Publications by authors named "Einar Aandahl"

50 Publications

The Presence of Activated T Cell Subsets prior to Transplantation Is Associated with Increased Rejection Risk in Pancreas Transplant Recipients.

J Immunol 2021 11 4;207(10):2501-2511. Epub 2021 Oct 4.

Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway;

Pancreas and islet transplantation (PTx) are currently the only curative treatment options for type 1 diabetes. CD4 and CD8 T cells play a pivotal role in graft function, rejection, and survival. However, characterization of immune cell status from patients with and without rejection of the pancreas graft is lacking. We performed multiparameter immune phenotyping of T cells from PTx patients prior to and 1 y post-PTx in nonrejectors and histologically confirmed rejectors. Our results suggest that rejection is associated with presence of elevated levels of activated CD4 and CD8 T cells with a gut-homing phenotype both prior to and 1 y post-PTx. The CD4 and CD8 T cells were highly differentiated, with elevated levels of type 1 inflammatory markers (T-bet and INF-γ) and cytotoxic components (granzyme B and perforin). Furthermore, we observed increased levels of activated FOXP3 regulatory T cells in rejectors, which was associated with a hyporesponsive phenotype of activated effector T cells. Finally, activated T and B cell status was correlated in PTx patients, indicating a potential interplay between these cell types. In vitro treatment of healthy CD4 and CD8 T cells with tacrolimus abrogated the proliferation and cytokine (INF-γ, IL-2, and TNF-α) secretion associated with the type 1 inflammatory phenotype observed in pre- and post-PTx rejectors. Together, our results suggest the presence of activated CD4 and CD8 T cells prior to PTx confer increased risk for rejection. These findings may be used to identify patients that may benefit from more intense immunosuppressive treatment that should be monitored more closely after transplantation.
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http://dx.doi.org/10.4049/jimmunol.2001103DOI Listing
November 2021

Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study.

PLoS One 2021 11;16(3):e0247615. Epub 2021 Mar 11.

Department of Anesthesiology, Oslo University Hospital, Oslo, Norway.

Background: Despite advances in immunosuppression and surgical technique, pancreas transplantation is encumbered with a high rate of complication and graft losses. Particularly, venous graft thrombi occur relatively frequently and are rarely detected before the transplant is irreversibly damaged.

Methods: To detect complications early, when the grafts are potentially salvageable, we placed microdialysis catheters anteriorly and posteriorly to the graft in a cohort of 34 consecutive patients. Glucose, lactate, pyruvate, and glycerol were measured at the bedside every 1-2 hours.

Results: Nine patients with graft venous thrombosis had significant lactate and lactate-to-pyruvate-ratio increases without concomitant rise in blood glucose or clinical symptoms. The median lactate in these patients was significantly higher in both catheters compared to non-events (n = 15). Out of the nine thrombi, four grafts underwent successful angiographic extraction, one did not require intervention and four grafts were irreversibly damaged and explanted. Four patients with enteric anastomosis leakages had significantly higher glycerol measurements compared to non-events. As with the venous thrombi, lactate and lactate-to-pyruvate ratio were also increased in six patients with graft surrounding hematomas.

Conclusions: Bedside monitoring with microdialysis catheters is a promising surveillance modality of pancreatic grafts, but differentiating between the various pathologies proves challenging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951931PMC
September 2021

Liver transplantation as last-resort treatment for patients with bile duct injuries following cholecystectomy: a multicenter analysis.

Ann Gastroenterol 2021 2;34(1):111-118. Epub 2020 Oct 2.

2 Department of Propaedeutic Surgery, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece (Peter Tsaparas, Nikolaos Machairas, Ioannis D. Kostakis, Georgios C. Sotiropoulos).

Background: Liver transplantation (LT) has been used as a last resort in patients with end-stage liver disease due to bile duct injuries (BDI) following cholecystectomy. Our study aimed to identify and evaluate factors that cause or contribute to an extended liver disease that requires LT as ultimate solution, after BDI during cholecystectomy.

Methods: Data from 8 high-volume LT centers relating to patients who underwent LT after suffering BDI during cholecystectomy were prospectively collected and retrospectively analyzed.

Results: Thirty-four patients (16 men, 18 women) with a median age of 45 (range 22-69) years were included in this study. Thirty of them (88.2%) underwent LT because of liver failure, most commonly as a result of secondary biliary cirrhosis. The median time interval between BDI and LT was 63 (range 0-336) months. There were 23 cases (67.6%) of postoperative morbidity, 6 cases (17.6%) of post-transplant 30-day mortality, and 10 deaths (29.4%) in total after LT. There was a higher probability that patients with concomitant vascular injury (hazard ratio 10.69, P=0.039) would be referred sooner for LT. Overall survival following LT at 1, 3, 5 and 10 years was 82.4%, 76.5%, 73.5% and 70.6%, respectively.

Conclusion: LT for selected patients with otherwise unmanageable BDI following cholecystectomy yields acceptable long-term outcomes.
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http://dx.doi.org/10.20524/aog.2020.0541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774661PMC
October 2020

Portal vein stent placement after hepatobiliary and pancreatic surgery.

Langenbecks Arch Surg 2020 Aug 3;405(5):657-664. Epub 2020 Jul 3.

Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway.

Purpose: To evaluate the long-term outcomes of percutaneous transhepatic stent placement for portal vein (PV) stenosis after liver transplantation (LT) and hepato-pancreato-biliary (HPB) surgery.

