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Krooniset bakteeri-infektiot (Luettu 221189 kertaa)
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Re: Krooniset bakteeri-infektiot
Vastaus #345 - 08.09.2018 - 01:37:21
 
STAT3 can be a therapeutic target for chronic active EBV infection, a fatal disorder

https://www.sciencedaily.com/releases/2018/08/180820113117.htm

August 20, 2018
Tokyo Medical and Dental University(TMDU) study shows that ruxolitinib-induced inhibition of STAT3 activity blocks survival and reduces pro-inflammatory cytokine production in Epstein-Barr virus (EBV)-infected clonally proliferating T- or NK-cells in Chronic active Epstein-Barr virus infection.

Tokyo, Japan -- Chronic active Epstein-Barr virus infection (CAEBV) is an EBV-positive T- or NK-cell neoplasm accompanied by sustained systemic inflammation. Many studies have attempted to understand the case of CAEBV; none have provided a clear explanation, until now.

A research team, led by experts from Tokyo Medical and Dental University(TMDU), investigated the activity of STAT3, a factor that helps to control cell proliferation and survival, in EBV-infected T- or NK-cells in CAEBV. They found that STAT3 was constitutively activated in those cells, reported in Oncotarget, "STAT3 is constitutively activated in chronic active Epstein-Barr virus infection and can be a therapeutic target."

CAEBV is a disorder which has 2 aspects: an inflammatory disorder and a lymphoid neoplasm. During the course, it may progress to chemotherapy-resistant lymphoma or leukemia, or to a life-threatening disorder known as hemophagocytic lymphohistiocytosis. Despite a variety of efforts to control or cure CAEBV, the sole effective treatment has been stem cell transplantation from a HLA-matched donor. Unfortunately, some patients cannot be candidates for this therapy, and there are many side effects.

"Constitutively activated STAT3 has been observed in a variety of primary tumor cells, including other tumors associated with Epstein-Barr virus infection," says Ayoko Arai, corresponding author on the study. "We suspected that STAT3 may be similarly activated in cells from patients with CAEBV."

In the study, increased phosphorylation, an important modification of cellular proteins, was observed on STAT3 in EBV-infected T- or NK-cells from patients with CAEBV. In those same cells from health individuals, the phosphorylation was absent, suggesting that it may provide a useful drug target.

"Our analyses revealed no mutations in STAT3, so we tested whether inhibitors of STAT3 phosphorylation might modify its activity in laboratory-grown," says Erika Onozawa, lead author on the study. "We found that ruxolitinib, a drug that is currently used for treatment of myelofibrosis and polycythemia vera, could suppress the survival of the EBV-infected cells in a dose-dependent manner."

In addition to the ability of ruxolitinib to induce the death of virus-infected T- or NK-cells from patients with CAEBV, the researchers showed that it could block the production of several important inflammatory cytokines that play a role in the progression of CAEBV.

CAEBV is a neoplastic and inflammatory disease that can become extremely destructive for some patients. This study showed that STAT3 could be an important new target for treatment of this disorder, and that ruxolitinib may provide a readily available therapy that may be effectively used in clinical treatment.
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Re: Krooniset bakteeri-infektiot
Vastaus #346 - 02.10.2018 - 18:42:50
 
Multiple sclerosis and mixed microbial infections. Direct identification of fungi and bacteria in nervous tissue.

https://www.ncbi.nlm.nih.gov/pubmed/29859870

Abstract

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system (CNS), leading to multifocal demyelination and neurodegeneration. The etiology of this incurable disease is unknown and remains a matter of intensive research. The possibility that microbial infections, such as viruses or bacteria, can trigger an autoimmune reaction in CNS tissue has been suggested. However, the recent demonstration that bacteria are present in CNS tissue points to a direct involvement of microbial infections in the etiology of MS. In the present study, we provide the first evidence of fungal infection in CNS tissue of MS patients, and demonstrate that fungal DNA from different species can be detected in the CNS. We used, nested PCR assays together with next-generation sequencing to identify the fungal species in the nervous tissue of 10 patients with MS. Strikingly, Trichosporon mucoides was found in the majority of MS patients, and particularly high levels of this fungus were found in two patients. Importantly, T. mucoides was not detected in the CNS of control subjects. We were also able to visualize fungal structures in CNS tissue sections by immunohistochemistry using specific antifungal antibodies, which also revealed the accumulation of a number of microbial cells in microfoci. Again, microbial structures were not observed in CNS sections from controls. In addition to fungi, neural tissue from MS patients was also positive for bacteria. In conclusion, our present observations point to the novel concept that MS could be caused by polymicrobial infections. Thus, mycosis of the CNS may be accompanied by opportunistic bacterial infection, promoting neuroinflammation and directly causing focal lesions, followed by demyelination and axonal injury.
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Re: Krooniset bakteeri-infektiot
Vastaus #347 - 13.11.2018 - 23:20:10
 

