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1
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Rybicka-Ramos M, Markiewicz M, Suszka-Świtek A, Wiaderkiewicz R, Mizia S, Dzierżak-Mietła M, Białas K. Profiles of interferon-gamma and interleukin-2 in patients after allogeneic hematopoietic stem cell transplantation. World J Biol Chem 2022; 13:72-82. [PMID: 36187719 PMCID: PMC9521416 DOI: 10.4331/wjbc.v13.i4.72] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/11/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be related to the occurrence of complications, including graft-versus-host disease (GvHD) and infections. The pathogenesis of acute GvHD is connected with T lymphocytes, which identify alloantigens on host's antigen-presenting cells, activate production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), and act on the immune effector cells and damage tissues and organs.
AIM The aim of the study was to investigate and distinguish serum concentration profiles of IFN-gamma and IL-2 within a 30-d period after allo-HSCT.
METHODS We enrolled 62 patients, i.e., 30 (48%) male and 32 (52%) female subjects [median age 49.5 (19-68) years], after allo-HSCT from siblings (n = 12) or unrelated donors (n = 50) due to acute myeloid leukemia with myeloablative conditioning (n = 26; 42%) and with non-myeloablative conditioning (n = 36; 58%). All patients were given standard immunosuppressive therapy with cyclosporin-A and methotrexate and pre-transplant antithymocyte globulin in the unrelated setting. Blood samples were collected pre-transplant before and after (on day -1) the conditioning therapy and on days +2,+4, +6, +10, +20, and +30 after allo-HSCT. Serum levels of IL-2 and IFN-gamma were determined using ELISA.
RESULTS Patients were divided into four groups depending on the presence of acute GvHD and clinical manifestations of infection. Group I included patients with neither acute GvHD nor infections [n = 15 (24%)], group II consisted of patients with infections without acute GvHD [n = 17 (27%)], group III was comprised of patients with acute GvHD without infections [n = 9 (15%)], and group IV included patients with both acute GvHD and infections [n = 21 (34%)]. IFN-gamma concentrations were higher in Group II than in other groups on days +20 (P = 0.014) and +30 (P = 0.008). Post-hoc tests showed lower concentrations of IFN-gamma on day +30 in groups I (P = 0.039) and IV (P = 0.017) compared to group II. The levels of IL-2 were mostly undetectable.
CONCLUSION Serum levels of IFN-gamma following allo-HSCT progressively escalate. High serum levels of IFN-gamma are related to infectious complications rather than acute GvHD. Serum concentrations of IL-2 in most patients are undetectable.
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Affiliation(s)
| | - Mirosław Markiewicz
- Department of Hematology, University of Rzeszow, College of Medical Sciences, Institute of Medical Sciences, Rzeszów 35-315, Poland
| | - Aleksandra Suszka-Świtek
- Department of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice 40-752, Poland
| | - Ryszard Wiaderkiewicz
- Department of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice 40-752, Poland
| | - Sylwia Mizia
- Department of Population Health, Division of Epidemiology and Health Education, Wroclaw Medical University, Wrocław 51-618, Poland
| | - Monika Dzierżak-Mietła
- Department of Bone Marrow Transplantation and Hematooncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice 44-102, Poland
| | - Krzysztof Białas
- Department of Hematology and Bone Marrow Transplantation, SPSK-M Hospital, Katowice 40-027, Poland
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2
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Choudhry H. The Microbiome and Its Implications in Cancer Immunotherapy. Molecules 2021; 26:E206. [PMID: 33401586 PMCID: PMC7795182 DOI: 10.3390/molecules26010206] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/22/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer is responsible for ~18 million deaths globally each year, representing a major cause of death. Several types of therapy strategies such as radiotherapy, chemotherapy and more recently immunotherapy, have been implemented in treating various types of cancer. Microbes have recently been found to be both directly and indirectly involved in cancer progression and regulation, and studies have provided novel and clear insights into the microbiome-mediated emergence of cancers. Scientists around the globe are striving hard to identify and characterize these microbes and the underlying mechanisms by which they promote or suppress various kinds of cancer. Microbes may influence immunotherapy by blocking various cell cycle checkpoints and the production of certain metabolites. Hence, there is an urgent need to better understand the role of these microbes in the promotion and suppression of cancer. The identification of microbes may help in the development of future diagnostic tools to cure cancers possibly associated with the microbiome. This review mainly focuses on various microbes and their association with different types of cancer, responses to immunotherapeutic modulation, physiological responses, and prebiotic and postbiotic effects.
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Affiliation(s)
- Hani Choudhry
- Department of Biochemistry, Faculty of Sciences, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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3
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Allogenic stem cell transplant-associated acute graft versus host disease: a computational drug discovery text mining approach using oral and gut microbiome signatures. Support Care Cancer 2020; 29:1765-1779. [PMID: 33094358 DOI: 10.1007/s00520-020-05821-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/07/2020] [Indexed: 12/23/2022]
Abstract
PURPOSE Acute graft versus host disease (aGVHD) is a major cause of non-relapse morbidity and mortality post-allogenic hematopoietic stem cell transplant (HSCT). Using conventional literature search and computational approaches, our objective was to identify oral and gut bacterial species associated with aGVHD, potentially affecting drug treatment via lipopolysaccharide (LPS) pathways. METHODS Medline, PubMed, PubMed Central, and Google Scholar were searched using MeSH terms. The top 100 hits per database were curated, and 25 research articles were selected to examine oral and gut microbiomes associated with health, HSCT, and aGVHD. Literature search validation, aGVHD drug targets, and microbial metabolic pathway identification were completed using BioReader, MACADAM, KEGG, and STRING programs. RESULTS Our review determined that (1) oral genera Rothia, Solobacterium, and Veillonella were identified in HSCT patients' stool and associated with aGVHD; (2) shifts in gut enterococci profiles were determined in HSCT-associated aGVHD; (3) gut microbiome dysbiosis prior or during HSCT and lower Shannon diversity index at time of HSCT were also associated with increased risk of aGVHD and transplant related death; and (4) Coriobacteriaceae family was negatively correlated with gut aGVHD, whereas Eubacterium limosum was associated with decreased risk of chronic GVHD relapse. Additionally, we identified molecular pathways related to TLR4/ LPS, including candidate aGVHD drug targets, impacted by oral and gut bacterial taxa. CONCLUSION Reduced microbial diversity reflects higher severity and mortality rate in HSCT patients with aGVHD. Multi-omics approaches to decipher oral and gut microbiome associations will be critical for developing aGVHD preventive therapies.
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4
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Kumari R, Palaniyandi S, Strattan E, Huang T, Kohler K, Jabbour N, Dalland J, Du J, Kesler MV, Chen YH, Hildebrandt GC. TNFAIP8 Deficiency Exacerbates Acute Graft Versus Host Disease in a Murine Model of Allogeneic Hematopoietic Cell Transplantation. Transplantation 2019; 104:500-510. [PMID: 31634333 DOI: 10.1097/tp.0000000000003013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Gastrointestinal acute graft-versus-host disease (GVHD) occurring after allogeneic hematopoietic cell transplant is an allo-reactive T cell and inflammatory cytokine driven organ injury with epithelial apoptosis as 1 of its hallmark findings and is associated with significant mortality. Tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8 or TIPE) acts as a negative mediator of apoptosis via inhibition of caspase-3 activation, promotes cell proliferation and Tipe deficiency is associated with increased inflammation. METHODS To evaluate the role of TIPE in acute GVHD, naive C57BL/6 and Tipe C57BL/6 mice were conditioned with 1000 cGy single dose total body irradiation, followed by transplantation of 10 million bone marrow cells and 20 million splenocytes from either syngeneic C57BL/6 or allogeneic BALB/c donors. RESULTS Allo TIPE-deficient mice developed exacerbated gut GVHD compared with allo controls and had significantly decreased survival (6 wk overall survival: 85% versus 37%; P < 0.05), higher clinical GVHD scores, more profound weight loss, increased serum proinflammatory cytokines (interleukin-17A, TNF, interleukin-6, and interferon-γ). T-cell infiltration into the ileum was increased; epithelial proliferation was decreased along with significantly higher levels of chemokines KC and monokine induced by gamma interferon. Using bone marrow chimeric experiments, TIPE was found to have a role in both hematopoietic and nonhematopoietic cells. CONCLUSIONS Absence of TIPE results in excessive inflammation and tissue injury after allo-HCT, supporting that TIPE confers immune homeostasis and has tissue-protective function during the development of gut GVHD and may be a potential future target to prevent or treat this complication after allogeneic HCT.
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Affiliation(s)
- Reena Kumari
- Division of Hematology & Blood and Marrow Transplantation, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY
| | - Senthilnathan Palaniyandi
- Division of Hematology & Blood and Marrow Transplantation, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY
| | - Ethan Strattan
- Division of Hematology & Blood and Marrow Transplantation, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY.,Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY
| | - Timothy Huang
- Division of Hematology & Blood and Marrow Transplantation, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY
| | - Katharina Kohler
- Division of Hematology & Blood and Marrow Transplantation, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY
| | - Nashwan Jabbour
- Division of Hematology & Blood and Marrow Transplantation, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY
| | - Joanna Dalland
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY
| | - Jing Du
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY
| | - Melissa V Kesler
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY
| | - Youhai H Chen
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
| | - Gerhard C Hildebrandt
- Division of Hematology & Blood and Marrow Transplantation, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY.,Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY
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Weiner LD, Retuerto M, Hager CL, El Kamari V, Shan L, Sattar A, Kulkarni M, Funderburg N, Ghannoum MA, Dirajlal-Fargo S, McComsey GA. Fungal Translocation Is Associated with Immune Activation and Systemic Inflammation in Treated HIV. AIDS Res Hum Retroviruses 2019; 35:461-472. [PMID: 30784316 DOI: 10.1089/aid.2018.0252] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The mechanisms causing HIV-associated immune activation remain incompletely understood. Alteration of intestinal integrity with subsequent translocation of bacterial products appears to play an important role; however, little is known about the impact of fungal translocation. We assessed the effect of fungal translocation and its association with immune activation in people living with HIV (PLWH) compared with uninfected controls. We measured serum levels of β-D-glucan (BDG) and anti-Saccharomyces cerevisiae antibodies (ASCA) immunoglobulin G (IgG) and immunoglobulin A (IgA) and markers of systemic inflammation and immune activation in virally suppressed PLWH on antiretroviral therapy (ART) and uninfected controls. T-test and Mann-Whitney tests were used to compare markers by HIV status and correlation and regression analyses were used to assess associations of fungal translocation markers with markers of inflammation. One hundred seventy-six participants were included (128 HIV+ and 48 HIV-); 72% male, 65% African American, median age was 50 years, and CD4 was 710 cells/cm3. Levels of BDG tended to be lower in HIV+ when compared with controls (p = .05). No significant difference in levels of ASCA IgG and IgA was seen between groups (p > .75). There was a significant correlation between BDG and several markers of inflammation and immune activation in PLWH, not seen in uninfected controls. In contrast, no correlations were seen between levels of ASCA IgG and IgA with inflammatory markers. PLWH on ART do not have higher levels of BDG or ASCA when compared with uninfected controls, however, the association found between BDG and several inflammation markers suggests a potential role of fungal translocation in the heightened immune activation seen in treated HIV.
