| 51. |
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| 52. |
- Lindh, Emma, et al.
(author)
-
Autoimmunity and cystatin SA1 deficiency behind chronic mucocutaneous candidiasis in autoimmune polyendocrine syndrome type 1
- 2013
-
In: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 42, s. 1-6
-
Journal article (peer-reviewed)abstract
- Patients with the monogenic disease autoimmune polyendocrine syndrome type I (APSI) develop autoimmunity against multiple endocrine organs and suffer from chronic mucocutaneous candidiasis (CMC), a paradoxical complication with an unknown mechanism. We report here that saliva from APSI patients with CMC is defective in inhibiting growth of Candida albicans in vitro and show reduced levels of a salivary protein identified as cystatin SA1. In contrast, APSI patients without CMC express salivary cystatin SA1 and can inhibit C. albicans to the same extent as healthy controls. We evaluated the anti-fungal activity of cystatin SA1 and found that synthesized full length cystatin SA1 efficiently inhibits growth of C. albicans in vitro. Moreover, APSI patients exhibit salivary IgA autoantibodies recognizing myosin-9, a protein expressed in the salivary glands, thus linking autoimmunity to cystatin SA1 deficiency and CMC. This data suggests an autoimmune mechanism behind CMC in APSI and provides rationale for evaluating cystatin SA1 in antifungal therapy.
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| 53. |
- Ling, Agnes, 1976-
(author)
-
Immune cell infiltration and prognosis in colorectal cancer
- 2018
-
Doctoral thesis (other academic/artistic)abstract
- Background: Colorectal cancer (CRC) is globally the second most common form of cancer among women, and third in men. It is also one of the most common causes of cancer-related death in high-income countries. Surgical resection is the basis for curative therapy but still almost half of the patients die from metastatic disease. It is therefore imperative to strive on in the search for more efficient strategies to improve patient survival. The success scores for accurate prediction of patient prognosis remain discouraging and novel markers to identify high-risk patients are called for.The tumour immune response has proven critical to prognosis in CRC. A high amount of tumour infiltrating lymphocytes have in studies been found to significantly improve patient outcome. The opposite has been seen in patients with sparsely infiltrated tumours. Findings in this area have driven forth the design of the Immunoscore® system, which may be implemented in clinic as a complement to the TNM staging system. Ongoing research is also focusing on which immune evading mechanisms CRC might deploy in order to progress and metastasize.Aim: To study immune cell infiltration in relation to prognosis in CRC. More specifically the aim has been to investigate the prognostic importance of different subsets of immune cells infiltrating the tumour, not only according to quantity but also to intratumoural subsite (tumour invasive front, tumour centre and within the tumour epithelium). The tumour immune response was also evaluated in different molecular subgroups of CRC. Another part of this thesis concerns possible molecular mechanisms involved in tumour immune escape in CRC.Methods: CRC cases in the Colorectal Cancer in Umeå Study (CRUMS) were evaluated using immunohistochemistry, gene expression analyses as well as methylation analyses. Cytokine and chemokine expression was evaluated in CRC tumour tissues and one CRC cell line (Caco2) and derivatives using semi-quantitative real-time PCR. Methylation was analysed using methylation-specific pyrosequencing.Results: We found high quantities of both cytotoxic T cells (CTLs) as well as of regulatory T cells (Tregs) to associate with a better patient outcome. The infiltration of CTLs within the tumour epithelium provided the strongest prognostic information, whilst Tregs withheld the strongest association to prognosis at the tumour invasive front and tumour centre. We could further show that a high Th1 lymphocyte infiltration was strongly associated with a better prognosis in patients with CRC, independently of intratumoural subsite. Another finding was that the extent of Th1 infiltration and patient outcome differed in different molecular subgroups of CRC. We also found down-regulation of TAP1, a protein involved in antigen presentation by MHC class I, to be significantly associated with low infiltration of various subtypes of immune cells. Down-regulation of TAP1 was also correlated to poor prognosis in patients with early stages of CRC. Furthermore, we found TAP1 expression to be inversely correlated with methylation at sites close to the TAP1 promoter region.Conclusion: Tumour infiltrating T lymphocytes have a significant positive impact on prognosis in CRC patients. Different subsets of T lymphocytes vary in their dependency on intratumoural subsite, in to what extent they exert their prognostic influence. We moreover found varying Th1 lymphocyte infiltration rates as well as prognostic impact thereof, in different molecular subgroups of CRC. Our results also show down-regulation of TAP1 to be a mechanism of tumour immune escape in CRC. Further findings suggest methylation of the TAP1 gene to be a putative mechanism for TAP1 down-regulation.
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| 54. |
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| 55. |
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| 56. |
- Marits, Per, et al.
(author)
-
Evaluation of T and B lymphocyte function in clinical practice using a flow cytometry based proliferation assay
- 2014
-
In: Clinical Immunology. - : Elsevier. - 1521-6616 .- 1521-7035. ; 153:2, s. 332-342
-
Journal article (peer-reviewed)abstract
- The golden standard for functional evaluation of immunodeficiencies is the incorporation of [H-3]-thymidine in a proliferation assay stimulated with mitogens. Recently developed whole blood proliferation assays have the advantage of parallel lymphocyte lineage analysis and in addition provide a non-radioactive alternative. Here we evaluate the Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) in a comparison with [H-3]-thymidine incorporation in four patients with severe combined immunodeficiency. The threshold for the mininium number of lymphocytes required for reliable responses in FASCIA is determined together with reference values from 100 healthy donors when stimulated with mitogens as well as antigen specific stimuli. Finally, responses against PWM and SEA + SEB stimuli are conducted with clinically relevant immunomodulatory compounds. We conclude that FASCIA is a rapid, stable and sensitive functional whole blood assay that requires small amounts of whole blood that can be used for reliable assessment of lymphocyte reactivity in patients. (C) 2014 Elsevier Inc. All rights reserved.
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| 57. |
- Marits, Per, 1977-
(author)
-
On CD4+ T Lymphocytes in Solid Tumours
- 2007
-
Doctoral thesis (other academic/artistic)abstract
- This thesis deals with recognition and elimination of tumours by T lymphocytes and their use in adoptive immunotherapy.The first tumour-draining lymph node; the sentinel node, is identified by peritumoural injection of a tracer. This is the hypothesised location for the activation of tumour-reactive lymphocytes. Accordingly, proliferation and IFN-γ production in response to autologous tumour extract was detected in sentinel nodes from patients with colon and urinary bladder cancer. Reactivity in metastatic nodes was generally lower or absent, but the non-responsiveness could be subdued in long-term cultures by addition of tumour antigen and IL-2. A novel padlock-probe based method was developed for measuring the T cell receptor Vβ repertoire. Common Vβ gene expansions were detected in tumour-infiltrating lymphocytes and sentinel nodes. Thus, tumour antigens are recognised in sentinel nodes by Th1 lymphocytes, resulting in a clonally expanded cell population that can be further propagated ex vivo.Regulatory T cells (Tregs) may contribute to tumour-induced immunosuppression. Immunohistochemical stainings against the pan-T cell marker CD3 and Treg marker FOXP3 was performed on tumour tissue from 20 historical urinary bladder cancer patients. The ratio of FOXP3+ to CD3+ cells was lower in patients alive 7 years post-cystectomy, suggesting that Tregs in bladder cancer have prognostic implications.Lymphocytes were isolated from sentinel nodes from sixteen patients with advanced or high-risk colon cancer. In vitro expansion with addition of autologous tumour extract and IL-2 mainly promoted the outgrowth of CD4+ Th1 lymphocytes, which were safely re-transfused to the patients. Four patients responded with complete tumour regression. Survival time in the Dukes’ D patients was significantly increased compared with conventionally treated controls (2.6 versus 0.8 years; p=0.048).In conclusion, human solid tumours are recognised in sentinel nodes and in vitro expanded sentinel node-acquired CD4+ T lymphocytes seem useful in the treatment of patients with disseminated cancer.
