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Larsson, Marie
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Publications (10 of 56) Show all publications
Yien Tan, H., Kong Yong, Y., Shankar, E. M., Paukovics, G., Ellegård, R., Larsson, M., . . . Crowe, S. M. (2016). Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome. Journal of Immunology, 196(10), 4052-4063
Open this publication in new window or tab >>Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome
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2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 10, p. 4052-4063Article in journal (Refereed) Published
Abstract [en]

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1 beta, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18R alpha on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.

Place, publisher, year, edition, pages
AMER ASSOC IMMUNOLOGISTS, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-128934 (URN)10.4049/jimmunol.1502203 (DOI)000375831200008 ()27076678 (PubMedID)
Note

Funding Agencies|University of Malaya; Ministry of Higher Education High Impact Research Grant [UM.C/625/1/HIR/MOHE/MED/01]; University of Malaya Research Grants of the Health and Translational Medicine Research Cluster [RP021A-13HTM, RG448-12HTM]; Research Officer Grant Scheme [BR003-2014]; Australian National Health and Medical Research Council; Swedish Research Council [AI52731]; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER from VINNOVA; Linkoping University Hospital research fund; Governmental Funding of Clinical Research within National Health Service; Swedish Society of Medicine; Victorian Operational Infrastructure Support Program

Available from: 2016-06-09 Created: 2016-06-07 Last updated: 2017-11-30
Crisci, E., Ellegård, R., Nyström, S., Rondahl, E., Serrander, L., Bergström, T., . . . Larsson, M. (2016). Complement opsonization promotes HSV-2 infection of human dendritic cells. Journal of Virology, 90(10), 4939-4950
Open this publication in new window or tab >>Complement opsonization promotes HSV-2 infection of human dendritic cells
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2016 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 90, no 10, p. 4939-4950Article in journal (Refereed) Published
Abstract [en]

Herpes virus type 2 (HSV2) is one of the most common sexually transmitted infections globally with a very high prevalence in many countries. During HSV2 infection viral particles become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. In genital mucosa, the primary target cells for HSV2 infection are epithelial cells, but resident immune cells such as dendritic cells (DCs) are also infected. The DCs are the activators of the ensuing immune responses directed against HSV2, and the aim of this study was to examine the effects opsonization of HSV2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV1 or HSV2 specific antibodies more or less abolished the HSV2 infection of DCs.Our results clearly demonstrate the importance of studying HSV2 infection under conditions that ensue in vivo, i.e. when the virions are covered in complement fragments and complement fragments and antibodies, as this will shape the infection and the subsequent immune response and needs to be further elucidated.

IMPORTANCE: During HSV2 infection viral particles should become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. The dendritic cells are the activators of the immune responses directed against HSV2, and the aim of this study was to examine the effects of complement alone or complement and antibodies, on the HSV2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses.Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV2 pathogenesis.

Place, publisher, year, edition, pages
American society of microbiology, 2016
Keywords
HSV2 infection, dendritic cells, complement, antibodies
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-126480 (URN)10.1128/JVI.00224-16 (DOI)000375126100009 ()26937039 (PubMedID)
Note

Funding agencies: Swedish Research Council [AI52731]; Swedish Physicians Against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; Swedish Society of Medicine; Swedis

Available from: 2016-03-29 Created: 2016-03-29 Last updated: 2018-03-23
Saeidi, A., Ellegård, R., Yong, Y. K., Tan, H. Y., Velu, V., Ussher, J. E., . . . Shankar, E. M. (2016). Functional role of mucosal-associated invariant T cells in HIV infection. Journal of Leukocyte Biology, 100(2), 305-314
Open this publication in new window or tab >>Functional role of mucosal-associated invariant T cells in HIV infection
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2016 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 100, no 2, p. 305-314Article, review/survey (Refereed) Published
Abstract [en]

MAIT cells represent an evolutionarily conserved, MR1-restricted, innate-like cell subset that express high levels of CD161; have a canonical semi-invariant TCR iV alpha 7.2; and may have an important role in mucosal immunity against various bacterial and fungal pathogens. Mature MAIT cells are CD161(hi)PLZF(hi)IL-18R alpha(+)iV alpha 7.2(+)gamma delta-CD3(+)CD8(+) T cells and occur in the peripheral blood, liver, and mucosa of humans. MAIT cells are activated by a metabolic precursor of riboflavin synthesis presented by MR1 and, therefore, respond to many bacteria and some fungi. Despite their broad antibacterial properties, their functional role in persistent viral infections is poorly understood. Although there is an increasing line of evidence portraying the depletion of MAIT cells in HIV disease, the magnitude and the potential mechanisms underlying such depletion remain unclear. Recent studies suggest that MAIT cells are vulnerable to immune exhaustion as a consequence of HIV and hepatitis C virus infections and HIV/tuberculosis coinfections. HIV infection also appears to cause functional depletion of MAIT cells resulting from abnormal expression of T-bet and EOMES, and effective ART is unable to completely salvage functional MAIT cell loss. Depletion and exhaustion of peripheral MAIT cells may affect mucosal immunity and could increase susceptibility to opportunistic infections during HIV infection. Here, we review some of the important mechanisms associated with depletion and functional loss of MAIT cells and also suggest potential immunotherapeutic strategies to restore MAIT cell functions, including the use of IL-7 to restore effector functions in HIV disease.

Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2016
Keywords
CD8(+) T cells; cytotoxicity; exhaustion; PD-1; TCR iV alpha 7.2
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-130371 (URN)10.1189/jlb.4RU0216-084R (DOI)000379738600006 ()27256572 (PubMedID)
Note

Funding Agencies|University of Malaya; Ministry of Higher Education [UM.C/625/1/HIR/MOHE/MED/01]; University of Malaya [RP021A-13HTM, RG448-12HTM]; Swedish Research Council [AI52731]; Swedish Physicians Against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER from VINNOVA; Linkoping University Hospital; National Health Service; Swedish Society of Medicine; U.S. National Institutes of Health National Institute of Allergy and Infectious Diseases [1U19AI109633-01]; [BR003-2014]

Available from: 2016-08-15 Created: 2016-08-05 Last updated: 2018-01-10
Kuninty, P. R., Bojmar, L., Tjomsland, V., Larsson, M., Storm, G., Östman, A., . . . Prakash, J. (2016). MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor. OncoTarget, 7(13), 16396-16408
Open this publication in new window or tab >>MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 13, p. 16396-16408Article in journal (Refereed) Published
Abstract [en]

Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. Although depletion of tumor stroma is debatable, attenuation of PSC activity is still an interesting strategy to treat pancreatic cancer. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs as well as in TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a or miR-214 using their hairpin inhibitors in hPSCs significantly inhibited their TGFβ-induced differentiation (gene and protein levels of α-SMA, Collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs were prepared, which attained smaller size when hPSCs were transfected with anti-miR-199a or -214 than those transfected with control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell proliferation and endothelial cell tube formation, but these effects were abrogated when hPSCs were transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in PSCs in pancreatic cancer.

Place, publisher, year, edition, pages
Impact press, 2016
National Category
Cancer and Oncology Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-122828 (URN)10.18632/oncotarget.7651 (DOI)000375692900085 ()
Note

Funding agencies: Swedish Research Council, Stockholm, Sweden [K7/60501283]

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Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2018-01-10
Barathan, M., Mohamed, R., Vadivelu, J., Chang, L. Y., Saeidi, A., Yong, Y. K., . . . Shankar, E. M. (2016). Peripheral loss of CD8(+)CD161(++)TCRV7 center dot 2(+) mucosal-associated invariant T cells in chronic hepatitis C virus-infected patients. European Journal of Clinical Investigation, 46(2), 170-180
Open this publication in new window or tab >>Peripheral loss of CD8(+)CD161(++)TCRV7 center dot 2(+) mucosal-associated invariant T cells in chronic hepatitis C virus-infected patients
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2016 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 46, no 2, p. 170-180Article in journal (Refereed) Published
Abstract [en]

BackgroundMucosal-associated invariant T (MAIT) cells play an important role in innate host defence. MAIT cells appear to undergo exhaustion and are functionally weakened in chronic viral infections. However, their role in chronic hepatitis C virus (HCV) infection remains unclear. Materials and methodsWe investigated the frequency of CD8(+)CD161(++)TCR V7.2(+) MAIT cells in a cross-sectional cohort of chronic HCV-infected patients (n = 25) and healthy controls (n = 25). Peripheral blood mononuclear cells were investigated for circulating MAIT cell frequency, liver-homing (CCR5 and CD103), biomarkers of immune exhaustion (PD-1, TIM-3 and CTLA-4), chronic immune activation (CD38 and HLA-DR), and immunosenescence (CD57) by flow cytometry. ResultsThe frequency of MAIT cells was significantly decreased, and increased signs of immune exhaustion and chronic immune activation were clearly evident on MAIT cells of HCV-infected patients. Decrease of CCR5 on circulating MAIT cells is suggestive of their peripheral loss in chronic HCV-infected patients. MAIT cells also showed significantly increased levels of HLA-DR, CD38, PD-1, TIM-3 and CTLA-4, besides CD57 in chronic HCV disease. ConclusionsImmune exhaustion and senescence of CD8(+)CD161(++)TCR V7.2(+) MAIT cells could contribute to diminished innate defence attributes likely facilitating viral persistence and HCV disease progression.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2016
Keywords
CD38; exhaustion; HCV infection; MAIT cells; PD-1; TCRV alpha 7.2
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-125301 (URN)10.1111/eci.12581 (DOI)000368689100007 ()26681320 (PubMedID)
Note