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Affiliation(s)
- Lukasz D. Weiner
- Pediatric Infectious Diseases, University Hospitals Cleveland Medical Center, Cleveland, Ohio
- Rainbow Babies and Children's Hospital, Cleveland, Ohio
| | - Mauricio Retuerto
- Case Western Reserve University, Cleveland, Ohio
- Center for Medical Mycology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Christopher L. Hager
- Case Western Reserve University, Cleveland, Ohio
- Center for Medical Mycology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | | | | | - Abdus Sattar
- Case Western Reserve University, Cleveland, Ohio
| | - Manjusha Kulkarni
- Ohio State University School of Health and Rehabilitation Sciences, Columbus, Ohio
| | - Nicholas Funderburg
- Ohio State University School of Health and Rehabilitation Sciences, Columbus, Ohio
| | - Mahmoud A. Ghannoum
- Case Western Reserve University, Cleveland, Ohio
- Center for Medical Mycology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Sahera Dirajlal-Fargo
- Pediatric Infectious Diseases, University Hospitals Cleveland Medical Center, Cleveland, Ohio
- Rainbow Babies and Children's Hospital, Cleveland, Ohio
- Case Western Reserve University, Cleveland, Ohio
| | - Grace A. McComsey
- Pediatric Infectious Diseases, University Hospitals Cleveland Medical Center, Cleveland, Ohio
- Rainbow Babies and Children's Hospital, Cleveland, Ohio
- Case Western Reserve University, Cleveland, Ohio
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6
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Rashidi A, Shanley R, Holtan SG, MacMillan ML, Blazar BR, Khoruts A, Weisdorf DJ. Pretransplant Serum Citrulline Predicts Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 2018; 24:2190-2196. [PMID: 30454871 PMCID: PMC6251308 DOI: 10.1016/j.bbmt.2018.06.036] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/29/2018] [Indexed: 12/11/2022]
Abstract
Post-transplant biomarkers of acute graft-versus-host disease (aGVHD) and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) have been extensively studied. However, pretransplant biomarkers may provide a greater window of opportunity to intervene. We measured serum biomarkers of various aspects of gut barrier physiology before HCT (median, day -7) and 7 and 28 days post-HCT in 95 consecutive allo-HCT recipients enrolled in an open-label biorepository protocol. Biomarkers included citrulline for total functional enterocyte mass, Reg3a for antibacterial activity of the gut, and intestinal fatty acid binding protein (I-FABP) for enterocyte turnover. Compared to 16 healthy control subjects, we demonstrated that patients came to transplant with abnormal levels of all 3 biomarkers (P < .05), reflecting residual damage from prior chemotherapy. All 3 biomarkers initially declined from pre-HCT to day +7 (more pronounced after myeloablative than reduced-intensive conditioning) followed by a recovery phase and return toward pre-HCT values by day +28. A lower pre-HCT citrulline was independently associated with a higher risk of aGVHD grades II to IV (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.69; P = .02), and this association was not specific to gut GVHD. The strongest correlate of NRM was a higher level of Reg3a at day +7 (P < .001). I-FABP did not predict transplant outcomes. In conclusion, pre-HCT serum citrulline levels identify patients at high risk for developing aGVHD. Our results suggest that pre-HCT interventions to augment the gut barrier may decrease the risk of aGVHD.
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Affiliation(s)
- Armin Rashidi
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
| | - Ryan Shanley
- Masonic Cancer Center Biostatistics Core, University of Minnesota, Minneapolis, Minnesota
| | - Shernan G Holtan
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Margaret L MacMillan
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Alexander Khoruts
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Daniel J Weisdorf
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
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7
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Lynn DJ, Pulendran B. The potential of the microbiota to influence vaccine responses. J Leukoc Biol 2017; 103:225-231. [PMID: 28864446 DOI: 10.1189/jlb.5mr0617-216r] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 07/21/2017] [Accepted: 08/01/2017] [Indexed: 12/25/2022] Open
Abstract
After clean water, vaccines are the primary public health intervention providing protection against serious infectious diseases. Antigen-specific antibody-mediated responses play a critical role in the protection conferred by vaccination; however these responses are highly variable among individuals. In addition, vaccine immunogenicity is frequently impaired in developing world populations, for reasons that are poorly understood. Although the factors that are associated with interindividual variation in vaccine responses are likely manifold, emerging evidence from mouse models and studies in human populations now suggests that the gut microbiome plays a key role in shaping systemic immune responses to both orally and parenterally administered vaccines. Herein, we review the evidence to date that the microbiota can influence vaccine responses and discuss the potential mechanisms through which these effects may be mediated. In addition, we highlight the gaps in this evidence and suggest future directions for research.
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Affiliation(s)
- David J Lynn
- Infection and Immunity Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia, Australia.,School of Medicine, Flinders University, Bedford Park, South Australia, Australia
| | - Bali Pulendran
- Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.,Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.,Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
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8
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Yong YK, Tan HY, Jen SH, Shankar EM, Natkunam SK, Sathar J, Manikam R, Sekaran SD. Aberrant monocyte responses predict and characterize dengue virus infection in individuals with severe disease. J Transl Med 2017; 15:121. [PMID: 28569153 PMCID: PMC5452397 DOI: 10.1186/s12967-017-1226-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 05/27/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Currently, several assays can diagnose acute dengue infection. However, none of these assays can predict the severity of the disease. Biomarkers that predicts the likelihood that a dengue patient will develop a severe form of the disease could permit more efficient patient triage and allows better supportive care for the individual in need, especially during dengue outbreaks. METHODS We measured 20 plasma markers i.e. IFN-γ, IL-10, granzyme-B, CX3CL1, IP-10, RANTES, CXCL8, CXCL6, VCAM, ICAM, VEGF, HGF, sCD25, IL-18, LBP, sCD14, sCD163, MIF, MCP-1 and MIP-1β in 141 dengue patients in over 230 specimens and correlate the levels of these plasma markers with the development of dengue without warning signs (DWS-), dengue with warning signs (DWS+) and severe dengue (SD). RESULTS Our results show that the elevation of plasma levels of IL-18 at both febrile and defervescence phase was significantly associated with DWS+ and SD; whilst increase of sCD14 and LBP at febrile phase were associated with severity of dengue disease. By using receiver operating characteristic (ROC) analysis, the IL-18, LBP and sCD14 were significantly predicted the development of more severe form of dengue disease (DWS+/SD) (AUC = 0.768, P < 0.0001; AUC = 0.819, P < 0.0001 and AUC = 0.647, P = 0.014 respectively). Furthermore, we also found that the levels of VEGF were directly correlated and sCD14 was inversely correlated with platelet count, suggesting that the endothelial activation and microbial translocation may played a role in pathogenesis of dengue disease. CONCLUSIONS Given that the elevation IL-18, LBP and sCD14 among patients with severe form of dengue disease, our findings suggest a pathogenic role for an aberrant inflammasome and monocyte activation in the development of severe form of dengue disease.
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Affiliation(s)
- Yean K Yong
- Centre of Excellence for Research in AIDS (CERiA), Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Hong Y Tan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia
| | - Soe Hui Jen
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia
| | - Esaki M Shankar
- Division of Infection Biology and Microbiology, Department of Life Sciences, School of Basic and Applied Sciences, Central University of Tamil Nadu (CUTN), Neelakudi Campus, Tiruvarur, India
| | - Santha K Natkunam
- Hospital Tengku Ampuan Rahimah, Persiaran Tengku Ampuan Rahimah, Klang, Selangor, Malaysia
| | - Jameela Sathar
- Clinical Hematology Laboratory, Department of Hematology, Hospital Ampang, Ampang, Selangor, Malaysia
| | - Rishya Manikam
- Department of Trauma and Emergency Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Shamala D Sekaran
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia.
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Depincé-Berger AE, Vergnon-Miszczycha D, Girard A, Frésard A, Botelho-Nevers E, Lambert C, Del Tedesco E, Genin C, Pozzetto B, Lucht F, Roblin X, Bourlet T, Paul S. Major influence of CD4 count at the initiation of cART on viral and immunological reservoir constitution in HIV-1 infected patients. Retrovirology 2016; 13:44. [PMID: 27363286 PMCID: PMC4929778 DOI: 10.1186/s12977-016-0278-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 06/20/2016] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND A persistent immune activation is observed in gut during HIV-1 infection, which is not completely reversed by a combined antiretroviral therapy (cART). The impact of the time of cART initiation may highly influence the size of the viral reservoir and the ratio of CD4(+)/CD8(+) T cells in the gut. In this study, we analyzed the characteristics of HIV rectal reservoir of long-term treated patients, regarding their blood CD4(+) T cells count at the time of cART initiation. RESULTS Twenty-four consenting men were enrolled: 9 exhibiting a CD4(+) T cells count >350/mm(3) ("high-level CD4 group") and 15 < 350/mm(3) ("low-level CD4 group") in blood, at the start of cART. An immunophenotypical analysis of T and B cells subpopulations was performed in blood and rectal biopsies. HIV cell-associated DNA loads and qualitative intra-cellular RNA were determined in both compartments. The ratio of CD4(+)/CD8(+) T cells was significantly decreased in the blood but not in the rectum of the "low-level CD4 group" of patients. The alteration in β7(+) CD4(+) T cells homing was higher in this group and was correlated to a low ratio of CD4(+)/CD8(+) T cells in blood. An initiation of cART in men exhibiting a low-level CD4 count was also associated with an alteration of B cells maturation. HIV blood and gut DNA reservoirs were significantly lower in the "high-level CD4 group" of men. A high HIV DNA level was associated to a detectable intracellular HIV RNA in rectum. CONCLUSIONS An early initiation of cART could significantly preserve gut immunity and limit the viral reservoir constitution.