Molecular signature of Epstein-Barr virus infection in MS brain lesions


http://nn.neurology.org/content/nnn/5/4/e466.full.pdf

Neurol Neuroimmunol Neuroinflamm. 2018

Abstract

Objective
We sought to confirm the presence and frequency of B cells and Epstein-Barr virus
(EBV) (latent and lytic phase) antigens in archived MS and non-MS brain tissue by
immunohistochemistry.

Methods
We quantified the type and location of B-cell subsets within active and chronic MS brain lesions
in relation to viral antigen expression. The presence of EBV-infected cells was further confirmed
by in situ hybridization to detect the EBV RNA transcript, EBV-encoded RNA-1 (EBER-1).

Results
We report the presence of EBV latent membrane protein 1 (LMP-1) in 93% of MS and 78% of
control brains, with a greater percentage of MS brains containing CD138+plasma cells and
LMP-1–rich populations. Notably, 78% of chronic MS lesions and 33.3% of non-MS brains
contained parenchymal CD138+plasma cells. EBV early lytic protein, EBV immediate-early
lytic gene (BZLF1), was also observed in 46% of MS, primarily in association with chronic
lesions and 44% of non-MS brain tissue. Furthermore, 85% of MS brains revealed frequent
EBER-positive cells, whereas non-MS brains seldom contained EBER-positive cells. EBV in-
fection was detectable, by immunohistochemistry and by in situ hybridization, in both MS and
non-MS brains, although latent virus was more prevalent in MS brains, while lytic virus was
restricted to chronic MS lesions.

Conclusions
Together, our observations suggest an uncharacterized link between the EBV virus life cycle and
MS pathogenesis.

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Re: Krooniset bakteeri-infektiot
Vastaus #348 - 23.11.2018 - 00:10:56
 
Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis.

https://www.ncbi.nlm.nih.gov/pubmed/30429369

JCI Insight. 2018 Nov 15

Abstract

BACKGROUND:
Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy.

METHODS:
An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses.

RESULTS:
Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher's exact test).

CONCLUSION:
EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS.

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Näiden kliinisten testien tarkoitus oli ainoastaan onko ATA-188 immunoterapia turvallinen. Eli on, ja seuraavaksi kliinisten testien kohteena on annostus. Toivottavasti myös eurooppalaiset osallistuisivat.
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Re: Krooniset bakteeri-infektiot
Vastaus #349 - 02.12.2018 - 19:48:44
 
About the Anti-EBV clinical trial


https://msra.org.au/news/anti-ebv-trial-results-explained-by-professor-michael-p...
ender/


A treatment to target EBV has been shown to improve symptoms in some people with progressive MS in a world-first clinical trial.

The small phase I safety trial used an ‘adoptive T cell immunotherapy’ treatment. This involves taking blood from patients, extracting their immune cells, and then ‘training’ these cells in the lab to recognise and destroy EBV. The cells are then reintroduced to the patient’s body and go to work in targeting the EBV hiding in the body.

The trial was carried out by Professor Michael Pender and Professor Rajiv Khanna and MS Research Australia is proud to have contributed to the funding of this project, as well as significantly supporting Professor Pender’s EBV research over the last decade.

In this video Professor Pender explains how the trial came about, what it involved and what the results may mean for the future.

About Professor Michael Pender

Professor Michael Pender is a neurologist and researcher from The University of Queensland and Royal Brisbane and Women’s Hospital. He has spent much of his career investigating EBV in MS with a great deal of support along the way from MS Research Australia.

