1, β-catenin, p53, p16, Ki67, CK7, and CK20) on all cases. The mean age of the patients was 64 years and 50% were female. Of the polyps, 71% were distal. Advanced histology (overt dysplasia or carcinoma) was present in 19% of cases. BRAF mutation was present in 67% and KRAS mutation in 22%. BRAF mutant traditional serrated adenomas were more frequently proximal (39% versus 2%; P≤0.0001), were exclusively associated with a precursor polyp (57% versus 0%; P≤0.0001), and were more frequently CpG island methylator phenotype high (60% versus 16%; P≤0.0001) than KRAS mutant traditional serrated adenomas. Advanced traditional serrated adenomas retained MLH1 expression in 97%, showed strong p53 staining in 55%, and nuclear β-catenin staining in 40%. P16 staining was lost in the advanced areas of 55% of BRAF mutant traditional serrated adenomas compared with 10% of the advanced areas of KRAS mutant or BRAF/KRAS wild-type traditional serrated adenomas. BRAF and KRAS mutant traditional serrated adenomas are morphologically related but biologically disparate polyps with distinctive clinicopathological and molecular features. The overwhelming majority of traditional serrated adenomas retain mismatch repair enzyme function indicating a microsatellite-stable phenotype. Malignant progression occurs via TP53 mutation and Wnt pathway activation regardless of mutation status. However, CDKN2A (encoding the p16 protein) is silenced nearly exclusively in the advanced areas of the BRAF mutant traditional serrated adenomas. Thus, the BRAF mutant traditional serrated adenoma represents an important precursor of the aggressive BRAF mutant, microsatellite-stable subtype of colorectal carcinoma.Modern Pathology advance online publication, 12 September 2014; doi:10.1038/modpathol.2014.122.
    Modern Pathology 09/2014; 28(3). DOI:10.1038/modpathol.2014.122 · 6.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Fibrosis in liver with hepatitis C virus (HCV) recurrence post-liver transplantation (LT) can be rapidly progressive and the mechanisms underlying this process are poorly understood. In liver with HCV infection in the non-LT setting, there is a significant relationship between the development of structures known as the ductular reaction (DR), hepatic progenitor cells (HPCs) and fibrosis. In this study, we have characterized the DR, HPCs and fibrosis associated with HCV recurrence post-LT.Methods: Immunohistochemistry and confocal microscopy were used to characterize the DR, HPC and fibrosis in liver biopsy specimens. Key findings were confirmed in a separate independent cohort.Results: The initial characterization cohort had 194 biopsy samples from 105 individuals with HCV recurrence post-LT. The immunophenotype, morphology and location of the DR was consistent with an HPC origin. The DR correlated with intrahepatic fibrosis (rs=0.529, p<0.001) and numbers of activated hepatic stellate cells (HSCs, rs=0.446, p<0.001). There was an early occurrence of hepatocyte replicative arrest and increased hepatocyte proliferation that correlated with the DR (rs=0.295, p<0.001). Replicative arrest preceded hepatocyte proliferation in early stage injury. Hepatocyte proliferation decreased with advanced fibrosis, in contrast the extent of the DR and numbers of activated HSCs continued to increase. In the second cohort of 37 individuals, the DR and numbers of HPCs similarly correlated with fibrosis and inflammation post-LT.Conclusions: This is the first characterization of the DR in HCV-associated liver injury post-LT. There was a significant correlation between the DR and the development of progressive fibrosis in HCV recurrence. These results suggest a pivotal role for both the DR and HPC responses in the aggressive fibrosis seen with HCV recurrence post-LT. Liver Transpl , 2014. © 2014 AASLD.
    Liver Transplantation 09/2014; 20(12). DOI:10.1002/lt.24007 · 4.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Celiac disease (CeD) is a common gluten-sensitive autoimmune enteropathy. A gluten-free diet is an effective treatment, but compliance is demanding; hence, new treatment strategies for CeD are required. Objective Parasitic helminths hold promise for treating inflammatory disorders, so we examined the influence of experimental hookworm infection on the predicted outcomes of escalating gluten challenges in CeD subjects. Methods A 52-week study was conducted involving 12 adults with diet-managed CeD. Subjects were inoculated with 20 Necator americanus larvae, and escalating gluten challenges consumed as pasta were subsequently administered: (1) 10 to 50 mg for 12 weeks (microchallenge); (2) 25 mg daily + 1 g twice weekly for 12 weeks (GC-1g); and (3) 3 g daily (60-75 straws of spaghetti) for 2 weeks (GC-3g). Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined. Results Two gluten-intolerant subjects were withdrawn after microchallenge. Ten completed GC-1g, 8 of whom enrolled in and completed GC-3g. Primary outcomes: median villous height-to-crypt depth ratios (2.60-2.63; P =.98) did not decrease as predicted after GC-1g, and the mean IgA-tissue transglutaminase titers declined, contrary to the predicted rise after GC-3g. Secondary outcomes: quality of life scores improved (46.3-40.6; P =.05); celiac symptom indices (24.3-24.3; P =.53), intra-epithelial lymphocyte percentages (32.5-35.0; P =.47), and Marsh scores were unchanged by gluten challenge. Intestinal T cells expressing IFNγ were reduced following hookworm infection (23.9%-11.5%; P =.04), with corresponding increases in CD4+ Foxp3+ regulatory T cells (0.19%-1.12%; P =.001). Conclusions Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD subjects.
    Journal of Allergy and Clinical Immunology 08/2014; 135(2). DOI:10.1016/j.jaci.2014.07.022 · 11.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17-dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80+CSF-1R+CD206+iNOS-). Cutaneous cGVHD developed in a CSF-1/CSF-1R-dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r-/- mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80+ macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and lung cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti-CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD.
    Journal of Clinical Investigation 08/2014; 124(10). DOI:10.1172/JCI75935 · 13.22 Impact Factor

Publication Stats

6k Citations
1,252.99 Total Impact Points


  • 1997–2015
    • University of Queensland
      • • Centre for Liver Disease Research
      • • Department of Medicine
      • • Department of Surgery
      Brisbane, Queensland, Australia
  • 2014
    • Translational Research Institute
      Sydney, New South Wales, Australia
  • 2008–2014
    • Speech Pathology Australia
      Brisbane, Queensland, Australia
  • 1999–2013
    • Princess Alexandra Hospital (Queensland Health)
      • • Division of Medicine
      • • Division of Surgery
      Brisbane, Queensland, Australia
  • 2005–2012
    • Queensland Institute of Medical Research
      • Bone Marrow Transplantation Laboratory
      Brisbane, Queensland, Australia
    • University of Pittsburgh
      • Department of Medicine
      Pittsburgh, Pennsylvania, United States
  • 2009
    • Wesley Hospital
      Brisbane, Queensland, Australia
  • 2007
    • University of Melbourne
      Melbourne, Victoria, Australia
    • Westmead Hospital
      • Department of Medicine
      Sydney, New South Wales, Australia
    • University of Adelaide
      Tarndarnya, South Australia, Australia
  • 2003–2006
    • Royal Brisbane Hospital
      Brisbane, Queensland, Australia
  • 2004
    • University of Southern Queensland 
      Toowoomba, Queensland, Australia
  • 2002
    • Sullivan Nicolaides Pathology
      Taringa, Queensland, Australia
    • The Princess Alexandra Hospital NHS Trust
      Harlow, England, United Kingdom