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Affiliation(s)
- Anne-Emmanuelle Depincé-Berger
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Laboratoire d’Immunologie, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Delphine Vergnon-Miszczycha
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Service de Maladies Infectieuses et Tropicales, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Alexandre Girard
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
| | - Anne Frésard
- />Service de Maladies Infectieuses et Tropicales, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Elisabeth Botelho-Nevers
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Service de Maladies Infectieuses et Tropicales, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Claude Lambert
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Laboratoire d’Immunologie, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Emilie Del Tedesco
- />Service d’Hépato-Gastroentérologie, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Christian Genin
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Laboratoire d’Immunologie, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Bruno Pozzetto
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Service des Agents Infectieux et d’Hygiène, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Frédéric Lucht
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Service de Maladies Infectieuses et Tropicales, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Xavier Roblin
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Service d’Hépato-Gastroentérologie, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Thomas Bourlet
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Service des Agents Infectieux et d’Hygiène, Centre Hospitalo-Universitaire, Saint-Étienne, France
| | - Stéphane Paul
- />Groupe Immunité des Muqueuses et Agents Pathogènes – GIMAP EA 3064, CIC 1408, Faculté de Médecine J. Lisfranc, Université de Saint-Etienne, Université de Lyon, 42023 Saint-Étienne Cedex 02, France
- />Laboratoire d’Immunologie, Centre Hospitalo-Universitaire, Saint-Étienne, France
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10
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Guinan E, Avigan DE, Soiffer RJ, Bunin NJ, Brennan LL, Bergelson I, Brightman S, Ozonoff A, Scannon PJ, Levy O. Pilot experience with opebacan/rBPI 21 in myeloablative hematopoietic cell transplantation. F1000Res 2016; 4:1480. [PMID: 26835003 PMCID: PMC4722698 DOI: 10.12688/f1000research.7558.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/15/2015] [Indexed: 12/26/2022] Open
Abstract
Bacterial infection and inflammation contribute significantly to the morbidity and mortality of myeloablative allogeneic hematopoietic cell transplantation (HCT). Endotoxin, a component of the outer membrane of Gram-negative bacteria, is a potent inflammatory stimulus in humans. Bactericidal/permeability increasing protein (BPI), a constituent of human neutrophil granules, binds endotoxin thereby precluding endotoxin-induced inflammation and also has direct anti-infective properties against bacteria. As a consequence of myeloablative therapy used in preparation for hematopoietic cell infusion, patients experience gastrointestinal leak of bacteria and bacterial toxins into the systemic circulation and a period of inflammatory cytokine elevation associated with subsequent regimen-related toxicities. Patients frequently become endotoxemic and febrile as well as BPI-deficient due to sustained neutropenia. To examine whether enhancing endotoxin-neutralizing and anti-infective activity by exogenous administration of a recombinant N-terminal fragment of BPI (rBPI
21, generic name opebacan) might ameliorate regimen-related toxicities including infection, we recruited patients scheduled to undergo myeloablative HCT to participate in a proof-of-concept prospective phase I/II trial. After the HCT preparative regimen was completed, opebacan was initiated 18-36 hours prior to administration of allogeneic hematopoietic stem cells (defined as Day 0) and continued for 72 hours. The trial was to have included escalation of rBPI
21 dose and duration but was stopped prematurely due to lack of further drug availability. Therefore, to better understand the clinical course of opebacan-treated patients (n=6), we compared their outcomes with a comparable cohort meeting the same eligibility criteria and enrolled in a non-interventional myeloablative HCT observational study (n = 35). Opebacan-treated participants had earlier platelet engraftment (p=0.005), mirroring beneficial effects of rBPI
21 previously observed in irradiated mice, fewer documented infections (p=0.03) and appeared less likely to experience significant regimen-related toxicities (p=0.05). This small pilot experience supports the potential utility of rBPI
21 in ameliorating HCT-related morbidity and merits further exploration.
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Affiliation(s)
- Eva Guinan
- Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA; Boston Children's Hospital, Boston, USA
| | - David E Avigan
- Harvard Medical School, Boston, USA; Beth Israel Deaconess Medical Center, Boston, USA
| | - Robert J Soiffer
- Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA; Brigham and Women's Hospital, Boston, USA
| | - Nancy J Bunin
- Children's Hospital of Philadelphia, Philadelphia, USA
| | | | | | | | - Al Ozonoff
- Harvard Medical School, Boston, USA; Boston Children's Hospital, Boston, USA
| | | | - Ofer Levy
- Harvard Medical School, Boston, USA; Boston Children's Hospital, Boston, USA
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11
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Espinosa-Carrasco G, Villard M, Le Saout C, Louis-Plence P, Vicente R, Hernandez J. Systemic LPS Translocation Activates Cross-Presenting Dendritic Cells but Is Dispensable for the Breakdown of CD8+ T Cell Peripheral Tolerance in Irradiated Mice. PLoS One 2015; 10:e0130041. [PMID: 26075613 PMCID: PMC4468093 DOI: 10.1371/journal.pone.0130041] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 05/15/2015] [Indexed: 11/26/2022] Open
Abstract
Lymphodepletion is currently used to enhance the efficacy of cytotoxic T lymphocyte adoptive transfer immunotherapy against cancer. This beneficial effect of conditioning regimens is due, at least in part, to promoting the breakdown of peripheral CD8+ T cell tolerance. Lymphodepletion by total body irradiation induces systemic translocation of commensal bacteria LPS from the gastrointestinal tract. Since LPS is a potent activator of the innate immune system, including antigen presenting dendritic cells, we hypothesized that LPS translocation could be required for the breakdown of peripheral tolerance observed in irradiated mice. To address this issue, we have treated irradiated mice with antibiotics in order to prevent LPS translocation and utilized them in T cell adoptive transfer experiments. Surprisingly, we found that despite of completely blocking LPS translocation into the bloodstream, antibiotic treatment did not prevent the breakdown of peripheral tolerance. Although irradiation induced the activation of cross-presenting CD8+ dendritic cells in the lymphoid tissue, LPS could not solely account for this effect. Activation of dendritic cells by mechanisms other than LPS translocation is sufficient to promote the differentiation of potentially autoreactive CD8+ T cells into effectors in irradiated mice. Our data indicate that LPS translocation is dispensable for the breakdown of CD8+ T cell tolerance in irradiated mice.
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Affiliation(s)
- Gabriel Espinosa-Carrasco
- Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France
- Université Montpellier, UFR de Médecine, Montpellier, F-34000, France
| | - Marine Villard
- Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France
- Université Montpellier, UFR de Médecine, Montpellier, F-34000, France
| | - Cecile Le Saout
- CMRS/Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland, United States of America
| | - Pascale Louis-Plence
- Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France
- Université Montpellier, UFR de Médecine, Montpellier, F-34000, France
| | - Rita Vicente
- Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France
- Université Montpellier, UFR de Médecine, Montpellier, F-34000, France
| | - Javier Hernandez
- Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France
- Université Montpellier, UFR de Médecine, Montpellier, F-34000, France
- * E-mail:
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12
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13
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Sporrer D, Gessner A, Hehlgans T, Oefner PJ, Holler E. The Microbiome and Allogeneic Stem Cell Transplantation. CURRENT STEM CELL REPORTS 2015. [DOI: 10.1007/s40778-014-0006-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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14
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Abstract
Acute graft versus host disease (GVHD), a common complication after allogeneic hematopoietic cell transplantation (HCT), occurs in as many as 70% of recipients of this life saving treatment. Front line therapy for GVHD with corticosteroids will fail in up to 40% of patients, which leads to high morbidity and mortality. Traditional prevention and treatment strategies have focused on reducing alloreactivity, typically with therapy to reduce cytotoxic T-cell function. Emerging evidence exists that promotion of regularly T-cell function, through treatments such as extracorporeal photopheresis, is effective for GVHD treatment and has potential for prevention as well. This review will focus on literature reporting the success of ECP for steroid refractory acute GVHD and the potential for delivery of ECP in the early pre and post-transplant periods that shows promise as a less immunosuppressive strategy to reduce rates of acute GVHD.
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Affiliation(s)
- Carrie L Kitko
- Blood and Marrow Transplant Program, Division of Pediatric Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr. MPB 4202, Ann Arbor, MI 48109-5718.
| | - John E Levine
- Blood and Marrow Transplant Program, Division of Pediatric Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr. MPB 4202, Ann Arbor, MI 48109-5718
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15
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Hernandez JC, Giraldo DM, Paul S, Urcuqui-Inchima S. Involvement of neutrophil hyporesponse and the role of Toll-like receptors in human immunodeficiency virus 1 protection. PLoS One 2015; 10:e0119844. [PMID: 25785697 PMCID: PMC4364960 DOI: 10.1371/journal.pone.0119844] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 01/16/2015] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVES Neutrophils contribute to pathogen clearance through pattern recognition receptors (PRRs) activation. However, the role of PRRs in neutrophils in both HIV-1-infected [HIV-1(+)] and HIV-1-exposed seronegative individuals (HESN) is unknown. Here, a study was carried out to evaluate the level of PRR mRNAs and cytokines produced after activation of neutrophils from HIV-1(+), HESN and healthy donors. METHODS The neutrophils were stimulated with specific agonists for TLR2, TLR4 and TLR9 in the presence of HIV-1 particles. Pro-inflammatory cytokine production, expression of neutrophil activation markers and reactive oxygen species (ROS) production were analyzed in neutrophils from HESN, HIV-1(+) and healthy donors (controls). RESULTS We found that neutrophils from HESN presented reduced expression of PRR mRNAs (TLR4, TLR9, NOD1, NOD2, NLRC4 and RIG-I) and reduced expression of cytokine mRNAs (IL-1β, IL-6, IL-18, TNF-α and TGF-β). Moreover, neutrophils from HESN were less sensitive to stimulation through TLR4. Furthermore, neutrophils from HESN challenged with HIV-1 and stimulated with TLR2 and TLR4 agonists, produced significantly lower levels of reactive oxygen species, versus HIV-1(+). CONCLUSIONS A differential pattern of PRR expression and release of innate immune factors in neutrophils from HESN is evident. Our results suggest that lower neutrophil activation can be involved in protection against HIV-1 infection.
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Affiliation(s)
- Juan C. Hernandez
- INFETTARE, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellin, Colombia
| | - Diana M. Giraldo
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - Stephane Paul
- GIMAP EA3064, Faculté de Medicine de Saint Etienne, Université de Lyon, Lyon, France
| | - Silvio Urcuqui-Inchima
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
- * E-mail:
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16
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Ricci MJ, Medin JA, Foley RS. Advances in haplo-identical stem cell transplantation in adults with high-risk hematological malignancies. World J Stem Cells 2014; 6:380-390. [PMID: 25258660 PMCID: PMC4172667 DOI: 10.4252/wjsc.v6.i4.380] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 04/24/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
Allogeneic bone marrow transplant is a life-saving procedure for adults and children that have high-risk or relapsed hematological malignancies. Incremental advances in the procedure, as well as expanded sources of donor hematopoietic cell grafts have significantly improved overall rates of success. Yet, the outcomes for patients for whom suitable donors cannot be found remain a significant limitation. These patients may benefit from a hematopoietic cell transplant wherein a relative donor is fully haplotype mismatched. Previously this procedure was limited by graft rejection, lethal graft-versus-host disease, and increased treatment-related toxicity. Recent approaches in haplo-identical transplantation have demonstrated significantly improved outcomes. Based on years of incremental pre-clinical research into this unique form of bone marrow transplant, a range of approaches have now been studied in patients in relatively large phase II trials that will be summarized in this review.