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| 58. |
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| 59. |
- Marits, Per, et al.
(author)
-
The many flavors of tumor-associated B cells
- 2013
-
In: Oncoimmunology. - : Landes Bioscience. - 2162-4011 .- 2162-402X. ; 2:8, s. e25237-
-
Journal article (peer-reviewed)abstract
- Little is known on the role of distinct B-cell subtypes in human malignancies. We have recently performed a multiplex characterization of B cells in patient-derived tumor-associated tissues, documenting the activation and antigen-driven differentiation of B cells in metastatic lymph nodes and neoplastic lesions. Here we discuss the role of B lymphocytes as antigen-presenting cells and catalysts of T cell-based immunotherapies in view of these findings.
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| 60. |
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| 61. |
- Melin, Jan, et al.
(author)
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A third dose SARS-CoV-2 BNT162b2 mRNA vaccine results in improved immune response in hemodialysis patients
- 2022
-
In: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 127:1
-
Journal article (peer-reviewed)abstract
- Background: The hemodialysis (HD) population has been a vulnerable group during the coronavirus disease 2019 (COVID-19) pandemic. Advanced chronic kidney disease with uremia is associated with weaker immune response to infections and an attenuated response to vaccines. The aim of this study was to study the humoral and cellular response to the second and third doses of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) BNT162b2 mRNA vaccine in HD patients and to follow the response over time.Methods: The patients received their first two vaccine doses from 28 December 2020 within a 4-week interval and the third dose in September 2021 and were followed-up for humoral and cellular immune response at 1) 7-15 weeks and 2) 6-8 months after dose two (no t-cell reactivity measured), and 3) 3 weeks and 4) 3 months after dose three. Fifty patients were initially enrolled, and 40 patients were followed during the entire study. Levels of COVID-19 (SARS-CoV-2) IgG antibody against the Spike antigen (anti-S) and T-cell reactivity testing against the Spike protein using Enzyme-Linked ImmunoSpot (ELISPOT) technology were evaluated.Results: IgG antibodies to anti-S were detected in 35 (88%) of the 40 patients 7-15 weeks after vaccine dose two, 31 (78%) were positive, and 4 (10%) borderline. The median anti-S titer was 606 Abbott Units/milliliter (AU/mL) (interquartile range [IQR] 134-1,712). Three months after the third dose, anti-S was detected in 38 (95%) of 40 patients (P < 0.01 compared to after dose two), and the median anti-S titer was 9,910 AU/mL (IQR 2,325-26,975). Cellular reactivity was detected in 22 (55%), 34 (85%), and 28 (71%) of the 40 patients, and the median T-cell response was 9.5 (IQR 3.5-80), 51.5 (14.8-132), and 19.5 (8.8-54.2) units, respectively, for 6-8 months after dose two, 3 weeks, and 3 months after dose three.Conclusions: Our data show that a third dose of SARS-CoV-2 BNT162b2 mRNA vaccine gives a robust and improved immunological response in HD patients, but a few patients did not develop any anti-S response during the entire study, indicating the importance to monitor the vaccine response since those who do not respond could now be given monoclonal antibodies if they contract a COVID-19 infection or in the future antivirals.
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| 62. |
- Melin, Jan, et al.
(author)
-
Humoral and cellular response to SARS-CoV-2 BNT162b2 mRNA vaccine in hemodialysis patients
- 2021
-
In: BMC Immunology. - : BioMed Central (BMC). - 1471-2172. ; 22:1
-
Journal article (peer-reviewed)abstract
- Background Hemodialysis (HD) patients have an increased risk of acquiring infections due to many health care contacts and may, in addition, have a suboptimal response to vaccination and a high mortality from Covid-19 infection. Methods In 50 HD patients (mean age 69.4 years, 62% men) administration of SARS-CoV-2BNT162b2 mRNA vaccine began in Dec 2020 and the immune response was evaluated 7-15 weeks after the last dose. Levels of Covid-19 (SARS-CoV-2) IgG antibody against the nucleocapsid antigen (anti-N) and the Spike antigen (anti-S) and T-cell reactivity testing against the Spike protein using ELISPOT technology were evaluated. Results Out of 50 patients, anti-S IgG antibodies indicating a vaccine effect or previous Covid-19 infection, were detected in 37 (74%), 5 (10%) had a borderline response and 8 (16%) were negative after two doses of vaccine. T-cell responses were detected in 29 (58%). Of the 37 patients with anti-S antibodies, 25 (68%) had a measurable T-cell response. 2 (40%) out of 5 patients with borderline anti-S and 2 (25%) without anti-S had a concomitant T-cell response. Twenty-seven (54%) had both an antibody and T-cell response. IgG antibodies to anti-N indicating a previous Covid-19 disease were detected in 7 (14%) patients. Conclusions Most HD patients develop a B- and/or T-cell response after vaccination against Covid-19 but approx. 20% had a limited immunological response. T-cell reactivity against Covid-19 was only present in a few of the anti-S antibody negative patients.
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| 63. |
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| 64. |
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| 65. |
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| 66. |
- Nordmark, Gunnel, 1961-
(author)
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Clinical and Experimental Studies in Primary Sjögren’s Syndrome and Systemic Lupus Erythematosus
- 2005
-
Doctoral thesis (other academic/artistic)abstract
- Autoimmune mechanisms and genetic susceptibility contribute to the pathogenesis of primary Sjögren’s syndrome and SLE. These chronic systemic autoimmune diseases have many serological and clinical features in common and have an impact on daily life. The studies in this thesis aim to elucidate their autoimmune mechanisms, define susceptibility genes and evaluate effects of androgen supplement on health-related quality of life. Autoantibodies against α-fodrin, a widely distributed cytoskeletal protein, were detected at similar frequencies in sera from patients with primary and secondary Sjögren’s syndrome and SLE. Consequently, testing for antibodies against α-fodrin would not add diagnostic value compared to conventional serological analysis and does not discriminate between these diseases. The type I interferon (IFN) system was found to be activated in primary Sjögren’s syndrome. IFN-α containing cells were detected in minor salivary gland biopsies, while sera from patients with primary Sjögren’s syndrome induced IFN-α production in the presence of apoptotic and necrotic cell material. This ability of sera correlated with the presence of antibodies against RNA-binding proteins and IFN-α production was dependent on RNA in immune complexes. The natural interferon producing cells/plasmacytoid dendritic cells (NIPC/PDC) were the IFN-α producers and blocking of FcγRIIa inhibited the production. Single nucleotide polymorphisms (SNPs) in two genes in the type I IFN signalling pathway, those for tyrosine kinase 2 and interferon regulatory factor 5, were strongly associated with SLE in a Swedish, Finnish and Icelandic population. The minor allele frequencies were lower in SLE patients than in healthy controls. These SNPs may decrease the function of the type I IFN system, thereby conferring protection against SLE. Supplementation with dehydroepiandrosterone (DHEA) in glucocorticoid treated women with SLE led to mild improvements in health-related quality of life in respect of mental well-being and sexuality, whereas physical well-being was unaffected.
