| 1. |
- Joona, Therse Björkin, et al.
(författare)
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Influenza vaccination in breast cancer patients during subcutaneous trastuzumab in adjuvant setting
- 2020
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Ingår i: Breast Cancer Research and Treatment. - : Springer. - 0167-6806 .- 1573-7217. ; 184:1, s. 45-52
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite the current recommendation for influenza vaccination in cancer patients with active oncological therapy, limited data are available on the efficacy of vaccination in cancer patients receiving targeted therapies. We aimed to investigate the immunogenicity and tolerability of influenza vaccination in breast cancer patients treated with trastuzumab in adjuvant setting.Methods: A prospective open-label multicenter study was performed including patients with breast cancer during trastuzumab treatment in adjuvant setting and healthy controls. Blood samples were taken before, 4 weeks after, and 12 weeks after a single dose of trivalent influenza vaccine containing inactivated A/California/7/2009 (H1N1) pdm09, A/Hongkong4801/2014 (H3N2), and B/Brisbane/60/2008. Levels of serum antibody titers to hemagglutinin for H1N1 and influenza B strains were measured.Results: Twenty breast cancer patients and 37 controls were included in the study. No difference in seroprotection rate between trastuzumab-treated patients and controls was observed for either H1N1 (100% in both groups) or B strain (78.9% vs. 89.2%,pvalue = 0.423). A statistically significant increase in geometric mean titers from baseline was seen in both groups and was evident both 4 weeks and 12 weeks after vaccination. Adverse events in the trastuzumab-treated group were uncommon and mild with only one serious adverse event not related to vaccination.Conclusion: Breast cancer patients treated with trastuzumab in adjuvant setting seem to benefit from influenza vaccination in terms of immunogenicity without increasing the risk for adverse events. The current data support the recommendation to offer influenza vaccination in breast cancer patients treated with this type of targeted therapy.
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| 2. |
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| 3. |
- Hernebring, Malin, 1978, et al.
(författare)
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Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28
- 2013
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 3:3, s. artikel nr 1381-
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Tidskriftsartikel (refereegranskat)abstract
- In embryonic stem cells, removal of oxidatively damaged proteins is triggered upon the first signs of cell fate specification but the underlying mechanism is not known. Here, we report that this phase of differentiation encompasses an unexpected induction of genes encoding the proteasome activator PA28 alpha beta (11S), subunits of the immunoproteasome (20Si), and the 20Si regulator TNF alpha. This induction is accompanied by assembly of mature PA28-20S(i) proteasomes and elevated proteasome activity. Inhibiting accumulation of PA28 alpha using miRNA counteracted the removal of damaged proteins demonstrating that PA28 alpha beta has a hitherto unidentified role required for resetting the levels of protein damage at the transition from self-renewal to cell differentiation.
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| 4. |
- Ingelsten, Madeleine, 1978, et al.
(författare)
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Is Indoleamine 2,3-Dioxygenase Important for Graft Acceptance in Highly Sensitized Patients After Combined Auxiliary Liver-Kidney Transplantation?
- 2009
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Ingår i: Transplantation. - 0041-1337. ; 88:7, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- Background. In the clinical setting, transplanted liver seems to protect other grafts from the same donor from rejection. Our previous findings suggest that an auxiliary liver transplantation a few hours before a renal transplantation not only inhibits hyperacute antibody-mediated rejection but also improves long-term kidney graft survival in sensitized recipients. Here, we investigated indoleamine 2,3-dioxygenase (IDO) activity, as one potential mechanism for liver-induced long-term acceptance of kidney grafts. Methods. Tryptophan degradation was measured to estimate IDO activity in patient sera and cell culture supernatants with high performance liquid chromatography. Gene expression in the grafted organs and cell lysates was studied using real time polymerase chain reaction analysis. Results. Tryptophan degradation increased in peripheral blood from patients undergoing combined auxiliary liver-kidney transplantation, whereas it decreased in patients after regular renal transplantation. A 100-fold increase in IDO mRNA, preceded by upregulation of the IDO-inducing cytokines tumor necrosis factor-[alpha], interleukin-1[beta], and interferon-[gamma], was observed in the transplanted organs after graft reperfusion in patients undergoing combined graft transplantation. Subsequent studies in vitro revealed that immature dendritic cells, but not hepatocytes, strongly activated IDO on maturation with tumor necrosis factor-[alpha], interleukin-1[beta], and interferon-[gamma]. Finally, serum from liver-transplanted patients elicited an even stronger IDO-activity in such cytokine-stimulated dendritic cells. Conclusions. Taken together these findings suggest that the liver-induced long-term acceptance seen in human combined auxiliary liver and kidney transplantation is at least partly mediated by IDO activity. (C) 2009 Lippincott Williams & Wilkins, Inc.
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| 5. |
- Ingelsten, Madeleine, 1978, et al.