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17
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van der Velden WJFM, Herbers AHE, Netea MG, Blijlevens NMA. Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br J Haematol 2014; 167:441-52. [PMID: 25196917 DOI: 10.1111/bjh.13113] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Infection remains one of the most prominent complications after cytotoxic treatment for cancer. The connection between neutropenia and both infections and fever has long been designated as 'febrile neutropenia', but treatment with antimicrobial agents and haematopoietic growth factors has failed to significantly reduce its incidence. Moreover, emerging antimicrobial resistance is becoming a concern that necessitates the judicious use of available antimicrobial agents. In addition to neutropenia, patients who receive cytotoxic therapy experience mucosal barrier injury (MBI) or 'mucositis'. MBI creates a port-de-entrée for resident micro-organisms to cause blood stream infections and contributes directly to the occurrence of fever by disrupting the highly regulated host-microbe interactions, which, even in the absence of an infection, can result in strong inflammatory reactions. Indeed, MBI has been shown to be a pivotal factor in the occurrence of inflammatory complications after cytotoxic therapy. Hence, the concept 'febrile neutropenia' alone may no longer suffice and a new concept 'febrile mucositis' should be recognized as the two are at least complementary. This review we summarizes the existing evidence for both paradigms and proposes new therapeutic approaches to tackle the perturbed host-microbe interactions arising from cytotoxic therapy-induced tissue damage in order to reduce fever in neutropenic patients with cancer.
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18
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Reducing the bioactivity of Tannerella forsythia lipopolysaccharide by Porphyromonas gingivalis. J Microbiol 2014; 52:702-8. [DOI: 10.1007/s12275-014-4324-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 06/23/2014] [Accepted: 06/27/2014] [Indexed: 01/01/2023]
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19
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Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals. PLoS Pathog 2014; 10:e1004198. [PMID: 24968145 PMCID: PMC4072797 DOI: 10.1371/journal.ppat.1004198] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Accepted: 05/06/2014] [Indexed: 01/11/2023] Open
Abstract
Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation--a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.
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20
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Fuji S, Kapp M, Einsele H. Possible implication of bacterial infection in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Front Oncol 2014; 4:89. [PMID: 24795865 PMCID: PMC4006055 DOI: 10.3389/fonc.2014.00089] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 04/10/2014] [Indexed: 12/24/2022] Open
Abstract
Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the pathogenesis of acute GVHD, it has been established that donor-derived T-cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T-cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT.
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Affiliation(s)
- Shigeo Fuji
- Division of Hematology, Department of Internal Medicine II, University Hospital of Würzburg , Würzburg , Germany ; Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital , Tokyo , Japan
| | - Markus Kapp
- Division of Hematology, Department of Internal Medicine II, University Hospital of Würzburg , Würzburg , Germany
| | - Hermann Einsele
- Division of Hematology, Department of Internal Medicine II, University Hospital of Würzburg , Würzburg , Germany
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21
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Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K, Zhu W, Sporrer D, Hehlgans T, Kreutz M, Holler B, Wolff D, Edinger M, Andreesen R, Levine JE, Ferrara JL, Gessner A, Spang R, Oefner PJ. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant 2014; 20:640-5. [PMID: 24492144 DOI: 10.1016/j.bbmt.2014.01.030] [Citation(s) in RCA: 414] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 01/28/2014] [Indexed: 12/12/2022]
Abstract
Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens collected from 31 patients receiving allogeneic stem cell transplantation (SCT) was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was complemented by strain-specific enterococcal PCR and indirect assessment of bacterial load by liquid chromatography-tandem mass spectrometry of urinary indoxyl sulfate. At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections. The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD). The mean proportion of enterococci in post-transplant stool specimens was 21% in patients who did not develop GI GVHD as compared with 46% in those that subsequently developed GI GVHD and 74% at the time of active GVHD. Enterococcal PCR confirmed predominance of Enterococcus faecium or both E. faecium and Enterococcus faecalis in these specimens. As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 ± 11 μmol/L to 11.8 ± 2.8 μmol/L in all post-transplant samples and to 3.5 ± 3 μmol/L in samples from patients with active GVHD. Our study reveals major microbiome shifts in the course of allogeneic SCT that occur in the period of antibiotic treatment but are more prominent in association with GI GVHD. Our data indicate early microbiome shifts and a loss of diversity of the intestinal microbiome that may affect intestinal inflammation in the setting of allogeneic SCT.
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Affiliation(s)
- Ernst Holler
- Department of Hematology/Oncology, University Medical Center, Regensburg, Germany.
| | - Peter Butzhammer
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Karin Schmid
- Department of Hematology/Oncology, University Medical Center, Regensburg, Germany
| | | | - Josef Koestler
- Institute of Microbiology, University Medical Center, Regensburg, Germany
| | - Katrin Peter
- Department of Hematology/Oncology, University Medical Center, Regensburg, Germany
| | - Wentao Zhu
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Daniela Sporrer
- Department of Hematology/Oncology, University Medical Center, Regensburg, Germany
| | - Thomas Hehlgans
- Institute of Immunology, University of Regensburg, Regensburg, Germany
| | - Marina Kreutz
- Department of Hematology/Oncology, University Medical Center, Regensburg, Germany
| | - Barbara Holler
- Department of Hematology/Oncology, University Medical Center, Regensburg, Germany
| | - Daniel Wolff
- Department of Hematology/Oncology, University Medical Center, Regensburg, Germany
| | - Matthias Edinger
- Department of Hematology/Oncology, University Medical Center, Regensburg, Germany
| | - Reinhard Andreesen
- Department of Hematology/Oncology, University Medical Center, Regensburg, Germany
| | - John E Levine
- University of Michigan Medical Center, Blood and Marrow Transplantation Program, Ann Arbor, Michigan
| | - James L Ferrara
- University of Michigan Medical Center, Blood and Marrow Transplantation Program, Ann Arbor, Michigan
| | - Andre Gessner
- Institute of Microbiology, University Medical Center, Regensburg, Germany
| | - Rainer Spang
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Peter J Oefner
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
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22
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Kourtis AP, Ibegbu CC, Wiener J, King CC, Tegha G, Kamwendo D, Kumwenda J, Kaur SP, Flax V, Ellington S, Kacheche Z, Kayira D, Chasela C, van der Horst C, Jamieson DJ. Role of intestinal mucosal integrity in HIV transmission to infants through breast-feeding: the BAN study. J Infect Dis 2013; 208:653-61. [PMID: 23687226 DOI: 10.1093/infdis/jit221] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Increased intestinal permeability may be one of the mechanisms of transmission of human immunodeficiency virus (HIV) to infants through breast-feeding. Intestinal permeability correlates with microbial translocation, which can be measured through quantification of bacterial lipopolysaccharide (LPS). METHODS We evaluated levels of plasma LPS (by the Limulus amebocyte lysate assay) and immune activation markers in serial specimens from infants exposed to but uninfected with HIV and infants infected with HIV from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study. RESULTS Plasma LPS levels increased after infants in the BAN study were weaned from the breast, at 24 weeks of age. Cotrimoxazole prophylaxis was associated with higher plasma LPS levels (P = .004). Infants with HIV infection had higher LPS levels, compared with uninfected infants (P = .004). Higher preinfection plasma LPS levels were a significant predictor of infant HIV infection through breast-feeding (hazard ratio = 1.60 for every unit increase in plasma LPS level; P = .01) and of lower infant length-for-age z scores (P = .02). CONCLUSIONS These findings suggest that disruption in intestinal integrity is a mechanism of HIV transmission to infants through breast-feeding. Weaning from breast milk and use of antibiotic prophylaxis was associated with increased levels of microbial translocation, which could facilitate HIV entry through the intestine. Complementary approaches to enhance intestinal mucosal integrity in the infant may further reduce breast-feeding transmission of HIV.
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Affiliation(s)
- Athena P Kourtis
- Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
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23
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Lee S, Baek D. Characteristics ofPorphyromonas gingivalislipopolysaccharide in co-culture withFusobacterium nucleatum. Mol Oral Microbiol 2013; 28:230-8. [DOI: 10.1111/omi.12020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/08/2012] [Indexed: 11/29/2022]
Affiliation(s)
- S.H. Lee
- Department of Oral Microbiology and Immunology; College of Dentistry; Dankook University; Cheonan; Korea
| | - D.H. Baek
- Department of Oral Microbiology and Immunology; College of Dentistry; Dankook University; Cheonan; Korea
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24
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TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Cell Mol Immunol 2012; 10:165-75. [PMID: 23262974 DOI: 10.1038/cmi.2012.58] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Graft-versus-host disease (GVHD) is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 (TLR4), which is a major receptor for bacterial lipopolysaccharides (LPS), in the development of acute GVHD, we used a TLR4-knockout (TLR4(-/-)) mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4(-/-) mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type (TLR4(+/+)) mice. In addition, histopathological analyses revealed that in TLR4(-/-)→BALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4(+/+), TLR4(-/-) mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4(-/-) mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 (Th1) development was obviously attenuated compared with TLR4(+/+) mice dendritic cells, and the levels of interferon-γ (IFN-γ) and IL-10, Th2-cell specific cytokines, were significantly higher in the serum of TLR4(-/-)→BALB/c than in TLR4(+/+)→BALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.
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25
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Stehle JR, Leng X, Kitzman DW, Nicklas BJ, Kritchevsky SB, High KP. Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults. J Gerontol A Biol Sci Med Sci 2012; 67:1212-8. [PMID: 22960476 DOI: 10.1093/gerona/gls178] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Physical function declines, and markers of inflammation increase with advancing age, even in healthy persons. Microbial translocation (MT) is the systemic exposure to mucosal surface microbes/microbial products without overt bacteremia and has been described in a number of pathologic conditions. We hypothesized that markers of MT, soluble CD14 (sCD14) and lipopolysaccharide (LPS) binding protein (LBP), may be a source of chronic inflammation in older persons and be associated with poorer physical function. METHODS We assessed cross-sectional relationships among two plasma biomarkers of MT (sCD14 and LBP), physical function (hand grip strength, short physical performance battery [SPPB], gait speed, walking distance, and disability questionnaire), and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor 1 [TNFsR1]) in 59 older (60-89 years), healthy (no evidence of acute or chronic illness) men and women. RESULTS LBP was inversely correlated with SPPB score and grip strength (p = .02 and p < .01, respectively) and positively correlated with CRP (p = 0.04) after adjusting for age, gender, and body mass index. sCD14 correlated with IL-6 (p = .01), TNF-α (p = .05), and TNFsR1 (p < .0001). Furthermore, the correlations between LBP and SPPB and grip strength remained significant after adjusting for each inflammatory biomarker. CONCLUSIONS In healthy older individuals, LBP, a surrogate marker of MT, is associated with worse physical function and inflammation. Additional study is needed to determine whether MT is a marker for or a cause of inflammation and the associated functional impairments.