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| 67. |
- Penno, Hendrik, et al.
(author)
-
Expression of RANK-ligand in prostate cancer cell lines
- 2009
-
In: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 69:1, s. 151-155
-
Journal article (peer-reviewed)abstract
- The molecular mediators of bone remodelling, receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK) and osteoprotegerine (OPG), are believed to be involved in the cellular mechanisms by which tumours metastasize to bone. RANKL is a potent stimulator of osteoclastic bone resorption and is expressed in a variety of tumour cells. We have investigated if the membrane bound form of RANKL is expressed in prostate cancer cell lines, and whether this expression might be regulated by the presence of human osteoblasts. Three prostate cancer cell lines were co-cultured with human osteoblast-like cells (hOB) and RANKL expression on cell surface was measured by FACS. We found basal expression of RANKL on the cell surface, and in co-culture with hOBs the number of cells expressing RANKL was increased between 2.5 and 4 times. These data suggest a signalling mechanism between bone cells and prostate cancer cells that might increase bone resorption and thereby promote bone metastases.
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| 68. |
- Ramsey, C, et al.
(author)
-
Aire deficient mice develop multiple features of APECED phenotype and showaltered immune response
- 2002
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 11:4, s. 397-409
-
Journal article (peer-reviewed)abstract
- Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autosomal recessive disease caused by mutations in the AIRE gene. Here we have produced knock-out mice for the Aire gene. The Aire-/- mice develop normally; however, autoimmune features of APECED in Aire-/- mice are evident, including multiorgan lymphocytic infiltration, circulating autoantibodies and infertility. The distribution of B and T cells and thymic maturation as well as activation of T cells appear normal, while the TCR-Vbeta repertoire is altered in peripheral T cells of Aire-/- mice. When mice are challenged with immunization, the peripheral T cells of Aire-/- mice have a 3-5-fold increased proliferation. These findings suggest that the Aire gene is not necessary for normal T cell education and development, while a defect in immune response detected in challenged Aire-/- mice underlines the crucial role of AIRE/Aire in maintaining homeostatic regulation in the immune system.
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| 69. |
- Rosenblatt, Robert, et al.
(author)
-
Blood transfusions during neoadjuvant chemotherapy for muscle-invasive urinary bladder cancer may have a negative impact on overall survival
- 2019
-
In: Scandinavian journal of urology. - : Taylor & Francis. - 2168-1805 .- 2168-1813. ; 53, s. 35-36
-
Journal article (other academic/artistic)abstract
- Introduction: Several studies have demonstrated a decreased overall survival for patients with muscle-invasive bladder cancer (MIBC) receiving allogenic peri- and postoperative blood transfusions at cystectomy. However, the extent and the effect of blood transfusions given during neoadjuvant chemotherapy (NAC) has never been addressed. The purpose of the present study, was to assess the impact of blood transfusions given during NAC on survival in patients with MIBC undergoing NAC and radical cystectomy.Materials and Methods: A cohort of 120 consecutive patients with MIBC (cT2-T4aN0M0) undergoing NAC and radical cystectomy at four Swedish centers was retrospectively evaluated. Clinical and pathoanatomical data was obtained, including data SCANDINAVIAN JOURNAL OF UROLOGY 35 on administeredallogenic blood at consecutive time-intervals. Overall survival was analyzed by Kaplan-Meier plotting and Cox regression.Results: One third of the cohort (n ¼ 40) received blood transfusions during NAC-therapy. The five-year overall survival rates were significantly lower in this group compared to the non-transfused patients (39.7% and 58.9% respectively, p ¼ 0.047). In a univariate analysis, blood transfusions, nodal status and locally advanced tumor growth (pT >2), were negative prognostic factors for survival. In multivariate analysis, only pNx and pT >2 remained significant negative prognostic factors. In subgroup analysis of localized and non-disseminated patients only (n ¼ 96), blood transfused patients showed a 18,5% absolute risk increase compared to blood naïve patients (p¼ 0.197).Conclusions: This is the first time that the extent and the effect of allogenic blood transfusions during NAC is examined in MIBC. Data suggest that there may be an association between blood transfusion and poor pathological and oncological outcome. Firm conclusions are difficult to draw due to the limited number of study participants and the retrospective nature of the study.
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| 70. |
- Rosenblatt, Robert, et al.
(author)
-
Blood transfusions during neoadjuvant chemotherapy for muscle-invasive urinary bladder cancer may have a negative impact on overall survival
- 2020
-
In: Scandinavian journal of urology. - : Taylor & Francis. - 2168-1805 .- 2168-1813. ; 54:1, s. 46-51
-
Journal article (peer-reviewed)abstract
- Objective: To evaluate the extent and plausible effects of blood transfusions given during cisplatin-based neoadjuvant chemotherapy (NAC) on overall survival in patients with muscle-invasive urothelial bladder cancer (MIBC) undergoing NAC and radical cystectomy (RC).Background: Several studies have demonstrated a decreased survival for MIBC patients receiving allogenic peri- and postoperative blood transfusions in conjunction with RC. No studies have previously investigated the effects of blood transfusions during NAC.Materials and methods: 120 patients with MIBC (cT2-T4aN0M0) undergoing NAC and RC between 2008 and 2014 at four Swedish cystectomy centers were retrospectively evaluated. Clinicopathological data were obtained, including data of allogenic blood administration. Survival data was analyzed by Kaplan–Meier plotting and Cox regression.Results: One third of the cohort received blood transfusions during the period of NAC. In univariate analysis, blood transfusions during NAC, nodal stage and advanced tumor stage (pT >2) were negative prognostic factors for survival. In multivariate analysis, only pNx and pT >2 remained significant negative prognostic factors. In a subgroup analysis consisting of patients with localized tumors without dissemination (n = 96), patients that received transfusions during NAC showed an 18.5% absolute risk increase of death at five years of observation, although without statistical significance (p = .197).Conclusions: This is the first time that the extent and plausible effects of allogenic blood transfusions during NAC is examined in MIBC. Data suggest that there may be an association between blood transfusion and poor pathological and oncological outcome. Firm conclusions are difficult to draw due to few study participants and the retrospective nature of the study.