Methods: Retrospective study of 455 patients who underwent LT and 522 patients who underwent resection of the pancreatic head between June 2011 and February 2016. Technical success, clinical success, patency, and complications were evaluated for both groups.

Results: A total of 23 patients were confirmed to have postoperative PV stenosis and were treated with percutaneous transhepatic PV stent placement. The technical success rate was 100%, the clinical success rate was 80%, and the long-term stent patency was 91.3% for the entire study population. Two procedure-related hemorrhages and two early stent thromboses occurred in the HPB group while no complications occurred in the LT group. A literature review of selected studies reporting PV stent placement for the treatment of PV stenosis after HPB surgery and LT showed a technical success rate of 78-100%, a clinical success rate of 72-100%, and a long-term patency of 57-100%, whereas the procedure-related complication rate varied from 0-33.3%.

Conclusions: Percutaneous transhepatic PV stent is a safe and effective treatment for postoperative PV stenosis/occlusion in patients undergoing LT regardless of symptoms. Due to increased risk of complications, the indication for percutaneous PV stent placement after HPB surgery should be limited to patients with clinical symptoms after an individual assessment.
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http://dx.doi.org/10.1007/s00423-020-01917-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449988PMC
August 2020

CD4 T cells persist for years in the human small intestine and display a T1 cytokine profile.

Mucosal Immunol 2021 03 22;14(2):402-410. Epub 2020 Jun 22.

Department of Pathology, Oslo University Hospital and University of Oslo, Oslo, Norway.

Studies in mice and humans have shown that CD8 T cell immunosurveillance in non-lymphoid tissues is dominated by resident populations. Whether CD4 T cells use the same strategies to survey peripheral tissues is less clear. Here, examining the turnover of CD4 T cells in transplanted duodenum in humans, we demonstrate that the majority of CD4 T cells were still donor-derived one year after transplantation. In contrast to memory CD4 T cells in peripheral blood, intestinal CD4 T cells expressed CD69 and CD161, but only a minor fraction expressed CD103. Functionally, intestinal CD4 T cells were very potent cytokine producers; the vast majority being polyfunctional T1 cells, whereas a minor fraction produced IL-17. Interestingly, a fraction of intestinal CD4 T cells produced granzyme-B and perforin after activation. Together, we show that the intestinal CD4 T-cell compartment is dominated by resident populations that survive for more than 1 year. This finding is of high relevance for the development of oral vaccines and therapies for diseases in the gut.
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http://dx.doi.org/10.1038/s41385-020-0315-5DOI Listing
March 2021

Resident memory CD8 T cells persist for years in human small intestine.

J Exp Med 2019 10 23;216(10):2412-2426. Epub 2019 Jul 23.

Department of Pathology, Oslo University Hospital and University of Oslo, Oslo, Norway

Resident memory CD8 T (Trm) cells have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI, we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for >1 yr in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokine producers, exhibiting a polyfunctional (IFN-γ IL-2 TNF-α) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders.
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http://dx.doi.org/10.1084/jem.20190414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781004PMC
October 2019

Liver transplantation as a lifesaving procedure for posthepatectomy liver failure and iatrogenic liver injuries.

Langenbecks Arch Surg 2019 May 30;404(3):301-308. Epub 2019 Mar 30.

Section for Transplant Surgery, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway.

Background: Iatrogenic injuries to vital structures of the liver and posthepatectomy liver failure are associated with high mortality. The current donor situation in Norway allows liver transplantation of patients beyond conventional criteria.

Methods: From 1984 to 2017, a total of 1510 liver transplantations were performed. In this retrospective study, we report the results of 13 patients undergoing liver transplantation due to iatrogenic injuries to the liver vasculature or posthepatectomy liver failure.

Results: Twelve men and one woman with a median age of 55 years (range 22-69) were included. Seven patients underwent radical surgery for cancer prior to transplantation. The median follow-up time was 70.5 months (range 2.2-177). Three of the patients with malignant disease did not experience disease recurrence, whereas four patients had cancer recurrence and died 7, 24, 45, and 78 months after transplantation. Five of six patients with non-malignant disease fully recovered, but one patient died after 9 months due to infectious complications.

Conclusions: Liver transplantation for liver failure due to portal vein and hepatic artery injury in patients with non-malignant disease seems justified. However, it may be questioned whether patients with malignant disease beyond established criteria should be offered liver transplantation.
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http://dx.doi.org/10.1007/s00423-019-01780-3DOI Listing
May 2019

The PI3K p110δ Isoform Inhibitor Idelalisib Preferentially Inhibits Human Regulatory T Cell Function.

J Immunol 2019 03 28;202(5):1397-1405. Epub 2019 Jan 28.

Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, N-0424 Oslo, Norway;

In chronic lymphocytic leukemia (CLL), signaling through several prosurvival B cell surface receptors activates the PI3K signaling pathway. Idelalisib is a highly selective PI3K (PI3Kδ) isoform-specific inhibitor effective in relapsed/refractory CLL and follicular lymphoma. However, severe autoimmune adverse effects in association with the use of idelalisib in the treatment of CLL, particularly as a first-line therapy, gave indications that idelalisib may preferentially target the suppressive function of regulatory T cells (Tregs). On this background, we examined the effect of idelalisib on the function of human Tregs ex vivo with respect to proliferation, TCR signaling, phenotype, and suppressive function. Our results show that human Tregs are highly susceptible to PI3Kδ inactivation using idelalisib compared with CD4 and CD8 effector T cells (Teffs) as evident from effects on anti-CD3/CD28/CD2-induced proliferation (order of susceptibility [IC]: Treg [.5 μM] > CD4 Teff [2.0 μM] > CD8 Teff [6.5 μM]) and acting at the level of AKT and NF-κB phosphorylation. Moreover, idelalisib treatment of Tregs altered their phenotype and reduced their suppressive function against CD4 and CD8 Teffs. Phenotyping Tregs from CLL patients treated with idelalisib supported our in vitro findings. Collectively, our data show that human Tregs are more dependent on PI3Kδ-mediated signaling compared with CD4 and CD8 Teffs. This Treg-preferential effect could explain why idelalisib produces adverse autoimmune effects by breaking Treg-mediated tolerance. However, balancing effects on Treg sensitivity versus CD8 Teff insensitivity to idelalisib could still potentially be exploited to enhance inherent antitumor immune responses in patients.
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http://dx.doi.org/10.4049/jimmunol.1701703DOI Listing
March 2019

Transcriptional and functional profiling defines human small intestinal macrophage subsets.

J Exp Med 2018 02 22;215(2):441-458. Epub 2017 Dec 22.

Centre for Immune Regulation, Department of Pathology, University of Oslo and Oslo University Hospital, Rikshospitalet, Oslo, Norway

Macrophages (Mfs) are instrumental in maintaining immune homeostasis in the intestine, yet studies on the origin and heterogeneity of human intestinal Mfs are scarce. Here, we identified four distinct Mf subpopulations in human small intestine (SI). Assessment of their turnover in duodenal transplants revealed that all Mf subsets were completely replaced over time; Mf1 and Mf2, phenotypically similar to peripheral blood monocytes (PBMos), were largely replaced within 3 wk, whereas two subsets with features of mature Mfs, Mf3 and Mf4, exhibited significantly slower replacement. Mf3 and Mf4 localized differently in SI; Mf3 formed a dense network in mucosal lamina propria, whereas Mf4 was enriched in submucosa. Transcriptional analysis showed that all Mf subsets were markedly distinct from PBMos and dendritic cells. Compared with PBMos, Mf subpopulations showed reduced responsiveness to proinflammatory stimuli but were proficient at endocytosis of particulate and soluble material. These data provide a comprehensive analysis of human SI Mf population and suggest a precursor-progeny relationship with PBMos.
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http://dx.doi.org/10.1084/jem.20170057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789404PMC
February 2018

Antibody-secreting plasma cells persist for decades in human intestine.

J Exp Med 2017 02 19;214(2):309-317. Epub 2017 Jan 19.

Department of Pathology, Centre for Immune Regulation, Oslo University Hospital-Rikshospitalet and The University of Oslo, 0372 Oslo, Norway

Plasma cells (PCs) produce antibodies that mediate immunity after infection or vaccination. In contrast to PCs in the bone marrow, PCs in the gut have been considered short lived. In this study, we studied PC dynamics in the human small intestine by cell-turnover analysis in organ transplants and by retrospective cell birth dating measuring carbon-14 in genomic DNA. We identified three distinct PC subsets: a CD19 PC subset was dynamically exchanged, whereas of two CD19 PC subsets, CD45 PCs exhibited little and CD45 PCs no replacement and had a median age of 11 and 22 yr, respectively. Accumulation of CD45 PCs during ageing and the presence of rotavirus-specific clones entirely within the CD19 PC subsets support selection and maintenance of protective PCs for life in human intestine.
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http://dx.doi.org/10.1084/jem.20161590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294861PMC
February 2017

CD8+ T Cells That Coexpress RORγt and T-bet Are Functionally Impaired and Expand in Patients with Distal Bile Duct Cancer.

J Immunol 2017 02 4;198(4):1729-1739. Epub 2017 Jan 4.

Center for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway;

CD8 T cells that express retinoic acid-related orphan receptor (ROR)γt (T17 cells) have been shown to promote procarcinogenic inflammation and contribute to a tolerogenic microenvironment in tumors. We investigated their phenotype and functional properties in relationship to the pathogenesis of human distal bile duct cancer (DBDC). DBDC patients had an elevated level of type 17 immune responses and the frequency of CD8RORγt T cells (T17 cells) was increased in peripheral blood. The CD8RORγt T cells represented a highly activated subset and produced IL-17A in equal amount as CD4RORγt T cells (T17 cells). Most CD8RORγt T cells coexpressed T-bet, a lineage transcription factor for T1 and T1 development, suggesting that CD8RORγt T cells undergo plasticity toward a T17/1-like phenotype with coproduction of IL-17A and INF-γ. In comparison with CD8RORγt T cells, the CD8RORγt T cells had a higher level of TCR signaling and were terminally differentiated and exhausted. These cells also had impaired ability to re-express perforin after degranulation and reduced cytotoxic immune function. A subset of CD8RORγt T cells expressing a low level of programmed cell death protein 1 and a high level of OX40 were associated with reduced patient survival. In conclusion, CD8RORγt T cells are proinflammatory and functionally impaired and may contribute to the pathogenesis of DBDC.
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http://dx.doi.org/10.4049/jimmunol.1600061DOI Listing
February 2017

Regulatory T cells that co-express RORγt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer.