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Affiliation(s)
- John R Stehle
- Section on Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
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Lipopolysaccharide-Induced Cellular Activation May Participate in the Immunopathogenesis of Visceral Leishmaniasis Alone or in HIV Coinfection. Int J Microbiol 2012; 2012:364534. [PMID: 22956960 PMCID: PMC3432364 DOI: 10.1155/2012/364534] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Accepted: 07/29/2012] [Indexed: 01/31/2023] Open
Abstract
Visceral Leishmaniasis (VL) is an infectious disease which constitutes a serious public health problem, integrating the list of neglected tropical diseases. The disease is characterized by a Leishmania-specific immune suppression T-cell depletion and a decrease of other hematopoietic cells. In parallel, an immunostimulatory response also occurs, represented by polyclonal B lymphocytes, T-cell activation, and systemic proinflammatory responses. Parasite antigens were believed to mediate both suppression and activation mechanisms, but these concepts are constantly being revised. Similar to reports on HIV/AIDS, we have proposed that gut parasitation by amastigotes and lymphocyte depletion could also affect gut-associated lymphoid tissue, leading to mucosal barrier breach and predisposing to microbial translocation. An increment of plasmatic lipopolysaccharide (LPS) levels observed in Brazilian VL patients was implicated in the reduced blood CD4+ and CD8+ T cell counts, systemic T-cell activation, pro-inflammatory cytokines and MIF plasma levels, suggesting that a bacterial molecule not associated with Leishmania infection can exert deleterious effects on immune system. Recent results also pointed that the proinflammatory response was potentiated in VL/HIV-AIDS coinfected patients. The LPS-mediated cell activation adds another concept to the immunopathogenesis of VL and can bring a rational for new therapeutic interventions that could ameliorate the management of these patients.
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Increased gut microbial translocation in HIV-infected children persists in virologic responders and virologic failures after antiretroviral therapy. Pediatr Infect Dis J 2012; 31:583-91. [PMID: 22333700 PMCID: PMC3648848 DOI: 10.1097/inf.0b013e31824da0f5] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Gut microbial translocation (MT) is considered a major cause of immune activation (IA) and failure of immune reconstitution in HIV infection. This study investigated the relationship of virus replication, IA, CD4 counts and MT in HIV-infected children. METHODS Lipopolysaccharide, bacterial 16S ribosomal DNA (16SrDNA) and soluble CD14 (sCD14) levels were determined in prospectively collected, stored plasma samples from the Pediatric AIDS Clinical Trials Group Protocol P338, a 48-week study initiated in 1997 to compare efficacy of dual nucleosides with a ritonavir-containing regimen. Results of MT were correlated with study data for T cell IA, plasma viral load and CD4 counts in 85 HIV-infected children (ages 2-17 years) designated as virologic responders or virologic failures (VF) at week 44 based on a cutoff of 400 HIV RNA copies/mL. RESULTS Levels of plasma lipopolysaccharide, 16SrDNA and sCD14 were increased in comparison with HIV-uninfected controls and did not decrease at week 44 even in virologic responders. T cell IA was correlated with viral load and sCD14 at entry and with 16SrDNA and sCD14 at week 44 in total patients and in the VF group. Changes in 16SrDNA correlated with changes in IA and negatively with changes in CD4 counts. 16SrDNA was correlated with sCD14 but not with lipopolysaccharide. CONCLUSIONS MT persists after 44 weeks of antiretroviral therapy in VS and VF patients. In VF, 16SrDNA exhibited relationships to monocyte and T cell IA and CD4 counts but not with viral load, suggesting a dominant role for MT in disease pathogenesis in HIV-infected children.
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Abstract
The lumen of the gastrointestinal (GI) tract is home to an enormous quantity of different bacterial species, our microbiota, that thrive in an often symbiotic relationship with the host. Given that the healthy host must regulate contact between the microbiota and its immune system to avoid overwhelming systemic immune activation, humans have evolved several mechanisms to attenuate systemic microbial translocation (MT) and its consequences. However, several diseases are associated with the failure of one or more of these mechanisms, with consequent immune activation and deleterious effects on health. Here, we discuss the mechanisms underlying MT, diseases associated with MT, and therapeutic interventions that aim to decrease it.
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Affiliation(s)
- Jason M Brenchley
- Program in Barrier Immunity and Repair and Immunopathogenesis Unit, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
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del Campo R, Martínez E, del Fresno C, Alenda R, Gómez-Piña V, Fernández-Ruíz I, Siliceo M, Jurado T, Toledano V, Arnalich F, García-Río F, López-Collazo E. Translocated LPS might cause endotoxin tolerance in circulating monocytes of cystic fibrosis patients. PLoS One 2011; 6:e29577. [PMID: 22216320 PMCID: PMC3247277 DOI: 10.1371/journal.pone.0029577] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Accepted: 11/30/2011] [Indexed: 12/04/2022] Open
Abstract
Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene codes of a chloride channel. The lungs of CF patients are chronically infected by several pathogens but bacteraemia have rarely been reported in this pathology. Besides that, circulating monocytes in CF patients exhibit a patent Endotoxin Tolerance (ET) state since they show a significant reduction of the inflammatory response to bacterial stimulus. Despite a previous description of this phenomenon, the direct cause of ET in CF patients remains unknown. In this study we have researched the possible role of microbial/endotoxin translocation from a localized infection to the bloodstream as a potential cause of ET induction in CF patients. Plasma analysis of fourteen CF patients revealed high levels of LPS compared to healthy volunteers and patients who suffer from Chronic Obstructive Pulmonary Disease. Experiments in vitro showed that endotoxin concentrations found in plasma of CF patients were enough to induce an ET phenotype in monocytes from healthy controls. In agreement with clinical data, we failed to detect bacterial DNA in CF plasma. Our results suggest that soluble endotoxin present in bloodstream of CF patients causes endotoxin tolerance in their circulating monocytes.
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Affiliation(s)
- Rosa del Campo
- Servicio de Microbiología and CIBER en Epidemiología y Salud Pública (CIBERESP), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Eriel Martínez
- EMPIREO Research S.L., Madrid, Spain
- Laboratory of Tumor Immunology, IdiPAZ, ‘La Paz’ Hospital, Madrid, Spain
| | - Carlos del Fresno
- Laboratory of Tumor Immunology, IdiPAZ, ‘La Paz’ Hospital, Madrid, Spain
| | - Raquel Alenda
- Department of Inmunology, University Hospital Ramon y Cajal and IRYCIS, Madrid, Spain
| | - Vanesa Gómez-Piña
- EMPIREO Research S.L., Madrid, Spain
- Laboratory of Tumor Immunology, IdiPAZ, ‘La Paz’ Hospital, Madrid, Spain
| | | | - María Siliceo
- Laboratory of Tumor Immunology, IdiPAZ, ‘La Paz’ Hospital, Madrid, Spain
| | - Teresa Jurado
- Laboratory of Tumor Immunology, IdiPAZ, ‘La Paz’ Hospital, Madrid, Spain
| | - Victor Toledano
- Laboratory of Tumor Immunology, IdiPAZ, ‘La Paz’ Hospital, Madrid, Spain
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van de Weg CAM, Koraka P, van Gorp ECM, Mairuhu ATA, Supriatna M, Soemantri A, van de Vijver DAMC, Osterhaus ADME, Martina BEE. Lipopolysaccharide levels are elevated in dengue virus infected patients and correlate with disease severity. J Clin Virol 2011; 53:38-42. [PMID: 22014848 DOI: 10.1016/j.jcv.2011.09.028] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 09/19/2011] [Accepted: 09/23/2011] [Indexed: 01/12/2023]
Abstract
BACKGROUND Although in the majority of cases dengue virus (DENV) infection results in a self-limiting febrile disease, it can cause severe plasma leakage in a minority of patients. The appearance of plasma leakage indicates an increased permeability of the vascular wall. In this study we investigated if DENV infection can lead to leakage of lipopolysaccharide (LPS) from the intestine into the blood of the patient, indicative of an increased permeability of the intestinal mucosal barrier. OBJECTIVES The aim of this study was to investigate if LPS levels were elevated in DENV infected patients and if these levels correlated with disease severity. STUDY DESIGN LPS levels in the blood of DENV infected children were determined using the Limulus Amebocyte Lysate assay. To determine disease severity we used the 1997-WHO criteria, the expert physician's judgement and a score that focused on plasma leakage in particular. Furthermore, the modulatory factors LPS binding protein (LBP) and sCD14, as well as the immune activation marker neopterin were determined. RESULTS We showed significantly elevated LPS levels in plasma of DENV infected children compared to healthy controls. The plasma leakage severity score had the strongest correlation with levels of LPS. LBP, sCD14 and neopterin were elevated compared to healthy controls. CONCLUSION In this study we show evidence of elevated LPS levels during DENV infection. Moreover, a correlation between LPS levels and disease severity was found, especially when disease severity was determined in terms of plasma leakage.