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| 71. |
- Rosenblatt, Robert, 1982-
(author)
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Neoadjuvant chemotherapy in muscle-invasive urinary bladder cancer : studies on treatment response, tumor draining lymph nodes and blood transfusion
- 2020
-
Doctoral thesis (other academic/artistic)abstract
- Muscle-invasive urinary bladder cancer is a deadly disease. Mortality rates remained unchanged for decades despite radical surgery.After several randomized trials, we today know that cisplatin based chemotherapy given prior to cystectomy, improves survival for every tenth patient. Markers that predict responsiveness to chemotherapy would spare unnecessary treatment to the majority of patients. In the search for signs of chemosensitivity, we performed a retrospective analysis of the Nordic cystectomy trials 1 & 2: Chemo treated patients had an almost doubled increase in tumor downstaging compared to the controls. More importantly, this group presented with a reduced absolute risk of death of more than 30% compared to the rest of the patients. These results were presented in paper I.Many cancers spread through the lymphatic system. Usually, there is at least one tumor draining lymph node, referred to as the sentinel node. If this node is free of metastases, there is no lymphatic spread of the disease, and consequently, no use of excavating all neighboring lymph nodes.Sentinel node detection, is an established method in breast cancer, penile cancer and malignant melanoma. Based on the same principles, members of our group developed a similar detection technique in bladder cancer. Unfortunately, sensitivity and specificity were too low to rely on this method as a diagnostic tool for lymphatic spread. Instead, it turned out in recent years that sentinel nodes in muscle invasive bladder cancer are valuable for translational research-lines - mainly in tumor immunology. As for example, sentinel nodes contain tumor specific T cells that are useful in adoptive immunotherapy.In paper II, we set out to test whether sentinel node detection was feasible after chemotherapy and/or tumor downstaging. In a prospective cohort of patients, we saw no difference in detection rates between the groups. Thus, we concluded, neither chemotherapy nor downstaging appeared to hamper the identification of sentinel nodes.The concept was expanded in paper III. After recruiting more patients to the cohort mentioned above, the average numbers of sentinel nodes in different categories of patients were compared. We saw a pattern of decreased number of sentinel nodes in those with locally advanced tumors. It seemed that the number of sentinel nodes had prognostic implications.In the last study, published in paper IV, we wanted to widen our knowledge on the clinical effects of blood transfusion. Mounting data suggests that perioperative blood products have a negative impact on long term survival after cancer surgery. How much allogenic blood was given during the chemotherapy prior to surgery ? It turned out that one third of the bladder cancer patients received blood, and these patients demonstrated a significantly worse overall survival.Neoadjuvant chemotherapy has added a new beneficial dimension to the treatment of muscle invasive bladder cancer. In these four studies, we addressed the effects of chemotherapy on pathoanatomical outcomes, on tumor lymphatics and further; we are suggesting consequences of neoadjuvant chemotherapy in conjunction with blood transfusion. It appears that the immune system is involved in all aspects investigated above. Most likely, an improved scientific understanding of the immune system will be crucial for future bladder cancer treatment options.
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| 72. |
- Rosenblatt, Robert, et al.
(author)
-
Sentinel node detection in muscle-invasive urothelial bladder cancer is feasible after neoadjuvant chemotherapy in all pT stages, a prospective multicenter report
- 2017
-
In: World journal of urology. - : Springer Science and Business Media LLC. - 0724-4983 .- 1433-8726. ; 35:6, s. 921-927
-
Journal article (peer-reviewed)abstract
- PURPOSE: To determine whether sentinel node detection (SNd) in muscle-invasive urothelial bladder cancer (MIBC) can be performed in patients undergoing neoadjuvant chemotherapy (NAC) and determine whether SNd is feasible in all pT stages, including pT0.BACKGROUND: Previous published series of SNd in MIBC have not included patients undergoing NAC, and systematic reports of pT0 patients w/wo NAC were absent. Translational immunological tumor research on MIBC focusing on SNd, in the era of NAC, requires technical feasibility. Additionally, SNd in MIBC requests further evaluations as a method for nodal staging.MATERIALS AND METHODS: Ninety-nine patients with suspected urothelial MIBC were prospectively selected from six urological centers. After TUR-B and primary staging, 65 MIBC patients qualified for radical cystectomy. Precystectomy staging was cT2a-T4aN0M0, including 47 NAC patients and 18 chemo-naïve patients. All 65 patients underwent intraoperative SNd by peritumoral injection of 80 Mbq Technetium and Geiger probe detection. Postcystectomy staging was pT0-T4aN0-N2M0. SNs were defined by two calculations, SNdef1 and SNdef2.RESULTS: Totally 1063 lymph nodes were removed (total SNs; 222-227). NAC patients with pT0 (n = 24) displayed a true positive detection in 91.7 % by either SNdef, with a median of 3.0 SNs. NACpT >0 patients had a true positive detection in 87 % (SNdef1) and 91.3 % (SNdef2). In a univariate analysis, patient group neither NAC nor tumor downstaging influenced detection rates, regardless of SN definition. In total eight patients, 4/22 metastatic nodes were SNs while 18/22 were non-SNs.CONCLUSIONS: Sentinel node detection in MIBC is feasible also in NAC patients, regardless of pT stage. SNd played no role in nodal staging.
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| 73. |
- Sandin, Linda, 1979-
(author)
-
Immunomodulatory Therapy of Solid Tumors : With a Focus on Monoclonal Antibodies
- 2013
-
Doctoral thesis (other academic/artistic)abstract
- Cancer, historically considered a genetic disease, is currently acknowledged to affect the whole body. Our immune system is one key player that can elicit a response against malignant cells but can also promote tumorigenesis. Tumors avoid immune recognition by creating a suppressive microenvironment and inducing tolerance. T-cells are regarded a major effector cell type in tumor immunotherapy. An important ”switch” needed for T-cell activation involves so-called costimulatory and coinhibitory receptors. In this thesis, experimental tumor models were used to investigate the potential of immunomodulatory antibodies to stimulate immune cells and subsequently eliminate tumors.First, systemic antibody blockade of two negative checkpoint regulators (CTLA-4 and PD-1) present on T-cells was evaluated in combination with local CpG therapy or standard BCG treatment. Indeed, this combinatorial therapy with CpG augmented anti-tumor effects with increased levels of tumor-directed T-cells and reduced tumor-infiltrating Tregs.Secondly, as these immunomodulatory antibodies elicit severe side effects in patients, a local low-dose delivery regimen was explored as an alternative to systemic bolus treatment. Our results demonstrated that an approximately seven times lower dose of aCTLA-4, compared to systemic delivery, could eradicate both primary and distant tumors.CD40-expressing APCs are another potential target in antibody-mediated cancer therapy. CD40-stimulated dendritic cells (DCs) have the capability to activate tumor-directed T-cells to kill tumor cells. We next sought to investigate agonistic CD40 antibody efficacy and in vivo biodistribution when delivered locally compared to the equivalent systemic dose. Anti-tumor effects were dependent on CD8+ T-cells, host CD40 expression and the presence of tumor antigen at the injection site. CD40 antibodies were cleared from the circulation and accumulated in lymphoid organs, where, upon repeated aCD40 dosing, target APC populations increased in numbers and upregulated their surface CD40 expression.Lastly, CD40 agonist antibodies were mixed with nanoparticles to enhance their stimulatory properties. B-cells demonstrated increased proliferative capacity and DCs became more activated when exposed to the cocktail. Further, this combination reduced serum levels of pro-inflammatory cytokines compared to plain antibodies. The results herein advocate further exploratory studies of the delivery of monoclonal antibodies at the tumor site in order to improve anti-tumor effects and reduce toxicity.
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| 74. |
- Sarhan, Dhifaf, et al.