Oncoimmunology 2016 Apr 29;5(4):e1102828. Epub 2015 Oct 29.

Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway; Biotechnology Center, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway.

Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4T cells that express RORγt and IL-17 (T17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (T) contribute to T17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to T17 associated functional plasticity in T. In this study, we investigated the phenotype and functional properties of T in patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3T, which exclusively occurred within the FOXP3RORγtT compartment. The FOXP3RORγtT retained FOXP3T markers and represented an activated subset. The expression of RORγt in T may indicate a phenotypic switch toward T17 cells. However, the FOXP3RORγtT produced both T17 and T2 associated pro-inflammatory cytokines, which corresponded with elevated T17 and T2 immune responses in PDAC patients. Both the FOXP3T and FOXP3RORγtT from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3RORγtT have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.
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http://dx.doi.org/10.1080/2162402X.2015.1102828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839385PMC
April 2016

Human regulatory T cells control TCR signaling and susceptibility to suppression in CD4+ T cells.

J Leukoc Biol 2016 07 29;100(1):5-16. Epub 2015 Dec 29.

Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Norway; Biotechnology Centre, University of Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Norway; Section for Transplantation Surgery Oslo University Hospital, Oslo, Norway; and

Human CD4(+)CD25(hi)FOXP3(+) regulatory T cells maintain immunologic tolerance and prevent autoimmune and inflammatory immune responses. Regulatory T cells undergo a similar activation cycle as conventional CD4(+) T cells upon antigen stimulation. Here, we demonstrate that T cell receptors and costimulation are required to activate the regulatory T cell suppressive function. Regulatory T cells suppressed the T cell receptor signaling in effector T cells in a time-dependent manner that corresponded with inhibition of cytokine production and proliferation. Modulation of the activation level and thereby the suppressive capacity of regulatory T cells imposed distinct T cell receptor signaling signatures and hyporesponsiveness in suppressed and proliferating effector T cells and established a threshold for effector T cell proliferation. The immune suppression of effector T cells was completely reversible upon removal of regulatory T cells. However, the strength of prior immune suppression by regulatory T cells and corresponding T cell receptor signaling in effector T cells determined the susceptibility to suppression upon later reexposure to regulatory T cells. These findings demonstrate how the strength of the regulatory T cell suppressive function determines intracellular signaling, immune responsiveness, and the later susceptibility of effector T cells to immune suppression and contribute to unveiling the complex interactions between regulatory T cells and effector T cells.
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http://dx.doi.org/10.1189/jlb.2HI0815-334RDOI Listing
July 2016

Transplantation With Livers From Deceased Donors Older Than 75 Years.

Transplantation 2015 Dec;99(12):2534-42

1 Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital, Oslo, Norway. 2 Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway. 3 Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway. 4 Department of Transplantation, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden. 5 Division of Transplantation Surgery, Karolinska University Hospital Huddinge, Solna, Sweden. 6 Department of Surgical Sciences, Upper Abdominal Surgery, Uppsala Academic Hospital, Uppsala, Sweden. 7 Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland. 8 Department of Surgical Gastroenterology and Transplantation, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. 9 Division of Cancer medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 10 Institute for Clinical Medicine, University of Oslo, Oslo, Norway.

Background: The availability of donor organs limits the number of patients in need who are offered liver transplantation. Measures to expand the donor pool are crucial to prevent on-list mortality. The aim of this study was to evaluate the use of livers from deceased donors who were older than 75 years.

Methods: Fifty-four patients who received a first liver transplant (D75 group) from 2001 to 2011 were included. Donor and recipient data were collected from the Nordic Liver Transplant Registry and medical records. The outcome was compared with a control group of 54 patients who received a liver graft from donors aged 20 to 49 years (D20-49 group). Median donor age was 77 years (range, 75-86 years) in the D75 group and 41 years (range, 20-49 years) in the D20-49 group. Median recipient age was 59 years (range, 31-73 years) in the D75 group and 58 years (range, 31-74 years) in the D20-49 group.

Results: The 1-, 3-, and 5-year patient/graft survival values were 87/87%, 81/81%, and 71/67% for the D75 group and 88/87%, 75/73%, and 75/73% for the D20-49 group, respectively. Patient (P = 0.89) and graft (P = 0.79) survival did not differ between groups. The frequency of biliary complications was higher in the D75 group (29.6/13%, P = 0.03).

Conclusions: Selected livers from donors over age 75 years should not be excluded based on age, which does not compromise patient or graft survival despite a higher frequency of biliary complications.
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http://dx.doi.org/10.1097/TP.0000000000000728DOI Listing
December 2015

Liver transplantation with deceased ABO-incompatible donors is life-saving but associated with increased risk of rejection and post-transplant complications.

Transpl Int 2015 Jul;28(7):800-12

Transplant Institute, Sahlgrenska University Hospital, Sahlgrenska Academy, Gothenburg, Sweden.