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Affiliation(s)
- Cornelia A M van de Weg
- Department of Virology, Erasmus Medical Center, Dr. Molewaterplein 50, Rotterdam, The Netherlands
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Santos-Oliveira JR, Regis EG, Leal CRB, Cunha RV, Bozza PT, Da-Cruz AM. Evidence that lipopolisaccharide may contribute to the cytokine storm and cellular activation in patients with visceral leishmaniasis. PLoS Negl Trop Dis 2011; 5:e1198. [PMID: 21765960 PMCID: PMC3134430 DOI: 10.1371/journal.pntd.0001198] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Accepted: 04/11/2011] [Indexed: 12/11/2022] Open
Abstract
Background Visceral leishmaniasis (VL) is characterized by parasite-specific immunosuppression besides an intense pro-inflammatory response. Lipopolisaccharide (LPS) has been implicated in the immune activation of T-cell deficient diseases such as HIV/AIDS and idiopathic lymphocytopenia. The source of LPS is gram-negative bacteria that enter the circulation because of immunological mucosal barrier breakdown. As gut parasitization also occurs in VL, it was hypothesized that LPS may be elevated in leishmaniasis, contributing to cell activation. Methodology/Principal Findings Flow cytometry analysis and immunoassays (ELISA and luminex micro-beads system) were used to quantify T-cells and soluble factors. Higher LPS and soluble CD14 levels were observed in active VL in comparison to healthy subjects, indicating that LPS was bioactive; there was a positive correlation between these molecules (r = 0.61;p<0.05). Interestingly, LPS was negatively correlated with CD4+ (r = −0.71;p<0.01) and CD8+ T-cells (r = −0.65;p<0.05). Moreover, higher levels of activation-associated molecules (HLA-DR, CD38, CD25) were seen on T lymphocytes, which were positively associated with LPS levels. Pro-inflammatory cytokines and macrophage migration inhibitory factor (MIF) were also augmented in VL patients. Consistent with the higher immune activation status, LPS levels were positively correlated with the inflammatory cytokines IL-6 (r = 0.63;p<0.05), IL-8 (r = 0.89;p<0.05), and MIF (r = 0.64;p<0.05). Also, higher plasma intestinal fatty acid binding protein (IFABP) levels were observed in VL patients, which correlated with LPS levels (r = 0.57;p<0.05). Conclusions/Significance Elevated levels of LPS in VL, in correlation with T-cell activation and elevated pro-inflammatory cytokines and MIF indicate that this bacterial product may contribute to the impairment in immune effector function. The cytokine storm and chronic immune hyperactivation status may contribute to the observed T-cell depletion. LPS probably originates from microbial translocation as suggested by IFABP levels and, along with Leishmania antigen-mediated immune suppression, may play a role in the immunopathogenesis of VL. These findings point to possible benefits of antimicrobial prophylaxis in conjunction with anti-Leishmania therapy. Visceral leishmaniasis (VL) affects organs rich in lymphocytes, being characterized by intense Leishmania-induced T-cell depletion and reduction in other hematopoietic cells. In other infectious and non-infectious diseases in which the immune system is affected, such as HIV-AIDS and inflammatory bowel disease, damage to gut-associated lymphocyte tissues occurs, enabling luminal bacteria to enter into the circulation. Lipopolisaccharide (LPS) is a bacterial product that stimulates macrophages, leading to the production of pro-inflammatory cytokines and other soluble factors such as MIF, which in turn activate lymphocytes. Continuous and exaggerated stimulation causes exhaustion of the T-cell compartment, contributing to immunosuppression. Herein, we show that an increment in LPS plasma levels also occurs in VL; the higher the LPS levels, the lower the TCD4+ and TCD8+ cell count in the blood. This T-cell depletion may affect the mucosal immune system, which, along with intestinal parasitization by amastigotes, may contribute to gut barrier damage and consequent microbial translocation. LPS levels were correlated with T-cell activation, pro-inflammatory cytokine plasma levels, MIF, and IFABP, showing that a bacterial molecule, probably from luminal origin, not associated with Leishmania infection can negatively affect the immune system. These findings points to possible benefits of antimicrobial prophylaxis in conjunction with anti-Leishmania therapy.
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Affiliation(s)
- Joanna R. Santos-Oliveira
- Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz – FIOCRUZ, Rio de Janeiro, Brazil
| | - Eduardo G. Regis
- Laboratório de Pesquisa sobre o Timo, Instituto Oswaldo Cruz – FIOCRUZ, Rio de Janeiro, Brazil
| | - Cássia R. B. Leal
- Departamento de Medicina Veterinária, Universidade Federal do Mato Grosso do Sul (UFMS), Mato Grosso do Sul, Brazil
| | - Rivaldo V. Cunha
- Departamento de Clínica Médica (FAMED), Universidade Federal de Mato Grosso do Sul (UFMS), Mato Grosso do Sul, Brazil
| | - Patrícia T. Bozza
- Laboratório de Imunofarmacologia, Plataforma Luminex, Instituto Oswaldo Cruz – FIOCRUZ, Rio de Janeiro, Brazil
| | - Alda M. Da-Cruz
- Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz – FIOCRUZ, Rio de Janeiro, Brazil
- * E-mail:
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Panoskaltsis-Mortari A, Griese M, Madtes DK, Belperio JA, Haddad IY, Folz RJ, Cooke KR. An official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome. Am J Respir Crit Care Med 2011; 183:1262-79. [PMID: 21531955 DOI: 10.1164/rccm.2007-413st] [Citation(s) in RCA: 217] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
RATIONALE Acute lung dysfunction of noninfectious etiology, known as idiopathic pneumonia syndrome (IPS), is a severe complication following hematopoietic stem cell transplantation (HSCT). Several mouse models have been recently developed to determine the underlying causes of IPS. A cohesive interpretation of experimental data and their relationship to the findings of clinical research studies in humans is needed to better understand the basis for current and future clinical trials for the prevention/treatment of IPS. OBJECTIVES Our goal was to perform a comprehensive review of the preclinical (i.e., murine models) and clinical research on IPS. METHODS An ATS committee performed PubMed and OVID searches for published, peer-reviewed articles using the keywords "idiopathic pneumonia syndrome" or "lung injury" or "pulmonary complications" AND "bone marrow transplant" or "hematopoietic stem cell transplant." No specific inclusion or exclusion criteria were determined a priori for this review. MEASUREMENTS AND MAIN RESULTS Experimental models that reproduce the various patterns of lung injury observed after HSCT have identified that both soluble and cellular inflammatory mediators contribute to the inflammation engendered during the development of IPS. To date, 10 preclinical murine models of the IPS spectrum have been established using various donor and host strain combinations used to study graft-versus-host disease (GVHD). This, as well as the demonstrated T cell dependency of IPS development in these models, supports the concept that the lung is a target of immune-mediated attack after HSCT. The most developed therapeutic strategy for IPS involves blocking TNF signaling with etanercept, which is currently being evaluated in clinical trials. CONCLUSIONS IPS remains a frequently fatal complication that limits the broader use of allogeneic HSCT as a successful treatment modality. Faced with the clinical syndrome of IPS, one can categorize the disease entity with the appropriate tools, although cases of unclassifiable IPS will remain. Significant research efforts have resulted in a paradigm shift away from identifying noninfectious lung injury after HSCT solely as an idiopathic clinical syndrome and toward understanding IPS as a process involving aspects of both the adaptive and the innate immune response. Importantly, new laboratory insights are currently being translated to the clinic and will likely prove important to the development of future strategies to prevent or treat this serious disorder.
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Hummelen R, Vos AP, van't Land B, van Norren K, Reid G. Altered host-microbe interaction in HIV: a target for intervention with pro- and prebiotics. Int Rev Immunol 2011; 29:485-513. [PMID: 20839912 DOI: 10.3109/08830185.2010.505310] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The intestinal immune system is severely affected by HIV and circulating microbial products from the intestinal tract that provide an ongoing source of systemic inflammation and concomitant viral replication. In addition, HIV-infected individuals can have a deregulated immune response that may hamper the anti-viral capacity of the host. Various probiotic organisms and prebiotic agents have been shown to enhance intestinal epithelial barrier functions, reduce inflammation, and support effective Th-1 responses. As these characteristics may benefit HIV patients, this review aims to provide a theoretical framework for the development of probiotic and prebiotic interventions specifically for this population.
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Affiliation(s)
- Ruben Hummelen
- Department of Public Health, Erasmus MC, University Medical Centre Rotterdam, The Netherlands
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Holler E, Landfried K, Meier J, Hausmann M, Rogler G. The role of bacteria and pattern recognition receptors in GVHD. Int J Inflam 2010; 2010:814326. [PMID: 21188220 PMCID: PMC3003997 DOI: 10.4061/2010/814326] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2010] [Accepted: 09/02/2010] [Indexed: 01/01/2023] Open
Abstract
Graft-versus-Host Disease (GvHD) is the most serious complication of allogeneic stem cell transplantation (SCT) and results from an activation of donor lymphocytes by recipient antigen-presenting cells (APCs). For a long time, it has been postulated that the intestinal microflora and endotoxin exert a crucial step in this APC activation, as there is early and severe gastrointestinal damage induced by pretransplant conditioning. With the detailed description of pathogen-associated molecular patterns and pathogen recognition receptors single nucleotide polymorphisms of TLRs and especially NOD2 have been identified as potential risk factors of GvHD and transplant related complications thus further supporting the crucial role of innate immunity in SCT, related complications. Gastrointestinal decontamination and neutralization of endotoxin have been used to interfere with this early axis of activation with some success but more specific approaches of modulation of innate immunity are needed for further improvement of clinical outcome.
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Affiliation(s)
- E Holler
- Department of Haematology/Oncology, University of Regensburg, 93042 Regensburg, Germany
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35
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Estes JD, Harris LD, Klatt NR, Tabb B, Pittaluga S, Paiardini M, Barclay GR, Smedley J, Pung R, Oliveira KM, Hirsch VM, Silvestri G, Douek DC, Miller CJ, Haase AT, Lifson J, Brenchley JM. Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog 2010; 6:e1001052. [PMID: 20808901 PMCID: PMC2924359 DOI: 10.1371/journal.ppat.1001052] [Citation(s) in RCA: 394] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Accepted: 07/20/2010] [Indexed: 12/12/2022] Open
Abstract
The chronic phase of HIV infection is marked by pathological activation of the immune system, the extent of which better predicts disease progression than either plasma viral load or CD4(+) T cell count. Recently, translocation of microbial products from the gastrointestinal tract has been proposed as an underlying cause of this immune activation, based on indirect evidence including the detection of microbial products and specific immune responses in the plasma of chronically HIV-infected humans or SIV-infected Asian macaques. We analyzed tissues from SIV-infected rhesus macaques (RMs) to provide direct in situ evidence for translocation of microbial constituents from the lumen of the intestine into the lamina propria and to draining and peripheral lymph nodes and liver, accompanied by local immune responses in affected tissues. In chronically SIV-infected RMs this translocation is associated with breakdown of the integrity of the epithelial barrier of the gastrointestinal (GI) tract and apparent inability of lamina propria macrophages to effectively phagocytose translocated microbial constituents. By contrast, in the chronic phase of SIV infection in sooty mangabeys, we found no evidence of epithelial barrier breakdown, no increased microbial translocation and no pathological immune activation. Because immune activation is characteristic of the chronic phase of progressive HIV/SIV infections, these findings suggest that increased microbial translocation from the GI tract, in excess of capacity to clear the translocated microbial constituents, helps drive pathological immune activation. Novel therapeutic approaches to inhibit microbial translocation and/or attenuate chronic immune activation in HIV-infected individuals may complement treatments aimed at direct suppression of viral replication.