(author)
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Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-gamma
- 2013
-
In: European Journal of Immunology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1521-4141 .- 0014-2980.
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Journal article (other academic/artistic)abstract
- Natural killer (NK) cells are innate lymphocytes that are able to directly kill tumor cells through different mechanisms including ligation of TNF-related apoptosis-inducing ligand (TRAIL) receptors. Zoledronic acid (ZA) is a bisphosphonate known to upregulate the expression of TRAIL on human γδ T cells. Here, we investigated whether exposure to ZA would upregulate TRAIL expression on human NK cells and augment their cytotoxicity against tumor cells. When cocultured with monocytes, treatment with ZA and IL-2 resulted in a significant upregulation of TRAIL expression on human NK cells (p = 0.002). Consequently, ZA-primed NK cells were significantly more cytotoxic against TRAIL sensitive tumor cells (p < 0.0001). In the presence of ZA and IL-2, monocytes produced high levels of IFN-γ; when cultured in the presence of neutralizing antibodies to IFN-γ, TRAIL expression and TRAIL-mediated cytotoxicity of NK cells were significantly reduced. Furthermore, in tumor-bearing SCID/Beige mice, a significant delayed tumor progression and prolonged survival was observed after infusion of ZA-primed NK cells compared with that observed in mice infused with unprimed NK cells. These findings represent a novel approach to potentiate TRAIL-mediated apoptosis by adoptively infused NK cells that could improve the outcome in patients with cancer.
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| 75. |
- Saudi, Aws, et al.
(author)
-
Immune-activated B cells are dominant in prostate cancer
- 2023
-
In: Cancers. - : MDPI. - 2072-6694. ; 15:3
-
Journal article (peer-reviewed)abstract
- B cells are multifaceted immune cells responding robustly during immune surveillance against tumor antigens by presentation to T cells and switched immunoglobulin production. However, B cells are unstudied in prostate cancer (PCa). We used flow cytometry to analyze B-cell subpopulations in peripheral blood and lymph nodes from intermediate-high risk PCa patients. B-cell subpopulations were related to clinicopathological factors. B-cell-receptor single-cell sequencing and VDJ analysis identified clonal B-cell expansion in blood and lymph nodes. Pathological staging was pT2 in 16%, pT3a in 48%, and pT3b in 36%. Lymph node metastases occurred in 5/25 patients (20%). Compared to healthy donors, the peripheral blood CD19+ B-cell compartment was significantly decreased in PCa patients and dominated by naïve B cells. The nodal B-cell compartment had significantly increased fractions of CD19+ B cells and switched memory B cells. Plasmablasts were observed in tumor-draining sentinel lymph nodes (SNs). VDJ analysis revealed clonal expansion in lymph nodes. Thus, activated B cells are increased in SNs from PCa patients. The increased fraction of switched memory cells and plasmablasts together with the presence of clonally expanded B cells indicate tumor-specific T-cell-dependent responses from B cells, supporting an important role for B cells in the protection against tumors.
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| 76. |
- Schiza, Aglaia, 1983-
(author)
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Experimental treatment of patients with disseminated malignant melanoma
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Malignant melanoma (MM) is the deadliest skin cancer with an ever-increasing incidence. New treatments have improved the prognosis for patients with advanced MM. Still, most patients do not respond, and the side effects can be severe, underlining the need for better therapies.The overall aim of this thesis was to evaluate new means to improve the treatment for patients with advanced MM. Immunostimulatory gene therapy (AdCD40L) was evaluated in a clinical study and BRAF-inhibitory treatment in rare cases of BRAF-mutated MM.Due to its immunogenicity, MM is an attractive target for immunostimulatory gene therapy. AdCD40L is an adenovirus carrying the human gene for CD40 ligand, which in different ways can stimulate the immune system to combat cancer. We conducted a Phase I/IIa study with AdCD40L in patients with metastatic MM having received established treatments. In cohort 1 (n=6), four weekly, intratumoural AdCD40L injections were given. In cohort 2 (n=9), low dose cyclophosphamide was added to increase the immune response. Since irradiation may act synergistically with immunotherapy, patients in cohort 3 (n=9) also received a single fraction of radiotherapy (8 Gy). This fraction was given towards the lesion selected for injections.The primary objectives were to assess the feasibility and safety of AdCD40L-treatment and secondarily its anti-tumour effects. Patients were thoroughly assessed for toxicity. The anti-tumour response was evaluated by imaging techniques (FDG-PET/CT, DW-MRI scans), tumour biopsies and blood tests. Plasma protein markers were measured with a multiplex platform. Another objective was to evaluate the potential of DW-MRI and FDG-PET/CT for prediction of AdCD40L treatment response, in terms of overall survival (OS).AdCD40L was well tolerated with mild transient reactions. Local and distant responses in PET/CT scans along with a significantly better 6-month survival in the cohorts that received cyclophosphamide conditioning were observed. Effector lymphocyte responses were elicited. All patients had an increased T effector/T regulatory-cell ratio and death receptors were significantly up-regulated post therapy. Inflammatory cytokines and other plasma proteins were altered in favourable ways by the AdCD40L treatment. The analyses support that the functional DWI parameters may be better early predictors of OS than the established metabolic and morphologic criteria of FDG-PET/CT and CT/MRI, respectively.In conclusion, the stimulation of the CD40 pathway to initiate anti-tumour immunity is a promising treatment alternative for MM patients. However, further studies with developed treatment schemes are warranted.In the first report ever on treatment of a pregnant patient with a BRAF-inhibitor, the therapy was initiated in the second trimester. The treatment with vemurafenib enabled prolonged gestation, hence reducing the risk of immaturity-related complications. Further, we report the first case worldwide of a patient with metastatic conjunctival melanoma who benefitted from treatment with vemurafenib. Additional studies are needed to assess the efficacy of BRAF -inhibitors in the different subtypes of ocular melanoma.
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| 77. |
- Sherif, Amir, et al.
(author)
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Immune responses to neoadjuvant chemotherapy in muscle invasive bladder cancer
- 2018
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In: Bladder cancer. - : IOS Press. - 2352-3727. ; 4:1, s. 1-7
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Journal article (peer-reviewed)abstract
- The secondary effects of chemotherapy, with bone marrow depression and risk of leukopenia, has traditionally been considered being detrimental for the immune system. However, growing evidence suggests a main role for chemotherapy in antitumor immunomodulation. With reference to cisplatin, which is the basis of neoadjuvant chemotherapy in muscle invasive bladder cancer, four different aspects of immunomodulation has thus far been described; increased MHC class I expression, recruitment and proliferation of effector cells, enhancement of tumor-lytic activity of cytotoxic effectors and downregulation of immunosuppressive actors in the microenvironment. Consequently, the role of chemotherapy in cancer is changing from a therapy solely aimed at inducing tumor cell death, to a potent inducer of immune responses and a potential future major partaker in cancer immunotherapy. This is a great opportunity for the urological community to broaden research in this field in order to increase knowledge, optimize and improve the neoadjuvant regimens of muscle invasive bladder cancer to ultimately improve patient outcome.
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| 78. |
- Sherif, Amir, et al.