(författare)
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Liver-derived IL-10 as a potential inhibitor of a TH1-deviating crosstalk between donor DC and recipient NK cells during combined liver-kidney transplantation
- 2009
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Ingår i: The Transplantation society XI Basic science symposium, European society for organ transplantation I Basic science meeting, Brussels 2009..
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Konferensbidrag (refereegranskat)abstract
- During transplantation DCs within the allograft become activated and migrate to secondary lymphoid organs (SLO) where they activate NK cells and alloreactive T cell. Previous findings suggest that a liver graft is less prone to induce rejection compared to a renal graft but the mechanisms are still unclear. We compared changes in graft gene expression of inflammatory mediators known to participate in transplantation-induced DC activation in the liver and kidney in patients undergoing combined liver-kidney transplantation (n=8). Real-time PCR analysis revealed a similar up-regulation of mRNA for the DC-activation-associated inflammatory mediators TNF-α, IL-1β and IFN-gamma after reperfusion in the liver and kidney. While no reperfusion-dependent mRNA increase for IL-10 was found in transplated grafts, serial measurement of cytokine levels in peripheral blood revealed that IL-10 levels increased 60-fold in serum shortly (within 1 h) after liver, but before kidney, reperfusion and returned to pre-transplant levels at day 2 post-transplantation (n=3). No significant changes were seen in IL-12 levels. DCs matured with a cocktail consisting of IFN-γ, TNF-α and IL-1β demonstrated a strong and sustained production of CXCR3-ligands which are indispensable for DC-mediated recruitment of blood NK cells into SLO and their subsequent boosting of TH1-deviated alloresponses. Addition of IL-10 during DC maturation significantly decreased the production of all three CXCR3-ligands (CXCL9, CXCL10 and CXCL11). These findings indicate that IL-10 is selectively and rapidly released during liver transplantation, probably due to accumulation during the ischehmia period. This release may potentially inhibit a TH1-deviating crosstalk between donor DC and recipient NK cells.
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| 6. |
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| 7. |
- Ingelsten, Madeleine, 1978, et al.
(författare)
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Rapid Increase of Interleukin-10 Plasma Levels After Combined Auxiliary Liver-Kidney Transplantation in Presensitized Patients
- 2014
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337. ; 98:2, s. 208-215
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Tidskriftsartikel (refereegranskat)abstract
- Background. After transplantation, donor dendritic cells (DCs) in the grafted organ are activated by an ischemia/reperfusion-induced inflammatory process that induces their migration to the recipient's secondary lymphoid tissues. The subsequent interaction between migrated and mature donor DCs, recipient T cells, and natural killer (NK) cells is proposed to be crucial in directing host immune reactions toward allograft rejection. A liver transplant is less prone to induce rejection compared with most other solid organ transplants, and simultaneous transplantation of liver and kidney is known to improve the clinical outcome of kidney transplantation. Methods and Results. Here we show that liver as well as combined auxiliary liver-kidney transplantation in patients induces a rapid increase in plasma interleukin-10 (IL-10) to levels that are significantly higher than those seen after standard kidney transplantation. Addition of IL-10 during in vitro maturation of human monocyte-derived DCs with ischemia/reperfusion-associated factors was found to affect phenotypic DC maturation significantly. Addition of IL-10 inhibited DC production of the NK cell- and T cell-recruiting chemokines CXCL9, CXCL10 and CXCL11. Conclusion. Our findings indicate that liver transplantation induces a substantial systemic release of IL-10, which may inhibit T cell- and NK cell- mediated rejection processes toward the transplanted liver and concurrently transplanted kidney.
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| 8. |
- Ingelsten, Madeleine, 1978, et al.
(författare)
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The role of IL-10 in the liver tolerance effect
- 2009
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Ingår i: World congress of Nephrology, Milan 2009.