Funding Agencies|High Impact Research (HIR), University of Malaya [UM.C.625/1/HIR/139]; University Malaya Fellowship Scheme [AI52731]; Swedish Research Council; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; CALF; Swedish Society of Medicine

Available from: 2016-02-24 Created: 2016-02-19 Last updated: 2017-11-30
Saeidi, A., Tien Tien, V. L., Al-Batran, R., Al-Darraji, H. A., Tan, H. Y., Yong, Y. K., . . . Shankar, E. M. (2015). Attrition of TCR Va7.2+CD161++ MAIT Cells in HIV-Tuberculosis Co-Infection Is Associated with Elevated Levels of PD-1 Expression. PLoS ONE, 10(4), e0124659
Open this publication in new window or tab >>Attrition of TCR Va7.2+CD161++ MAIT Cells in HIV-Tuberculosis Co-Infection Is Associated with Elevated Levels of PD-1 Expression
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, p. e0124659-Article in journal (Refereed) Published
Abstract [en]

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved antimicrobial MR1-restricted CD8+ T cells co-expressing the semi-invariant TCR V alpha 7.2, and are numerous in the blood and mucosal tissues of humans. MAIT cells appear to undergo exhaustion in chronic viral infections. However, their role in human immunodeficiency virus type 1 (HIV1) mono-infection and HIV/tuberculosis (TB) co-infection have seldom been elaborately investigated. We conducted a cross-sectional study to investigate the frequencies and phenotypes of CD161++ CD8+ T cells among anti-retroviral therapy (ART)/anti-TB therapy (ATT) treatment-naive HIV/TB co-infected, ART/TB treated HIV/TB co-infected, ART naive HIV-infected, ART-treated HIV-infected patients, and HIV negative healthy controls (HCs) by flow cytometry. Our data revealed that the frequency of MAIT cells was severely depleted in HIV mono-and HIV/TB co-infections. Further, PD-1 expression on MAIT cells was significantly increased in HIV mono-and HIV-TB co-infected patients. The frequency of MAIT cells did not show any significant increase despite the initiation of ART and/or ATT. Majority of the MAIT cells in HCs showed a significant increase in CCR6 expression as compared to HIV/TB co-infections. No marked difference was seen with expressions of chemokine co-receptor CCR5 and CD103 among the study groups. Decrease of CCR6 expression appears to explain why HIV-infected patients display weakened mucosal immune responses.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-118050 (URN)10.1371/journal.pone.0124659 (DOI)000353211700114 ()25894562 (PubMedID)
Note

Funding Agencies|High Impact Research [UM.C/625/1/HIR/MOHE/MED/014]; University of Malaya Research of the Health and Translational Medicine Research Cluster [RP021A-13HTM, RG448-12HTM]; Swedish Research Council [AI52731]; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; CALF; Swedish Society of Medicine

Available from: 2015-05-20 Created: 2015-05-20 Last updated: 2017-12-04
Barathan, M., Gopal, K., Mohamed, R., Ellegård, R., Saeidi, A., Vadivelu, J., . . . Shankar, E. M. (2015). Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes. Apoptosis (London), 20(4), 466-480
Open this publication in new window or tab >>Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes
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2015 (English)In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 20, no 4, p. 466-480Article in journal (Refereed) Published
Abstract [en]

Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex(A (R)) 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2015
Keywords
Apoptosis; Caspase; Hepatitis C; Spontaneous immune exhaustion; TRAIL
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-116813 (URN)10.1007/s10495-014-1084-y (DOI)000350669500005 ()25577277 (PubMedID)
Note

Funding Agencies|High Impact Research, University of Malaya [UM.C.625/1/HIR/139]; HIRG-MOHE Grant of University of Malaya [A000003-50001]; Swedish Research Council [AI52731]; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; CALF; Swedish Society of Medicine; University of Malaya Research Grant (UMRG) of the Health and Translational Medicine Research Cluster, University of Malaya [RG448-12HTM]

Available from: 2015-04-07 Created: 2015-04-07 Last updated: 2017-12-04
Saeidi, A., Chong, Y. K., Yong, Y. K., Tan, H. Y., Barathan, M., Rajarajeswaran, J., . . . Shankar, E. M. (2015). Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8(+) T cells in HIV/TB co-infection. Cellular Immunology, 297(1), 19-32
Open this publication in new window or tab >>Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8(+) T cells in HIV/TB co-infection
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2015 (English)In: Cellular Immunology, ISSN 0008-8749, E-ISSN 1090-2163, Vol. 297, no 1, p. 19-32Article in journal (Refereed) Published
Abstract [en]