(author)
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Pilot study of adoptive immunotherapy with sentinel node-derived T cells in muscle-invasive urinary bladder cancer
- 2015
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In: Scandinavian journal of urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 49:6, s. 453-462
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim of this study was to determine by computed tomography (CT) whether treatment with tumor-draining lymph-node-derived expanded autologous T lymphocytes results in objective responses and/or improved survival in patients with metastatic urinary bladder cancer (UBC) and to record the toxicity of the treatment.MATERIALS AND METHODS: Eighteen patients with metastatic UBC were prospectively selected from two centers. The preoperative staging was T2-T4bN1-2 and/or M0-M1 or MX. Tumor-draining lymph nodes were harvested at intended cystectomy for the extraction of T lymphocytes. This was followed by expansion of the T lymphocytes in a cell culture, and subsequent reinfusion of these autologous tumor-specific T lymphocytes. Responses to therapy were evaluated by CT scans according to Response Evaluation Criteria In Solid Tumors (RECIST) and clinical follow-up, according to the research protocol.RESULTS: Nine out of 18 patients were treated. Treatment was feasible and safe. In two out of nine immunologically treated patients, objective responses were detected in terms of diminished or obliterated nodal metastases. When excluding three patients with disseminated osseous metastases plus one with a T4b tumor left in situ, a success rate of two out of six treated patients was seen. The two responders had survival times of 35 and 11 months, respectively. No toxicity was recorded.CONCLUSIONS: Infusion of expanded autologous tumor-specific T lymphocytes is feasible and safe, and objective responses according to RECIST were recorded. One objective responder to immunotherapy displayed notably long overall survival.
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| 79. |
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| 80. |
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| 81. |
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| 82. |
- Soderberg, Karin C., et al.
(author)
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Autoimmune diseases, asthma and risk of haematological malignancies: A nationwide case-control study in Sweden
- 2006
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In: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 42:17, s. 3028-3033
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Journal article (peer-reviewed)abstract
- To investigate potential associations between several autoimmune diseases and haematological malignancies, we studied 39,908 cases of leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma and myeloma that occurred during 1987-1999 in Sweden, and 149,344 controls. Hospital discharge diagnoses of psoriasis, Sjogren's syndrome, autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, pernicious anaemia, multiple sclerosis, rheumatic fever or asthma from 1969 to 1999 were retrieved from the Swedish Hospital Discharge Registry. Psoriasis was positively associated with leukaemia, excluding chronic lymphocytic leukaemia, (odds ratio [OR] = 1.6, 95% confidence interval [CI] 1.1-2.3) and non-Hodgkin's lymphoma (OR = 1.6, 95% CI 1.3-2.1). Sjogren's syndrome increased the risks of all haematological malignancies combined (OR = 4.0, 95% CI 2.3-7.0), and of non-Hodgkin's lymphoma (OR = 6.4, 95% CI 3.5-12). These findings, together with increased risks of several haematological malignancies in autoimmune haemolytic anaemia and idiopathic thrombocytopenic purpura but not in asthma, suggest chronic autoimmunity and immune stimulation as mechanisms contributing to the development of haematological malignancies.
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| 83. |
- Sonkoly, Enikö, et al.
(author)
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MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4.
- 2010
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 126:3, s. 581-9.e1
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Journal article (peer-reviewed)abstract
- BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs that suppress gene expression at the posttranscriptional level. Atopic dermatitis is a common chronic inflammatory skin disease characterized by the presence of activated T cells within the skin.OBJECTIVE: We sought to explore the role of miRNAs in the pathogenesis of atopic dermatitis.METHODS: Global miRNA expression in healthy and lesional skin of patients with atopic dermatitis was compared by using TaqMan MicroRNA Low Density Arrays. miR-155 expression in tissues and cells was quantified by means of quantitative real-time PCR. The cellular localization of miR-155 was analyzed by means of in situ hybridization. The regulation of cytotoxic T lymphocyte-associated antigen (CTLA-4) by miR-155 was investigated by using luciferase reporter assays and flow cytometry. CTLA-4 expression and functional assays were performed on T(H) cells overexpressing miR-155.RESULTS: miR-155 was one of the highest-ranked upregulated miRNAs in patients with atopic dermatitis. In the skin miR-155 was predominantly expressed in infiltrating immune cells. miR-155 was upregulated during T-cell differentiation/activation and was markedly induced by T-cell activators in PBMCs in vitro and by superantigens and allergens in the skin in vivo. CTLA-4, an important negative regulator of T-cell activation, was identified as a direct target of miR-155. Overexpression of miR-155 in T(H) cells resulted in decreased CTLA-4 levels accompanied by an increased proliferative response.CONCLUSION: miR-155 is significantly overexpressed in patients with atopic dermatitis and might contribute to chronic skin inflammation by increasing the proliferative response of T(H) cells through the downregulation of CTLA-4.
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| 84. |
- Vollmer, Tino, et al.
(author)
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The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer
- 2021
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:576
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Journal article (peer-reviewed)abstract
- Chemotherapy has direct toxic effects on cancer cells; however, long-term cancer control and complete remission are likely to involve CD8+ T cell immune responses. To study the role of CD8+ T cell infiltration in the success of chemotherapy, we examined patients with muscle invasive bladder cancer (MIBC) who were categorized on the basis of the response to neoadjuvant chemotherapy (NAC). We identified the intratumoral CXCR3 chemokine system (ligands and receptor splice variants) as a critical component for tumor eradication upon NAC in MIBC. Through characterization of CD8+ T cells, we found that stem-like T cell subpopulations with abundant CXCR3alt, a variant form of the CXCL11 receptor, responded to CXCL11 in culture as demonstrated by migration and enhanced effector function. In tumor biopsies of patients with MIBC accessed before treatment, CXCL11 abundance correlated with high numbers of tumor-infiltrating T cells and response to NAC. The presence of CXCR3alt and CXCL11 was associated with improved overall survival in MIBC. Evaluation of both CXCR3alt and CXCL11 enabled discrimination between responder and nonresponder patients with MIBC before treatment. We validated the prognostic role of the CXCR3-CXCL11 chemokine system in an independent cohort of chemotherapy-treated and chemotherapy-naïve patients with MIBC from data in TCGA. In summary, our data revealed stimulatory activity of the CXCR3alt-CXCL11 chemokine system on CD8+ T cells that is predictive of chemotherapy responsiveness in MIBC. This may offer immunotherapeutic options for targeted activation of intratumoral stem-like T cells in solid tumors.
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| 85. |
- Wahlstrom, Jan, et al.
(author)
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Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis
- 2009
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In: CLINICAL IMMUNOLOGY. - : Elsevier BV. - 1521-6616 .- 1521-7035. ; 133:3, s. 353-363
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Journal article (peer-reviewed)abstract
- The etiology of sarcoidosis remains unknown. Recently, by mass spectrometric sequencing of peptides eluted from HLA-DR molecules of bronchoalveolar lavage (BAL) cells from DRB1*0301(pos) patients, we identified potential self-antigens in sarcoidosis. The aim of the present study was to investigate the capacity of selected peptides to stimulate tung and blood T cells of sarcoidosis patients using an interferon-gamma ELISPOT assay. In peripheral blood, there were strong T cell responses to a peptide derived from the cytoskeletal protein vimentin in 6 out of 11 DRBI*0301(pos) patients with active disease but not in patients with other HLA types. BAL T cell responses against peptides derived from ATP synthase or from lysyl-tRNA synthetase were detected in DRB1*0301(pos) as welt as DRB1*0301(neg) patients. By using antigenic peptides presented in vivo in the lungs of sarcoidosis patients, we have identified blood and lung T cell autoimmune responses that may help sustain the inflammation in this disease.