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Konferensbidrag (refereegranskat)abstract
- Introduction and aim: A liver graft is less prone to induce rejection compared to a renal graft and previous findings suggest that an auxiliary liver transplantation a few hours before a renal transplantation improves kidney graft survival in highly sensitized patients. Dendritic cells (DC) are important initiators of rejection. During transplantation DC within the allograft become activated and migrate to secondary lymphoid organs where they activate NK cells and alloreactive T cell. The aim of this study was to investigate the role of DC maturation in the liver mediated acceptance of a renal graft. Methods: Real-time PCR was used to compare changes in graft gene expression of IFN-γ, TNF-α, IL-1β and IL-10 in the liver and kidney in patients undergoing combined auxiliary liver-kidney transplantation (n=8). These are inflammatory mediators known to participate in transplantation-induced DC activation. Presence of interleukin (IL) 10 and 12 was measured in peripheral blood in these patients. Monocyte-derived DCs was matured with a cytokine-cocktail consisting of IFN-γ, TNF-α and IL-1β +/- IL-10. The effect of these cytokines on DC secretion of chemokines MIG, IP-10 and I-TAC was investigated with ELISA. Results: The DC-activation-associated inflammatory mediators TNF-α, IL-1β and IFN-γ were similarly upregulated in both liver and kidney grafts after reperfusion. While no reperfusion-dependent mRNA increase for IL-10 was found in transplated grafts, serial measurement of cytokine levels in peripheral blood revealed that IL-10 levels increased 60-fold in serum shortly (within 1 h) after liver, but before kidney, reperfusion and returned to pre-transplant levels at day 2 post-transplantation (n=3). No significant changes were seen in IL-12 levels. DCs matured with a cocktail consisting of IFN-γ, TNF-α and IL-1β demonstrated a strong production of CXCR3-ligands (MIG 280 ng/ml, IP-10 19 ng/ml, I-TAC 619 pg/ml) which was sustained even after removal of the cytokine-cocktail. These chemokines are indispensable for DC-mediated recruitment of blood NK cells into secondary lymphoid organs and their subsequent boosting of TH1-deviated alloresponses. Addition of IL-10 during DC maturation significantly decreased the production of all three CXCR3-ligands (MIG -33%, IP-10 -25%, I-TAC -67%). Conclusions: These findings indicate that IL-10 is selectively and rapidly released during liver transplantation, probably due to accumulation during the ischehmia period. This release may potentially inhibit a TH1-deviating crosstalk between donor DC and recipient NK cells, suggesting a role for IL-10 in the liver-mediated acceptance of a renal graft in highly sensitized patients.
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| 9. |
- Mishra, Rajesh, 1973-, et al.
(författare)
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Lysozyme Amyloidogenesis Is Accelerated by Specific Nicking and Fragmentation but Decelerated by Intact Protein Binding and Conversion
- 2007
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 366:3, s. 1029-1044
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Tidskriftsartikel (refereegranskat)abstract
- We have revisited the well-studied heat and acidic amyloid fibril formation pathway (pH 1.6, 65 °C) of hen egg-white lysozyme (HEWL) to map the barriers of the misfolding and amyloidogenesis pathways. A comprehensive kinetic mechanism is presented where all steps involving protein hydrolysis, fragmentation, assembly and conversion into amyloid fibrils are accounted for. Amyloid fibril formation of lysozyme has multiple kinetic barriers. First, HEWL unfolds within minutes, followed by irreversible steps of partial acid hydrolysis affording a large amount of nicked HEWL, the 49-101 amyloidogenic fragment and a variety of other species over 5-40 h. Fragmentation forming the 49-101 fragment is a requirement for efficient amyloid fibril formation, indicating that it forms the rate-determining nucleus. Nicked full-length HEWL is recruited efficiently into amyloid fibrils in the fibril growth phase or using mature fibrils as seeds, which abolished the lag phase completely. Mature amyloid fibrils of HEWL are composed mainly of nicked HEWL in the early equilibrium phase but go through a "fibril shaving" process, affording fibrils composed of the 49-101 fragment and 53-101 fragment during more extensive maturation (incubation for longer than ten days). Seeding of the amyloid fibril formation process using sonicated mature amyloid fibrils accelerates the fibril formation process efficiently, however, addition of intact full-length lysozyme at the end of the lag phase slows the rate of amyloidogenesis. The intact full-length protein, in contrast to nicked lysozyme, slows fibril formation due to its slow conversion into the amyloid fold, probably due to inclusion of the non-amyloidogenic 1-48/102-129 portion of HEWL in the fibrils, which can function as a "molecular bumper" stalling further growth. © 2006 Elsevier Ltd. All rights reserved.
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| 10. |
- Muslimovic, Aida, et al.
(författare)
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Novel clearance of muscle proteins by muscle cells
- 2020
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Ingår i: European Journal of Cell Biology. - : Elsevier BV. - 0171-9335 .- 1618-1298. ; 99:8
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Tidskriftsartikel (refereegranskat)abstract
- Blood levels of cardiac troponins (cTn) and myoglobin are analysed when myocardial infarction (MI) is suspected. Here we describe a novel clearance mechanism for muscle proteins by muscle cells. The complete plasma clearance profile of cTn and myoglobin was followed in rats after intravenous or intermuscular injections and analysed by PET and fluorescence microscopy of muscle biopsies and muscle cells. Compared with intravenous injections, only 5 % of cTnT, 0.6 % of cTnI and 8 % of myoglobin were recovered in the circulation following intramuscular injection. In contrast, 47 % of the renal filtration marker FITC-sinistrin and 81 % of cTn fragments from MI-patients were recovered after intramuscular injection. In addition, PET and biopsy analysis revealed that cTn was taken up by the quadriceps muscle and both cTn and myoglobin were endocytosed by cultured muscle cells. This local clearance mechanism could possibly be the dominant clearance mechanism for cTn, myoglobin and other muscle damage biomarkers released by muscle cells.
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