The role of T-cell immunosenescence and functional CD8(+) T-cell responses in HIV/TB co-infection is unclear. We examined and correlated surrogate markers of HIV disease progression with immune activation, immunosenescence and differentiation using T-cell pools of HIV/TB co-infected, HIV-infected and healthy controls. Our investigations showed increased plasma viremia and reduced CD4/CD8 T-cell ratio in HIV/TB co-infected subjects relative to HIV-infected, and also a closer association with changes in the expression of CD38, a cyclic ADP ribose hydrolase and CD57, which were consistently expressed on late-senescent CD8(+) T cells. Up-regulation of CD57 and CD38 were directly proportional to lack of co-stimulatory markers on CD8(+) T cells, besides diminished expression of CD127 (IL-7R alpha) on CD57(+)CD4(+) T cells. Notably, intracellular IFN-gamma, perforin and granzyme B levels in HIV-specific CD8(+) T cells of HIV/TB co-infected subjects were diminished. Intracellular CD57 levels in HIV gag p24-specific CD8(+) T cells were significantly increased in HIV/TB co-infection. We suggest that HIV-TB co-infection contributes to senescence associated with chronic immune activation, which could be due to functional insufficiency of CD8(+) T cells. (C) 2015 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2015
Keywords
Co-stimulation; HIV/TB co-infection; Immune activation; Immunosenescence; T-cell activation
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121751 (URN)10.1016/j.cellimm.2015.05.005 (DOI)000361173100003 ()26071876 (PubMedID)
Available from: 2015-10-06 Created: 2015-10-05 Last updated: 2017-12-01
Campbell, D., Saenz, R., Bharati, I. S., Seible, D., Zhang, L., Esener, S., . . . Messmer, D. (2015). Enhanced anti-tumor immune responses and delay of tumor development in human epidermal growth factor receptor 2 mice immunized with an immunostimulatory peptide in poly(D, L-lactic-co-glycolic) acid nanoparticles nanoparticles. Breast Cancer Research, 17(48)
Open this publication in new window or tab >>Enhanced anti-tumor immune responses and delay of tumor development in human epidermal growth factor receptor 2 mice immunized with an immunostimulatory peptide in poly(D, L-lactic-co-glycolic) acid nanoparticles nanoparticles
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2015 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, no 48Article in journal (Refereed) Published
Abstract [en]

Introduction Cancer vaccines have the potential to induce curative anti-tumor immune responses and better adjuvants may improve vaccine efficacy. We have previously shown that Hp91, a peptide derived from the B box domain in high-mobility group box protein 1 (HMGB1), acts as potent immune adjuvant. Method In this study, Hp91 was tested as part of a therapeutic vaccine against human epidermal growth factor receptor 2 (HER2) positive breast cancer. Results Free peptide did not significantly augment immune responses but, when delivered in poly(D, L-lactic-co-glycolic) acid nanoparticles (PLGA-NPs), robust activation of dendritic cells (DCs) and increased activation of HER2 specific T cells was observed in vitro. Vaccination of HER2NEU transgenic mice, a mouse breast cancer model that closely mimics the immune modulation and tolerance in some breast cancer patients, with Hp91 loaded PLGA-NPs enhanced the activation of HER2 specific cytotoxic T lymphocyte (CTL) responses, delayed tumor development, and prolonged survival. Conclusion Taken together these findings demonstrate that the delivery of the immunostimulatory peptide Hp91 inside PLGA-NPs enhances the potency of the peptide and efficacy of a breast cancer vaccine.

Place, publisher, year, edition, pages
BioMed Central, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117376 (URN)10.1186/s13058-015-0552-9 (DOI)000352093600001 ()25882711 (PubMedID)
Note

Funding Agencies|US Army Medical Research and Material Command from the National Institutes of Health/NCI [W81XWH-07-1-0412, 5U54CA119335]

Available from: 2015-04-24 Created: 2015-04-24 Last updated: 2017-12-04
Ellegård, R., Crisci, E., Andersson, J., Shankar, E. M., Nyström, S., Hinkula, J. & Larsson, M. (2015). Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1. Journal of Immunology, 195(4), 1698-1704
Open this publication in new window or tab >>Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1
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2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 4, p. 1698-1704Article in journal (Refereed) Published
Abstract [en]

Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFN gamma and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection.

Place, publisher, year, edition, pages
American Association of Immunologists, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121313 (URN)10.4049/jimmunol.1500618 (DOI)000360013200039 ()26157174 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation [AI52731]; Swedish International Development Cooperation Agency/Swedish Agency for Research Cooperation with Developing Countries-Special Assistant; VINNMER for Vinnova; Linkoping University Hospital Research Fund; central regional agreement on medical training and clinical research (CALF) between Ostergotland County Council and Linkoping University; Swedish Society of Medicine; High Impact Research; University of Malaya [UM.C.625/1/HIR/139]

Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2018-09-28
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