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| 86. |
- Wermeling, Fredrik, et al.
(author)
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Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus
- 2007
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 204:10, s. 2259-2265
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Journal article (peer-reviewed)abstract
- Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell-derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.
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| 87. |
- Winerdal, Malin E, et al.
(author)
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FOXP3 and survival in urinary bladder cancer
- 2011
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In: BJU International. - 1464-4096 .- 1464-410X. ; 108:10, s. 1672-1678
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Journal article (peer-reviewed)abstract
- OBJECTIVE:To investigate the possible impact of FOXP3 expression in T-cells, as well as in tumour cells, on long-term survival in patients with urinary bladder cancer (UBC) invading muscle.PATIENTS AND METHODS:In a retrospective study, tumour specimens from 37 patients cystectomized for T1-T4 UBC during 1999-2002 at the Karolinska University Hospital were examined by immunohistochemistry for tumour expression and/or infiltration of immune cells expressing FOXP3 as well as CD3. The results obtained were correlated with clinicopathological parameters, where the primary and secondary outcomes investigated were overall survival and progression-free survival, respectively.RESULTS:Infiltration of CD3(+) and FOXP3(+) lymphocytes (≥3 cells per high-power field) were both correlated with better survival, and this relationship persisted throughout the whole study period (all P < 0.05). Patients with FOXP3(+) tumour cells had decreased long-term survival compared to those patients with FOXP3(-) tumours (P < 0.05). Despite a limited amount of patient material, the results of the present study indicate that FOXP3 expression, in both lymphocytes and tumour cells, is an important prognostic factor in UBC.CONCLUSIONS:FOXP3 expression in UBC cells is associated with decreased long-term survival and thus may be a novel negative prognostic factor in UBC invading muscle. By contrast, the presence of FOXP3(+) tumour-infiltrating lymphocytes was correlated with a positive prognosis. Because FOXP3 is up-regulated upon activation in human T-cells, FOXP3 may serve more as an activation marker than as a regulatory T-cell indicator in this case. These results support the need for larger prospective studies aiming to confirm the results obtained and to examine the underlying mechanisms in detail.
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| 88. |
- Winerdal, Malin E., et al.
(author)
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Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness
- 2018
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In: CANCER IMMUNOLOGY RESEARCH. - : American Association for Cancer Research (AACR). - 2326-6066 .- 2326-6074. ; 6:5, s. 528-538
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Journal article (peer-reviewed)abstract
- Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3+ (FOXP3+) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients (n = 52) with suspected UBC were prospectively included. We show, by using a broad range of analytical approaches, that tumor-infiltrating CD4+FOXP3+ T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key proinvasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and UBC cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC.
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| 89. |
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| 90. |
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| 91. |
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| 92. |
- Winqvist, Ola, et al.
(author)
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Autoimmune adrenal insufficiency : recognition and management
- 2000
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In: BioDrugs. - 1173-8804 .- 1179-190X. ; 13:2, s. 107-114
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Journal article (peer-reviewed)abstract
- The main cause of Addison's disease is an autoimmune organ-specific destruction of the cells in the adrenal cortex by an autoreactive process of activated immune cells directed against the steroid-synthesising enzyme 21-hydroxylase. The diagnosis of Addison's disease is suspected in a patient presenting with symptoms of fatigue, bodyweight loss, anorexia, salt craving, and signs of low blood pressure and hyperpigmentation of the skin. Laboratory findings include electrolyte disturbances, and typically an elevated serum potassium level and sometimes a low serum sodium level is found together with low plasma levels of basal and corticotropin-stimulated hydrocortisone (cortisol). An aetiological diagnosis can rapidly be made using commercially available assays demonstrating the presence of autoantibodies directed against 21-hydroxylase. Determination of 21-hydroxylase autoantibodies also permits early diagnosis before a complete adrenocortical destruction has occurred. Thus, a window of opportunity for an early immunomodulatory intervention therapy may exist. Patients presenting with an acute adrenocortical crisis should be treated with 100mg of hydrocortisone and saline intravenously without awaiting laboratory results. Maintenance therapy includes substitution of glucocorticoid and mineralocorticoid steroids, using divided and lower total dosages of glucocorticoids than previously used.
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| 93. |
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| 94. |
- Wågström, Per, 1967-
(author)
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Clinical and immunological aspects of IgG subclass deficiency : Predictors for the need of immunoglobulin replacement therapy
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Background: Predominantly antibody deficiencies (PAD) are inborn errors of immunity, and associate with increased susceptibility to infections. Life-long immunoglobulin replacement therapy (IgRT) is introduced based on Ig-levels and the frequencies and severity of infections. The subgroup of PAD with immunoglobulin G subclass deficiency (IgGsd) is often less severe and the need of IgRT in these patients is unclear. Often many years pass before IgGsd is diagnosed, and repeated respiratory tract infections risk to confer lung tissue damage. The Swedish standard regimen in IgGsd is IgRT during 18 months followed by a period of discontinuation in order to evaluate the effect and restart it, if infections reoccur. It is a challenge to identify the subgroup of IgGsd-individuals in need of life-long treatment, and early reliable markers are warranted. Aim: The aim of this thesis was to identify clinical and laboratory factors predicting the need of long-term IgRT in IgGsd and evaluate its effects on immunological functions. Results: In paper I, the established clinical warning sign that is used to identify individuals with PAD in need of IgRT, was evaluated regarding the accuracy to identify IgGsd in a primary care register with data from 350,000 visits due to respiratory tract infections. The predictive value was low and according to medical records, a primary immunodeficiency was rarely suspected. In paper II, a lower frequency of homozygosity for the high affinity IgG receptor FcγRIIa H/H131 were found in IgGsd compared to controls. The finding supports the hypothesis that FcγR-polymorphisms may be of importance for susceptibility to infections in IgGsd and may have impact on the need of IgRT. In paper III, patient reported outcome showed that severe fatigue and low health related quality of life associated with the need of life-long IgRT. Systemic inflammation is known to associate with fatigue and in paper III and IV extensive immunophenotyping was performed when on and off IgRT. IgGsd patients were characterized by dysregulated plasma protein profiles enriched for factors associated with interleukin 10 signaling that were unaffected by IgRT. Among circulating immune cells, decreased proportions of activated B- and T cell subsets, as well as regulatory T cells, were found and partly restored during IgRT. Individuals needing life-long IgRT had a lower prevalence of protective pneumococcal specific IgG against 21 tested capsular serotypes. Co-morbidity with autoimmunity, atopy, lung disease and other factors such as higher age and occupation also associated to the need of IgRT. Conclusion: IgGsd patients were characterized by increased systemic inflammation, which was unaffected by IgRT. Decreased activation of lymphocyte subsets was partly restored during IgRT. Severe fatigue, protective IgG levels against a low number of pneumococcal serotypes, especially in conjunction with comorbidities were associated with the need for IgRT. Overall, no factor alone could predict the need of life-long IgRT.