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Affiliation(s)
- Jacob D. Estes
- AIDS and Cancer Virus Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America
- * E-mail: (JDE); (JMB)
| | - Levelle D. Harris
- Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America
| | - Nichole R. Klatt
- Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America
| | - Brian Tabb
- AIDS and Cancer Virus Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America
| | - Stefania Pittaluga
- Lab of Pathology, NCI, NIH, Bethesda, Maryland, United States of America
| | - Mirko Paiardini
- Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - G. Robin Barclay
- Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Jeremy Smedley
- Laboratory Animal Science Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America
| | - Rhonda Pung
- Laboratory Animal Science Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America
| | | | - Vanessa M. Hirsch
- Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America
| | - Guido Silvestri
- Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Daniel C. Douek
- Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America
| | - Christopher J. Miller
- Center for Comparative Medicine, California National Primate Research Center, University of California, Davis, California, United States of America
| | - Ashley T. Haase
- Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Jeffrey Lifson
- AIDS and Cancer Virus Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America
| | - Jason M. Brenchley
- Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America
- * E-mail: (JDE); (JMB)
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The incidence of acute graft-versus-host disease increases with Candida colonization depending the dectin-1 gene status. Clin Immunol 2010; 136:302-6. [DOI: 10.1016/j.clim.2010.04.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2009] [Revised: 03/20/2010] [Accepted: 04/08/2010] [Indexed: 01/28/2023]
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Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses. Blood 2010; 115:5249-58. [PMID: 20382845 DOI: 10.1182/blood-2009-11-255422] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Allogeneic stem cell transplantation is the most potent form of effective adoptive immunotherapy. The graft-versus-leukemia (GVL) effect mediated by the allogeneic graft, however, is typically coexpressed with graft-versus-host disease (GVHD), which is the major complication of allogeneic stem cell transplantation. In this study, we used genetic and antibody-based strategies to examine the effect that blockade of interleukin 23 (IL-23) signaling had on GVH and GVL reactivity in murine transplantation recipients. These studies demonstrate that the selective protection of the colon that occurs as a consequence of inhibition of IL-23 signaling reduces GVHD without loss of the GVL effect. The separation of GVH and GVL reactivity was noted in both acute and chronic hematologic malignancy models, indicating that this approach was not restricted by the kinetic profile of the underlying leukemia. Furthermore, a potent GVL response could be mounted in the colon under conditions where tumor cells migrated to this site, indicating that this organ did not serve as a sanctuary site for subsequent systemic relapse in GVHD-protected animals. These studies demonstrate that blockade of IL-23 signaling is an effective strategy for separating GVH and GVL responses and identify IL-23 as a therapeutic target for the regulation of alloresponses in humans.
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Polymorphisms in toll-like receptor 4 and toll-like receptor 9 influence viral load in a seroincident cohort of HIV-1-infected individuals. AIDS 2009; 23:2387-95. [PMID: 19855253 DOI: 10.1097/qad.0b013e328330b489] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Toll-like receptors (TLRs) are innate immune sensors that are integral to resisting chronic and opportunistic infections. Mounting evidence implicates TLR polymorphisms in susceptibilities to various infectious diseases, including HIV-1. We investigated the impact of TLR single nucleotide polymorphisms (SNPs) on clinical outcome in a seroincident cohort of HIV-1-infected volunteers. DESIGN We analyzed TLR SNPs in 201 antiretroviral treatment-naive HIV-1-infected volunteers from a longitudinal seroincident cohort with regular follow-up intervals (median follow-up 4.2 years, interquartile range 4.4). Participants were stratified into two groups according to either disease progression, defined as peripheral blood CD4(+) T-cell decline over time, or peak and setpoint viral load. METHODS Haplotype tagging SNPs from TLR2, TLR3, TLR4, and TLR9 were detected by mass array genotyping, and CD4(+) T-cell counts and viral load measurements were determined prior to antiretroviral therapy initiation. The association of TLR haplotypes with viral load and rapid progression was assessed by multivariate regression models using age and sex as covariates. RESULTS Two TLR4 SNPs in strong linkage disequilibrium [1063 A/G (D299G) and 1363 C/T (T399I)] were more frequent among individuals with high peak viral load compared with low/moderate peak viral load (odds ratio 6.65, 95% confidence interval 2.19-20.46, P < 0.001; adjusted P = 0.002 for 1063 A/G). In addition, a TLR9 SNP previously associated with slow progression was found less frequently among individuals with high viral setpoint compared with low/moderate setpoint (odds ratio 0.29, 95% confidence interval 0.13-0.65, P = 0.003, adjusted P = 0.04). CONCLUSION This study suggests a potentially new role for TLR4 polymorphisms in HIV-1 peak viral load and confirms a role for TLR9 polymorphisms in disease progression.
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Redd AD, Dabitao D, Bream JH, Charvat B, Laeyendecker O, Kiwanuka N, Lutalo T, Kigozi G, Tobian AAR, Gamiel J, Neal JD, Oliver AE, Margolick JB, Sewankambo N, Reynolds SJ, Wawer MJ, Serwadda D, Gray RH, Quinn TC. Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa. Proc Natl Acad Sci U S A 2009; 106:6718-23. [PMID: 19357303 PMCID: PMC2667149 DOI: 10.1073/pnas.0901983106] [Citation(s) in RCA: 100] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2008] [Indexed: 12/11/2022] Open
Abstract
Reports from the United States have demonstrated that elevated markers of microbial translocation from the gut may be found in chronic and advanced HIV-1 infection and are associated with an increase in immune activation. However, this phenomenon's role in HIV-1 disease in Africa is unknown. This study examined the longitudinal relationship between microbial translocation and circulating inflammatory cytokine responses in a cohort of people with varying rates of HIV-1 disease progression in Rakai, Uganda. Multiple markers for microbial translocation (lipopolysaccharide, endotoxin antibody, and sCD14) did not change significantly during HIV-1 disease progression. Moreover, circulating immunoreactive cytokine levels either decreased or remained virtually unchanged throughout disease progression. These data suggest that microbial translocation and its subsequent inflammatory immune response do not have a causal relationship with HIV-1 disease progression in Africa.
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Affiliation(s)
- Andrew D. Redd
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| | | | - Jay H. Bream
- Departments of Molecular Microbiology and Immunology and
| | - Blake Charvat
- Population, Family, and Reproductive Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205
| | - Oliver Laeyendecker
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
- Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287; and
| | - Noah Kiwanuka
- Rakai Health Science Program, P.O. Box 49, Entebbe, Uganda
| | - Tom Lutalo
- Rakai Health Science Program, P.O. Box 49, Entebbe, Uganda
| | - Godfrey Kigozi
- Rakai Health Science Program, P.O. Box 49, Entebbe, Uganda
| | | | - Jordyn Gamiel
- Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287; and
| | - Jessica D. Neal
- Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287; and
| | - Amy E. Oliver
- Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287; and
| | | | | | - Steven J. Reynolds
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
- Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287; and
| | - Maria J. Wawer
- Population, Family, and Reproductive Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205
| | - David Serwadda
- School of Public Health, Makerere University, P.O. Box 7072, Kampala, Uganda
| | - Ronald H. Gray
- Population, Family, and Reproductive Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205
| | - Thomas C. Quinn
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
- Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287; and
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Abstract
There is an intense interplay between HIV and the immune system, and the literature is replete with studies describing various immunological phenomena associated with HIV infection. Many of these phenomena seem too broad in scope to be attributable either to HIV-infected cells or to the HIV-specific immune response. Recently, a more fundamental understanding of how HIV affects various T cells and T cell compartments has emerged. This review covers the role of immune activation in HIV immunopathogenesis, how that activation could be mediated directly by HIV replicating within and damaging the gut mucosal barrier, how HIV affects multiple T cell functions and phenotypes, and how chronic HIV replication induces immune modulatory pathways to negatively regulate certain functions in HIV-specific T cells.
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Affiliation(s)
- Daniel C. Douek
- Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Mario Roederer
- ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Richard A. Koup
- Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Fuji S, Kim SW, Fukuda T, Mori SI, Yamasaki S, Morita-Hoshi Y, Ohara-Waki F, Heike Y, Tobinai K, Tanosaki R, Takaue Y. Preengraftment serum C-reactive protein (CRP) value may predict acute graft-versus-host disease and nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2008; 14:510-7. [PMID: 18410893 DOI: 10.1016/j.bbmt.2008.02.008] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2007] [Accepted: 02/10/2008] [Indexed: 11/28/2022]
Abstract
In a mouse model, inflammatory cytokines play a primary role in the development of acute graft-versus-host disease (aGVHD). Here, we retrospectively evaluated whether the preengraftment C-reactive protein (CRP) value, which is used as a surrogate marker of inflammation, could predict posttransplant complications including GVHD. Two hundred twenty-four adult patients (median age, 47 years; range: 18-68 years) underwent conventional stem cell transplantation (CST, n = 105) or reduced-intensity stem cell transplantation (RIST, n = 119). Patients were categorized according to the maximum CRP value during neutropenia: the "low-CRP" group (CRP < 15 mg/dL, n = 157) and the "high-CRP" group (CRP >or= 15 mg/dL, n = 67). The incidence of documented infections during neutropenia was higher in the high-CRP group (34% versus 17%, P = .004). When patients with proven infections were excluded, the CRP value was significantly lower after RIST than after CST (P = .017) or after related than after unrelated transplantation (P < .001). A multivariate analysis showed that male sex, unrelated donor, and HLA-mismatched donor were associated with high CRP values. The high-CRP group developed significantly more grade II-IV aGVHD (P = .01) and nonrelapse mortality (NRM) (P < .001), but less relapse (P = .02). The present findings suggest that the CRP value may reflect the net degree of tissue damage because of the conditioning regimen, infection, and allogeneic immune reactions, all of which lead to subsequent aGVHD and NRM.
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Affiliation(s)
- Shigeo Fuji
- Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
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Duran-Struuck R, Hartigan A, Clouthier SG, Dyson MC, Lowler K, Gatza E, Tawara I, Toubai T, Weisiger E, Hugunin K, Reddy P, Wilkinson JE. Differential susceptibility of C57BL/6NCr and B6.Cg-Ptprca mice to commensal bacteria after whole body irradiation in translational bone marrow transplant studies. J Transl Med 2008; 6:10. [PMID: 18307812 PMCID: PMC2292684 DOI: 10.1186/1479-5876-6-10] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2007] [Accepted: 02/28/2008] [Indexed: 11/10/2022] Open
Abstract
Background The mouse is an important and widely utilized animal model for bone marrow transplant (BMT) translational studies. Here, we document the course of an unexpected increase in mortality of congenic mice that underwent BMT. Methods Thirty five BMTs were analyzed for survival differences utilizing the Log Rank test. Affected animals were evaluated by physical examination, necropsy, histopathology, serology for antibodies to infectious disease, and bacterial cultures. Results Severe bacteremia was identified as the main cause of death. Gastrointestinal (GI) damage was observed in histopathology. The bacteremia was most likely caused by the translocation of bacteria from the GI tract and immunosuppression caused by the myeloablative irradiation. Variability in groups of animals affected was caused by increased levels of gamma and X-ray radiation and the differing sensitivity of the two nearly genetically identical mouse strains used in the studies. Conclusion Our retrospective analysis of thirty five murine BMTs performed in three different laboratories, identified C57BL/6NCr (Ly5.1) as being more radiation sensitive than B6.Cg-Ptprca/NCr (Ly5.2). This is the first report documenting a measurable difference in radiation sensitivity and its effects between an inbred strain of mice and its congenic counterpart eventually succumbing to sepsis after BMT.