ABO-incompatible (ABOi) liver transplantation (LT) with deceased donor organs is performed occasionally when no ABO-compatible (ABOc) graft is available. From 1996 to 2011, 61 ABOi LTs were performed in Oslo and Gothenburg. Median patient age was 51 years (range 13-75); 33 patients were transplanted on urgent indications, 13 had malignancy-related indications, and eight received ABOi grafts for urgent retransplantations. Median donor age was 55 years (range 10-86). Forty-four patients received standard triple immunosuppression with steroids, tacrolimus, and mycophenolate mofetil, and forty-four patients received induction with IL-2 antagonist or anti-CD20 antibody. Median follow-up time was 29 months (range 0-200). The 1-, 3-, 5-, and 10-year Kaplan-Meier estimates of patient survival (PS) and graft survival (GS) were 85/71%, 79/57%, 75/55%, and 59/51%, respectively, compared to 90/87%, 84/79%, 79/73%, and 65/60% for all other LT recipients in the same period. The 1-, 3-, 5-, and 10-year GS for A2 grafts were 81%, 67%, 62%, and 57%, respectively. In conclusion, ABOi LT performed with non-A2 grafts is associated with inferior graft survival and increased risk of rejection, vascular and biliary complications. ABOi LT with A2 grafts is associated with acceptable graft survival and can be used safely in urgent cases.
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http://dx.doi.org/10.1111/tri.12552DOI Listing
July 2015

Low use of surveillance and early diagnosis of hepatocellular carcinoma in Norway--a population-based cohort study.

Cancer Epidemiol 2014 Dec;38(6):741-7

Department of Infectious Diseases, Medical Division, Akershus University Hospital, Lørenskog, Norway.

Background And Aims: Curative treatment of hepatocellular carcinoma (HCC) is dependent on early diagnosis. Surveillance of patients at high risk for HCC is a key determinant to achieve this goal, but may be an underutilized tool. The aim of this study was to determine the rate of pre-diagnosis surveillance in patients with HCC in a large population-based cohort and to assess to what extent cirrhosis was known prior to the diagnosis of HCC.

Methods: All patients diagnosed with HCC during 2000-2009 in The South-Eastern Regional Health Authority, representing 56% of the Norwegian population, were identified from The National Cancer Registry and the medical records were reviewed.

Results: Fifteen out of 486 patients (3%) were diagnosed by surveillance. Potential curative treatment was offered to 58% of the patients who underwent surveillance as opposed to 15% in the non-surveillance group. Only age ≤ 65 years was an independent predictor of screening in a multivariate model. Almost two thirds of the patients with cirrhosis were unrecognized prior to the HCC diagnosis. Two hundred and fourteen patients (44%) were non-cirrhotics.

Conclusion: Regular HCC surveillance in at-risk populations is virtually not applied in Norway and this may contribute to inferior overall survival. Failure to recognize cirrhosis and a high rate of HCC in non-cirrhotic patients will be limiting factors for the overall effectiveness of a potential surveillance program.
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http://dx.doi.org/10.1016/j.canep.2014.10.005DOI Listing
December 2014

Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients.

Cancer Immunol Immunother 2015 Mar 22;64(3):337-47. Epub 2014 Nov 22.

Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.

Invasive ovarian cancer is associated with poor outcome. The presence of infiltrating regulatory T-cells (Tregs) suppresses protective anti-tumor immune responses, and their accumulation into the tumor microenvironment correlates with reduced survival in ovarian cancer patients. Here, we conducted a detailed characterization of CD4(+) T-cells, CD8(+) T-cells and Treg subsets in the peripheral blood and malignant ascites fluid from seventeen patients with ovarian carcinoma of epithelial origin. Cell distribution, activation status and proliferation status were assessed by multi-color flow cytometry. In ascites fluid, a significant accumulation of CD8(+) cytotoxic T-cells and Tregs was observed compared to peripheral blood. Furthermore, a skewing toward the CD45RA(-) effector/memory compartment was observed in all T-cell subsets in the ascites fluid, but was most pronounced in the Treg population. Regulatory T-cells in the malignant ascites were more activated and had a higher proliferation rate compared to blood-derived cells from the same patient, and their number in ascites was positively correlated with the number of epithelial cells in effusion. In summary, we demonstrate an accumulation of activated CD4(+), CD8(+) and regulatory T-cells in the cancer microenvironment of ovarian carcinoma.
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http://dx.doi.org/10.1007/s00262-014-1636-6DOI Listing
March 2015

T-cell co-stimulation through the CD2 and CD28 co-receptors induces distinct signalling responses.

Biochem J 2014 Jun;460(3):399-410

†Biotechnology Centre, K. G. Jebsen Centre for Inflammation Research and K. G. Jebsen Centre for Cancer Immunotherapy, University of Oslo, N-0318 Oslo, Norway.

Full T-cell activation critically depends on the engagement of the TCR (T-cell receptor) in conjunction with a second signal by co-stimulatory receptors that boost the immune response. In the present study we have compared signalling patterns induced by the two co-receptors CD2 and CD28 in human peripheral blood T-cells. These co-receptors were previously suggested to be redundant in function. By a combination of multi-parameter phosphoflow cytometry, phosphokinase arrays and Western blot analyses, we demonstrate that CD2 co-stimulation induces phosphorylation of the TCR-proximal signalling complex, whereas CD28 activates distal signalling molecules, including the transcription factors NF-κB (nuclear factor κB), ATF (activating transcription factor)-2, STAT3/5 (signal transducer and activator of transcription 3/5), p53 and c-Jun. These signalling patterns were conserved in both naïve and effector/memory T-cell subsets. We show that free intracellular Ca(2+) and signalling through the PI3K (phosphoinositide 3-kinase)/Akt pathway are required for proper CD28-induced NF-κB activation. The signalling patterns induced by CD2 and CD28 co-stimulation lead to distinct functional immune responses in T-cell proliferation and cytokine production. In conclusion, CD2 and CD28 co-stimulation induces distinct signalling responses and functional outcomes in T-cells.
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http://dx.doi.org/10.1042/BJ20140040DOI Listing
June 2014

Aggressive treatment of patients with metastatic colorectal cancer increases survival: a scandinavian single-center experience.