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| 95. |
- Yang, Ting, et al.
(author)
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Genetic Abrogation of Adenosine A(3) Receptor Prevents Uninephrectomy and High Salt-Induced Hypertension
- 2016
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In: Journal of the American Heart Association. - 2047-9980. ; 5:7
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Journal article (peer-reviewed)abstract
- Background - Early-life reduction in nephron number (uninephrectomy [UNX]) and chronic high salt (HS) intake increase the risk of hypertension and chronic kidney disease. Adenosine signaling via its different receptors has been implicated in modulating renal, cardiovascular, and metabolic functions as well as inflammatory processes; however, the specific role of the A(3) receptor in cardiovascular diseases is not clear. In this study, gene-modified mice were used to investigate the hypothesis that lack of A(3) signaling prevents the development of hypertension and attenuates renal and cardiovascular injuries following UNX in combination with HS (UNX-HS) in mice.Methods and Results - Wild-type (A(3)(+/+)) mice subjected to UNX-HS developed hypertension compared with controls (mean arterial pressure 106 +/- 3 versus 82 +/- 3 mm Hg; P<0.05) and displayed an impaired metabolic phenotype (eg, increased adiposity, reduced glucose tolerance, hyperinsulinemia). These changes were associated with both cardiac hypertrophy and fibrosis together with renal injuries and proteinuria. All of these pathological hallmarks were significantly attenuated in the A(3)(-/-) mice. Mechanistically, absence of A(3) receptors protected from UNX-HS-associated increase in renal NADPH oxidase activity and Nox2 expression. In addition, circulating cytokines including interleukins 1 beta, 6, 12, and 10 were increased in A(3)(+/+) following UNX-HS, but these cytokines were already elevated in naive A(3)(-/-) mice and did not change following UNX-HS.Conclusions - Reduction in nephron number combined with chronic HS intake is associated with oxidative stress, chronic inflammation, and development of hypertension in mice. Absence of adenosine A(3) receptor signaling was strongly protective in this novel mouse model of renal and cardiovascular disease.
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| 96. |
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| 97. |
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| 98. |
- Zhang, Lu, et al.
(author)
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Detection of micro-metastases by flow cytometry in lymph nodes from patients with penile cancer
- 2018
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In: BMC Urology. - : BioMed Central (BMC). - 1471-2490. ; 18:1
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The tumor draining lymph node concept was first described in penile cancer for staging. Immunohistochemistry and histopathology evaluations are routinely used in clinical practice to examine lymph nodes for metastasis. However, these methods are time-consuming with low diagnostic accuracy and micro-metastases might be missed. In this study, we aim to evaluate detection of metastatic cells in draining lymph nodes by flow cytometry.METHODS: To assess the sensitivity of micro-metastasis detection by FACS (Fluorescence-activated cell sorting), HeLa cells were titrated into Peripheral blood mononuclear cells (PBMCs) and expression of pan-cytokeratin AE1/AE3 was analyzed. Single cell suspensions were separately prepared from 10 regional lymph nodes obtained from 5 patients with invasive penile cancer undergoing radical surgery and lymph node dissection. Lymph node dereived cells were examined for cell surface expression of EpCAM, E-cadherin and intracellular expression of pan-cytokeratin AE1/AE3 by FACS.RESULTS: Ten lymph nodes from 5 penile cancer patients were investigated in a head-to-head comparison between FACS and pathology examination of sections. All metastatic lymph nodes verified by pathology examination were also identified by FACS. Two additional lymph nodes with micro-metastases were diagnosed by FACS only.CONCLUSIONS: FACS analyses of pan-cytokeratin AE1/AE3 stained single cells from tumor draining lymph nodes can be used to detect micro-metastases in patients with penile cancer patients.
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| 99. |
- Zhang, Lu, et al.
(author)
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Immune responses against autologous tumor and human papilloma virus in lymph nodes from patients with penile cancer
- 2021
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In: Investigative and Clinical Urology. - : The Korean Urological Association. - 2466-0493 .- 2466-054X. ; 62
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Journal article (peer-reviewed)abstract
- PURPOSE: Nearly half of penile cancers are related to human papillomavirus (HPV) infection. Investigations of tumor- and HPV-specific T cell reactivity in regional lymph nodes (LNs) from patients with penile cancer are warranted.MATERIALS AND METHODS: In this study, single-cell suspensions from LNs and peripheral blood from 11 patients with penile cancer were stained with antibodies for lymphocyte markers and analyzed by fluorescence-activated cell sorting (FACS). DNA was extracted from the tumor tissue and HPV status was investigated by PCR.RESULTS: T-cell reactivity against autologous tumor-extract and against the HPV-vaccine Gardasil® was tested by flow-cytometric assay of specific cell-mediated immune response in activated whole blood (FASCIA). CD4+/CD8+ ratios were significantly lower in HPV positive LNs (p<0.05). Immune responses to tumor extract assessed by blast transformation and expansion in vitro, of either CD4+ or CD8+ T-cells, were found in 9 of 13 LNs (69%). 5 of 6 tested patients demonstrated T cell recognition of tumor-associated antigen(s). In HPV-positive patients, dose-dependent T cell responses against L1 (late) HPV proteins (Gardasil vaccine) were demonstrated.CONCLUSIONS: LN-derived T cells from patients with penile cancer recognize tumor antigen(s) and in HPV-positive cases, there is a response against L1 (late) HPV proteins, being constituents of the Gardasil vaccine.
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| 100. |
- Zhang, Lu, et al.
(author)
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Immune responses against Human Papilloma virus in draining lymph nodes from patients with penile cancer
- 2017
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In: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 86:4, s. 339-339
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Journal article (other academic/artistic)abstract
- Human papillomavirus (HPV) is a DNA virus which accounts for 5.2% of all cancers worldwide and is a well‐known cause of cervical, vulvar, head and neck cancer, but studies on penile cancer (PC) are rare. There are more than 170 HPV strains, where HPV16 is the main strain accounting for 94.7% of all PCs. Additional studies have detected HPV DNA in both primary tumors and metastases, indicating the potential role of HPV in tumor progression. We have investigated immune responses against autologous tumor‐extract in draining lymph nodes (LNs) in colon and urinary bladder cancer. There are several indications that HPV associated malignancies eliciting a virus‐antigen‐specific immune response. HPV E6 and E7 as oncogenes are widely studied in HPV associated cancer. A study comparing different HPV antigen‐specific T cell efficiency in killing autologous HPV positive tumor cells in cervical cancer patients, suggests that L1‐specific CD8+ cytotoxic T lymphocytes (CTLs) are equally effective as E7‐specific CD8+ CTLs. We set out to evaluate immune responses in LNs from PC patients against the HPV vaccine Gardasil (L1). In this study, nearly half of the PC patients were detected as HPV positive by PCR. Phenotypes of the lymphocytes from LNs were characterized. We used FASCIA to investigate lymphocyte responses towards tumor‐extract and Gardasil in LNs, found a good response towards Gardasil among HPV‐positive patients but not in HPV‐negative patients. A dose dependent reactivity was observed. Strategies using HPV L1 proteins as antigens may be useful for adoptive T cell therapy of patients with PC.
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