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Affiliation(s)
- Raimon Duran-Struuck
- Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
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Abstract
There has recently been a resurgence of interest in the gastrointestinal pathology observed in patients infected with HIV. The gastrointestinal tract is a major site of HIV replication, which results in massive depletion of lamina propria CD4 T cells during acute infection. Highly active antiretroviral therapy leads to incomplete suppression of viral replication and substantially delayed and only partial restoration of gastrointestinal CD4 T cells. The gastrointestinal pathology associated with HIV infection comprises significant enteropathy with increased levels of inflammation and decreased levels of mucosal repair and regeneration. Assessment of gut mucosal immune system has provided novel directions for therapeutic interventions that modify the consequences of acute HIV infection.
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Affiliation(s)
- JM Brenchley
- Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - DC Douek
- Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Shankar EM, Vignesh R, Murugavel KG, Balakrishnan P, Sekar R, Lloyd CAC, Solomon S, Kumarasamy N. Immune reconstitution inflammatory syndrome in association with HIV/AIDS and tuberculosis: views over hidden possibilities. AIDS Res Ther 2007; 4:29. [PMID: 18053126 PMCID: PMC2216023 DOI: 10.1186/1742-6405-4-29] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2007] [Accepted: 11/30/2007] [Indexed: 11/10/2022] Open
Abstract
Gut immune components are severely compromised among persons with AIDS, which allows increased translocation of bacterial lipopolysaccharides (LPS) into the systemic circulation. These microbial LPS are reportedly increased in chronically HIV-infected individuals and findings have correlated convincingly with measures of immune activation. Immune reconstitution inflammatory syndrome (IRIS) is an adverse consequence of the restoration of pathogen-specific immune responses in a subset of HIV-infected subjects with underlying latent infections during the initial months of highly active antiretroviral treatment (HAART). Whether IRIS is the result of a response to a high antigen burden, an excessive response by the recovering immune system, exacerbated production of pro-inflammatory cytokines or a lack of immune regulation due to inability to produce regulatory cytokines remains to be determined. We theorize that those who develop IRIS have a high burden of proinflammatory cytokines produced also in response to systemic bacterial LPS that nonspecifically act on latent mycobacterial antigens. We also hypothesize that subjects that do not develop IRIS could have developed either tolerance (anergy) to persistent LPS/tubercle antigens or could have normal FOXP3+ gene and that those with defective FOXP3+ gene or those with enormous plasma LPS could be vulnerable to IRIS. The measure of microbial LPS, anti-LPS antibodies and nonspecific plasma cytokines in subjects on HAART shall predict the role of these components in IRIS.
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Morecki S, Yacovlev E, Gelfand Y, Eizik O, Slavin S. Pretransplant treatment of donors with immunomodulators to control graft-versus-host disease (GVHD) in transplant recipients. Exp Hematol 2007; 35:748-56. [PMID: 17577924 DOI: 10.1016/j.exphem.2007.01.050] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Prevention of graft-versus-host disease (GVHD) by pretransplant donor treatment with known immunomodulators like complete Freund's adjuvant (CFA) and synthetic oligo-deoxynucleotides expressing CpG motifs (CpG). METHODS Induction of GVHD by inoculation of C57BL/6 (C57) splenocytes into sublethally irradiated (BALB/c x C57BL/6) F1 (F1) mice. Splenocytes were derived from either naive C57 mice or from C57 mice that were treated previously with the immunomodulators. RESULTS Inoculation of CFA or CpG into C57 mice led to an increase in the total number of spleen cells and resulted in activation of immunoregulatory cells that significantly suppressed mixed allogeneic lymphocyte reaction in vitro. CFA-treated C57 splenocytes led to GVHD-related death in only 14 out of 61 F1 recipients while the remaining 47 mice survived without disease for more than 200 days. Pretransplant treatment of donor C57 mice with GpG emulsified in incomplete Freund's adjuvant resulted in 19/20 GVHD-free survivors of sublethally irradiated F1 mice for more than 200 days. In contrast, naive C57 splenocytes injected into sublethally irradiated F1 recipients induced severe GVHD, which resulted in the death of 77/78 recipient mice (median of survival was 16 days). CONCLUSION Our results suggest that adjuvant-induced immunoregulation of donor cells prior to allogeneic cell therapy may augur a new strategy that will bring the benefits of safe cellular immunotherapy aiming to eradicate malignant and nonmalignant pathological cells while avoiding or minimizing the risk of GVHD.
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Affiliation(s)
- Shoshana Morecki
- Department of Bone Marrow Transplantation & Cancer Immunotherapy, Cell Therapy & Transplantation Research Laboratory, Hadassah University Hospital, Jerusalem, Israel.
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Paulos CM, Kaiser A, Wrzesinski C, Hinrichs CS, Cassard L, Boni A, Muranski P, Sanchez-Perez L, Palmer DC, Yu Z, Antony PA, Gattinoni L, Rosenberg SA, Restifo NP. Toll-like receptors in tumor immunotherapy. Clin Cancer Res 2007; 13:5280-9. [PMID: 17875756 PMCID: PMC2131730 DOI: 10.1158/1078-0432.ccr-07-1378] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Lymphodepletion with chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells is a critical advancement in the treatment of patients with melanoma. More than 50% of patients that are refractory to other treatments experience an objective or curative response with this approach. Emerging data indicate that the key mechanisms underlying how TBI augments the functions of adoptively transferred T cells include (a) the depletion of regulatory T cells (T(reg)) and myeloid-derived suppressor cells that limit the function and proliferation of adoptively transferred cells; (b) the removal of immune cells that act as "sinks" for homeostatic cytokines, whose levels increase after lymphodepletion; and (c) the activation of the innate immune system via Toll-like receptor 4 signaling, which is engaged by microbial lipopolysaccharide that translocated across the radiation-injured gut. Here, we review these mechanisms and focus on the effect of Toll-like receptor agonists in adoptive immunotherapy. We also discuss alternate regimens to chemotherapy or TBI, which might be used to safely treat patients with advanced disease and promote tumor regression.
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Affiliation(s)
- Chrystal M Paulos
- National Cancer Institute, NIH, Mark O. Hatfield Clinical Research Center, Bethesda, Maryland 20892-1502, USA.
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van der Velden WJFM, Blijlevens NMA, Donnelly JP. The potential role of lactoferrin and derivatives in the management of infectious and inflammatory complications of hematology patients receiving a hematopoietic stem cell transplantation. Transpl Infect Dis 2007; 10:80-9. [PMID: 17605731 DOI: 10.1111/j.1399-3062.2007.00260.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Human lactoferrin is a natural defense protein belonging to the innate immune system present in several body fluids and secretions, as well as in the secondary granules of polymorphonuclear neutrophils. Lactoferrin and its derivatives have pleiotropic functions including broad-spectrum anti-microbial activity, anti-tumor activity, regulation of cell growth and differentiation, and modulation of inflammatory as well as humoral and cellular immune responses. This is the reason why much research has addressed the potential therapeutic activity of these molecules in different clinical settings, especially regarding infectious diseases and uncontrolled inflammatory conditions. In patients with hematological malignancies treated with a hematopoietic stem cell transplantation (HSCT), morbidity and mortality due to infections and uncontrolled inflammation remains high, despite many advances in supportive care. These life-threatening complications are a result of the damage caused by the conditioning regimens to the mucosal barrier, and the innate and adaptive, humoral, and cellular immune defenses. These complications necessitate the continued exploration of new treatment modalities. Systemic and probably local levels of lactoferrin are decreased following HSCT. Therefore, the use of lactoferrin, or short peptide derivatives that retain the cationic N-terminal moiety that is essential for the anti-microbial and anti-inflammatory activity, may prove to be a promising versatile class of agents for managing the complications that arise from HSCT.
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Affiliation(s)
- W J F M van der Velden
- Department of Hematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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Mullighan CG, Bardy PG. New directions in the genomics of allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2007; 13:127-44. [PMID: 17241919 DOI: 10.1016/j.bbmt.2006.10.018] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2006] [Accepted: 10/10/2006] [Indexed: 01/09/2023]
Abstract
Despite optimal supportive care and high-resolution HLA matching, complications such as GVHD and infection remain major barriers to the success of allogeneic HCT (allo-HCT). This has led to growing interest in the non-HLA genetic determinants of complications after allo-HCT. Most studies have examined genetic predictors of GVHD, relapse, and mortality and have focused on 3 main areas: minor histocompatibility antigen (miHAs), inflammatory mediators of GVHD, and more recently NK cell-mediated allorecognition. The genetic basis of other outcomes such as infection and drug toxicity are less well studied but are being actively investigated. High-throughput methodologies such as single nucleotide polymorphism arrays are enabling the study of hundreds of thousands of genetic markers throughout the genome and the interrogation of novel genetic variants such as copy number variations. These data offer the opportunity to better predict those at risk of complications and to identify novel targets for therapeutic intervention. This review examines the current data regarding the non-HLA genomics of allo-HCT and appraises the promises and pitfalls for integration of this new genetic information into clinical transplantation practice.
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Affiliation(s)
- Charles G Mullighan
- Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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Abstract
Despite significant advances in critical care and transplantation medicine, non-infectious lung injury remains a major problem following allogeneic hematopoietic stem cell transplantation (HSCT) both in the immediate post-transplant period and in the months to years that follow. Historically, approximately 50% of all pneumonias seen after HSCT have been secondary to infection. Although non-infectious lung injury occasionally occurs following autologous transplants, the allogeneic setting greatly exacerbates toxicity acutely and chronically. Pulmonary injury is associated with significant morbidity and mortality and responds poorly to standard therapies. Insights generated using animal models suggest that the immunologic mechanisms contributing to lung inflammation after HSCT may be similar to those responsible for graft-versus-host disease (GVHD).
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Affiliation(s)
- Gregory Yanik
- Department of Pediatrics, Division of Hematology/Oncology, Blood and Marrow Transplantation Program, University of Michigan Cancer Center, Ann Arbor, MI 48109-0942, USA
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Pulmonary toxicity following hematopoietic cell transplantation: Is the lung a target organ of graft-versus-host disease? Curr Opin Organ Transplant 2006. [DOI: 10.1097/01.mot.0000209295.10407.98] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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