HPB Surg 2013 6;2013:727095. Epub 2013 Jun 6.

Centre for Molecular Medicine Norway, University of Oslo, 0318 Oslo, Norway ; Biotechnology Centre, University of Oslo, 0317 Oslo, Norway ; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, 0424 Oslo, Norway.

Background. We examined overall and disease-free survivals in a cohort of patients subjected to resection of liver metastasis from colorectal cancer (CRLM) in a 10-year period when new treatment strategies were implemented. Methods. Data from 239 consecutive patients selected for liver resection of CRLM during the period from 2002 to 2011 at a single center were used to estimate overall and disease-free survival. The results were assessed against new treatment strategies and established risk factors. Results. The 5-year cumulative overall and disease-free survivals were 46 and 24%. The overall survival was the same after reresection, independently of the number of prior resections and irrespectively of the location of the recurrent disease. The time intervals between each recurrence were similar (11 ± 1 months). Patients with high tumor load given neoadjuvant chemotherapy had comparable survival to those with less extensive disease without neoadjuvant chemotherapy. Positive resection margin or resectable extrahepatic disease did not affect overall survival. Conclusion. Our data support that one still, and perhaps to an even greater extent, should seek an aggressive therapeutic strategy to achieve resectable status for recurrent hepatic and extrahepatic metastases. The data should be viewed in the context of recent advances in the understanding of cancer biology and the metastatic process.
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http://dx.doi.org/10.1155/2013/727095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690245PMC
July 2013

Kinetics and activation requirements of contact-dependent immune suppression by human regulatory T cells.

J Immunol 2012 Jun 25;188(11):5459-66. Epub 2012 Apr 25.

Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo, N-0318 Oslo, Norway.

Naturally occurring regulatory T cells (Tregs) maintain self tolerance by dominant suppression of potentially self-reactive T cells in peripheral tissues. However, the activation requirements, the temporal aspects of the suppressive activity, and mode of action of human Tregs are subjects of controversy. In this study, we show that Tregs display significant variability in the suppressive activity ex vivo as 54% of healthy blood donors examined had fully suppressive Tregs spontaneously, whereas in the remaining donors, anti-CD3/CD2/CD28 stimulation was required for Treg suppressive activity. Furthermore, anti-CD3/CD2/CD28 stimulation for 6 h and subsequent fixation in paraformaldehyde rendered the Tregs fully suppressive in all donors. The fixation-resistant suppressive activity of Tregs operated in a contact-dependent manner that was not dependent on APCs, but could be fully obliterated by trypsin treatment, indicating that a cell surface protein is directly involved. By add-back of active, fixed Tregs at different time points after activation of responding T cells, the responder cells were susceptible to Treg-mediated immune suppression up to 24 h after stimulation. This defines a time window in which effector T cells are susceptible to Treg-mediated immune suppression. Lastly, we examined the effect of a set of signaling inhibitors that perturb effector T cell activation and found that none of the examined inhibitors affected Treg activation, indicating pathway redundancy or that Treg activation proceeds by signaling mechanisms distinct from those of effector T cells.
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http://dx.doi.org/10.4049/jimmunol.1101367DOI Listing
June 2012

Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

Mol Cancer 2011 Dec 15;10:149. Epub 2011 Dec 15.

Centre for Molecular Medicine Norway, Nordic EMBL Partnership and Biotechnology Centre, University of Oslo, Oslo, Norway.

Background: The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of β-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E(2) (PGE(2)) - PI-3 kinase pathways. Recent reports show that PGE(2)-induced phosphorylation of β-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE(2) on β-catenin homeostasis.

Findings: Treatment of Apc(Min/+) mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of β-catenin, β-catenin nuclear translocation and expression of the β-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE(2)-induced β-catenin phosphorylation and c-Myc upregulation.

Conclusion: Based on our findings we suggest that PGE(2) act through PKA to promote β-catenin nuclear translocation and tumor development in Apc(Min/+) mice in vivo, indicating that the direct regulatory effect of PKA on β-catenin nuclear translocation is operative in intestinal cancer.
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http://dx.doi.org/10.1186/1476-4598-10-149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278393PMC
December 2011

Regulatory T-cell-mediated inhibition of antitumor immune responses is associated with clinical outcome in patients with liver metastasis from colorectal cancer.

Cancer Immunol Immunother 2012 Jul 11;61(7):1045-53. Epub 2011 Dec 11.

Centre for Molecular Medicine Norway, University of Oslo, Blindern, Norway.

Adaptive regulatory T cells (Tregs) contribute to an immunosuppressive microenvironment in colorectal cancer (CRC). Here, we examined whether the level of Treg-mediated inhibition of antitumor immune responses in patients with metastatic CRC (metCRC) selected for liver resection is associated with clinical outcome. Preoperatively and at follow-ups, we did flow-based phenotyping, examined antitumor immunity using peptides from carcinoembryonic antigen (CEA) protein in the presence or absence of CD4(+)CD25(+)CD127(dim/-) cells (Tregs) and determined cytokine and PGE(2) levels in patient blood samples. At 18 months post-surgery, 8 patients were disease free (7 alive and 1 dead of unrelated cause) and 10 had experienced disease recurrence (7 alive and 3 dead of metCRC). Prior to surgery, the patients demonstrated Treg-mediated suppression of TNFα and IFNγ expression that could be perturbed through the PGE(2)/cAMP pathway and the immune suppression was significantly higher in the group that later developed disease recurrence (P = 0.046). Furthermore, the post-surgery plasma PGE(2) levels were related to the clinical outcome (PGE(2) levels of 280 ± 47 vs. 704 ± 153 pg/ml (mean ± SEM) for disease free and recurrent disease, respectively). T-cell phenotyping revealed higher frequencies of COX-2(+) cells in the patients with recurrent disease. These findings support the notion that the level of Treg-mediated suppression of adaptive antitumor immune responses at the time of surgery may influence later clinical outcome of metCRC and provide valuable prognostic information.
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http://dx.doi.org/10.1007/s00262-011-1174-4DOI Listing
July 2012

CD147 (Basigin/Emmprin) identifies FoxP3+CD45RO+CTLA4+-activated human regulatory T cells.

Blood 2011 Nov 21;118(19):5141-51. Epub 2011 Sep 21.

Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Oslo, Norway.

Human CD4(+)FoxP3(+) T cells are functionally and phenotypically heterogeneous providing plasticity to immune activation and regulation. To better understand the functional dynamics within this subset, we first used a combined strategy of subcellular fractionation and proteomics to describe differences at the protein level between highly purified human CD4(+)CD25(+) and CD4(+)CD25(-) T-cell populations. This identified a set of membrane proteins highly expressed on the cell surface of human regulatory T cells (Tregs), including CD71, CD95, CD147, and CD148. CD147 (Basigin or Emmprin) divided CD4(+)CD25(+) cells into distinct subsets. Furthermore, CD147, CD25, FoxP3, and in particular CTLA-4 expression correlated. Phenotypical and functional analyses suggested that CD147 marks the switch between resting (CD45RA(+)) and activated (CD45RO(+)) subsets within the FoxP3(+) T-cell population. Sorting of regulatory T cells into CD147(-) and CD147(+) populations demonstrated that CD147 identifies an activated and highly suppressive CD45RO(+) Treg subset. When analyzing CD4(+) T cells for their cytokine producing potential, CD147 levels grouped the FoxP3(+) subset into 3 categories with different ability to produce IL-2, TNF-α, IFN-γ, and IL-17. Together, this suggests that CD147 is a direct marker for activated Tregs within the CD4(+)FoxP3(+) subset and may provide means to manipulate cells important for immune homeostasis.
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http://dx.doi.org/10.1182/blood-2011-02-339242DOI Listing
November 2011

An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses.

J Virol 2011 Jul 13;85(13):6557-66. Epub 2011 Apr 13.

Department of Infectious Diseases, Oslo University Hospital, P.O. Box 4950 Nydalen, NO-0424 Oslo, Norway.

Chronic HIV infection is characterized by chronic immune activation and dysfunctional T cells with elevated intracellular cyclic AMP (cAMP), which inhibits the T cell activation capability. cAMP may be induced by prostaglandin E(2) following lipopolysaccharide (LPS)-induced upregulation of cyclooxygenase type 2 (COX-2) in monocytes due to the elevated LPS levels in patients with chronic HIV infection. This hypothesis was tested using celecoxib, a COX-2 inhibitor, for 12 weeks in HIV-infected patients without antiretroviral treatment in a prospective, open, randomized exploratory trial. Thirty-one patients were randomized in the trial; 27 completed the study, including 13 patients on celecoxib. Celecoxib reduced chronic immune activation in terms of CD38 density on CD8(+) T cells (-24%; P = 0.04), IgA levels (P = 0.04), and a combined score for inflammatory markers (P < 0.05). Celecoxib further reduced the inhibitory surface receptor programmed death 1 (PD-1) on CD8(+) T cells (P = 0.01), including PD-1 on the HIV Gag-specific subset (P = 0.02), enhanced the number of CD3(+) CD4(+) CD25(+) CD127(lo/-) Treg or activated cells (P = 0.02), and improved humoral memory recall responses to a T cell-dependent vaccine (P = 0.04). HIV RNA (P = 0.06) and D dimers (P = 0.07) tended to increase in the controls, whereas interleukin-6 (IL-6) possibly decreased in the treatment arm (P = 0.10). In conclusion, celecoxib downmodulated the immune activation related to clinical progression of chronic HIV infection and improved T cell-dependent functions in vivo.
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http://dx.doi.org/10.1128/JVI.00073-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126508PMC
July 2011

Inflammation versus adaptive immunity in cancer pathogenesis.

Crit Rev Oncog 2009 ;15(1-2):43-63

The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.

Cancer pathogenesis is initiated and modulated in an interplay between the malignant transformed cells, the surrounding stroma, and the innate and adaptive immune system. These interactions are complex, and components of the immune system act as both defense mechanisms against and contributors to tumor initiation, tumor growth, invasivity, and development of metastases. Inflammatory conditions help to establish a microenvironment promoting cancer development, whereas a malignant tumor feeds the inflammatory response and accelerates tumor growth. However, mouse models and epidemiological and clinical data demonstrate that an intact immune system is associated with a favorable prognosis, although the inflammatory response and the adaptive immune system share many cellular and humoral features. Here, we review the emerging concepts in cancer pathogenesis where the inflammatory and adaptive components of the immune system play an important role in the interaction with the tumor and stromal tissue.
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http://dx.doi.org/10.1615/critrevoncog.v15.i1-2.20DOI Listing
April 2010

A novel human CD4+ T-cell inducer subset with potent immunostimulatory properties.

Eur J Immunol 2010 Jan;40(1):134-41

Division of Experimental Medicine, Department of Medicine, University of California San Francisco, and HIV/AIDS Division, San Francisco General Hospital, San Francisco, CA 94110, USA.

The complexity of immunoregulation has focused attention on the CD4+ T "suppressor" regulatory cell (Treg), which helps maintain balance between immunity and tolerance. An immunoregulatory T-cell population that upon activation amplifies cellular immune responses was described in murine models more than 30 years ago; however, no study has yet identified a naturally occurring T "inducer" cell type. Here, we report that the ectoenzyme CD39/NTPDase1 (ecto-nucleoside triphosphate diphosphohydrolase 1) helps to delineate a novel population of human "inducer" CD4+ T cells (Tind) that significantly increases the proliferation and cytokine production of responder T cells in a dose-dependent manner. Furthermore, this unique Tind subset produces a distinct repertoire of cytokines in comparison to the other CD4+ T-cell subsets. We propose that this novel CD4+ T-cell population counterbalances the suppressive activity of suppressor Treg in peripheral blood and serves as a calibrator of immunoregulation.
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http://dx.doi.org/10.1002/eji.200939258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902274PMC
January 2010

Interleukin-10-secreting T cells define a suppressive subset within the HIV-1-specific T-cell population.

Eur J Immunol 2009 May;39(5):1280-7

The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.

Recent studies have indicated that Treg contribute to the HIV type 1 (HIV-1)-related immune pathogenesis. However, it is not clear whether T cells with suppressive properties reside within the HIV-1-specific T-cell population. Here, PBMC from HIV-1-infected individuals were stimulated with a 15-mer Gag peptide pool, and HIV-1-specific T cells were enriched by virtue of their secretion of IL-10 or IFN-gamma using immunomagnetic cell-sorting. Neither the IL-10-secreting cells nor the IFN-gamma-secreting cells expressed the Treg marker FOXP3, yet the IL-10-secreting cells potently suppressed anti-CD3/CD28-induced CD4(+) as well as CD8(+) T-cell proliferative responses. As shown by intracellular cytokine staining, IL-10- and IFN-gamma-producing T cells represent distinct subsets of the HIV-1-specific T cells. Our data collectively suggest that functionally defined HIV-1-specific T-cell subsets harbor potent immunoregulatory properties that may contribute to HIV-1-associated T-cell dysfunction.
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http://dx.doi.org/10.1002/eji.200839002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742768PMC
May 2009

CD8+ regulatory T cells-A distinct T-cell lineage or a transient T-cell phenotype?

Hum Immunol 2008 Nov 24;69(11):696-9. Epub 2008 Sep 24.

The Biotechnology Centre of Oslo, University of Oslo, N-0317 Oslo, Norway.

Regulation of the immune system is fundamental for proper immune function and homeostasis. In the periphery, regulatory T cells provide self-tolerance and protect the host from harmful autoreactive T cells. Regulatory T cells are also involved in the pathogenesis of chronic viral infectious diseases and cancer. Both the CD4(+) and the CD8(+) T cell compartments contain regulatory T cells. Although various CD4(+) regulatory T-cell subsets represent the best characterized regulatory T-cell populations, CD8(+) regulatory T cells also have strong immunosuppressive properties and are involved in the pathogenesis of various clinical conditions. In this review, we will discuss the phenotypic and functional characteristics of CD8(+) regulatory T cells in comparison to CD4(+) regulatory T cells.
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http://dx.doi.org/10.1016/j.humimm.2008.08.291DOI Listing
November 2008

Differentiation of naive CD4+ T cells into CD4+CD25+FOXP3+ regulatory T cells by continuous antigen stimulation.

J Leukoc Biol 2008 May 12;83(5):1111-7. Epub 2008 Feb 12.

The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, N-0349 Oslo, Norway.

Human CD4+CD25+ regulatory T (T(R)) cells express the transcription factor forkhead box p3 (FOXP3) and have potent immunosuppressive properties. While naturally occurring T(R) cells develop in the thymus, adaptive T(R) cells develop in the periphery from naive CD4+ T cells. Adaptive T(R) cells may express cyclooxygenase type 2 (COX-2) and suppress effector T cells by a PGE(2)-dependent mechanism, which is reversible with COX inhibitors. In this study we have characterized the differentiation of naive CD4+ T cells into adaptive T(R) cells in detail during 7 days of continuous antigen stimulation. After 2 days of stimulation of CD4+CD25- T cells, the cells expressed FOXP3 and COX-2 and displayed potent immunosuppressive properties. The suppressive phenotype was present at all observed time-points from Day 2, although suppression was merely present at Day 7. The adaptive T(R) cells expressed cell surface markers consistent with an activated phenotype and secreted high levels of TGF-beta, IL-10, and PGE(2). However, the suppressive phenotype was found exclusively in cells that proliferated upon activation. These data support the notion that activation of naive CD4+ T cells leads to concomitant acquisition of effector and suppressive properties.
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http://dx.doi.org/10.1189/jlb.0507329DOI Listing
May 2008
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