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Katso video, jossa Dr Pender selittää kliinisen kokeen tuloksia.
Vaikka kukaan ei sano sitä, on tämä paras uutinen vuosiin.
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Re: Krooniset bakteeri-infektiot
Vastaus #350 - 02.12.2018 - 19:58:30
 

Anti-EBV trial shows promise in progressive MS

https://msra.org.au/news/anti-ebv-trial-shows-promise-in-progressive-ms/


20 November, 2018

   A treatment called ‘adoptive T cell immunotherapy’ – which targets the Epstein Barr virus (EBV) – was shown to be safe in a group of 10 patients with primary and secondary MS in a small phase I (safety) trial
   EBV infects B cells of the immune system and is a known risk factor for developing MS
   The treatment takes the patient’s own T cells from the immune system and primes them to recognise and kill EBV-infected B cells
   Seven of the 10 patients showed clinical improvements including some reduction in disability and improvements in fatigue
   Larger studies are now underway to test the safety and effectiveness of the treatment

Overview

A treatment to target EBV has been shown to improve symptoms in some people with progressive MS in a world-first clinical trial.

The small phase I safety trial used an ‘adoptive T cell immunotherapy’ treatment. This involves taking blood from patients, extracting their immune cells, and then ‘training’ these cells in the lab to recognise and destroy EBV. The cells are then reintroduced to the patient’s body and go to work in targeting the EBV hiding in the body.

The trial was carried out by Professor Michael Pender and Professor Rajiv Khanna and MS Research Australia is proud to have contributed to the funding of this project, as well as significantly supporting Professor Pender’s EBV research over the last decade.

What is EBV and its relationship with MS?

EBV is a virus which infects a subset of white blood cells in the body called B cells. Most people won’t know they have had it as it is a common childhood illness with non-specific symptoms, although in adolescents it can cause the more serious glandular fever (infectious mononucleosis).

Once a person becomes infected with EBV, they carry the virus in their B cells for the rest of their life, mostly without any symptoms or problems. The infected cells are usually kept under control by other cells of the immune system called T cells which recognise and kill virus-infected cells.

While we know that EBV is a risk factor for the development of MS, there has been intense research to understand exactly how the virus contributes to MS and how we might tackle it to prevent or treat MS.

How did this EBV trial come about?

Professor Michael Pender, a neurologist and researcher from The University of Queensland and Royal Brisbane and Women’s Hospital has spent much of his career investigating EBV in MS with a great deal of support along the way from MS Research Australia.

Previous studies by Professor Pender’s research group have shown that people with MS have a reduced number of T cells capable of killing EBV-infected B cells, compared with people who do not have MS. This led to the idea that boosting a person’s ability to kill EBV-infected cells might help treat MS.

In recent years Professor Pender has teamed up with Professor Rajiv Khanna from QIMR Berghofer Medical Research Institute to test a novel treatment that targets EBV infected cells in the body.

Professor Khanna had developed a technique where the T cells could be removed from a patient, grown in the laboratory and primed to recognise and destroy EBV infected cells. The T cells are then returned to the patient where they act like heat-seeking missiles to kill the problem cells. He has primarily been testing the type of treatment called ‘adoptive T cell immunotherapy’ on certain cancers that are associated with EBV.

After initially treating just one patient with secondary progressive MS with some success (reported in 2014), the pair set up a phase I clinical trial to test the safety of the therapy in a small group of five people with primary progressive MS and five with secondary progressive MS.

What did the trial involve?

13 people with progressive MS were enrolled into the study. The scientists were able to collect the EBV-targeting T cells from 11 of 13 people and grow them in the laboratory.

One patient had to drop out of the trial before being treated due to an unrelated health condition, leaving 10 patients still in the trial. 5 with primary progressive MS and 5 with secondary progressive MS. The T cells were primed against EBV and then infused back into their body in four doses.

The participants were then monitored for a period of 27 weeks with a range of tests including MRI scans, the EDSS neurological disability scoring system, fatigue, quality of life and thinking and memory skills.

Were there any improvements in MS symptoms?

This very small study was first and foremost designed to identify any safety issues with the treatment, however, it did appear to have some positive effects.

Seven of the 10 participants showed a clinical improvement on the tests of neurological disability. Of the three that did not improve, two remained stable and one experienced worsening of disability.

Overall for the whole group, fatigue was significantly improved across the 27 week period, this being a prominent feature in five of the seven patients who showed neurological improvements.

Thinking and memory skills, while not improved, did not worsen over the period of the study.

In general, the treatment did not appear to prevent the appearance of new or active lesions in the MRI scans of some of the participants, but these people were still among those who did show neurological improvement.

Were there any side-effects?

None of the 10 people experienced any serious side effects as a result of the treatment. Just one patient experienced a minor side effect of an alteration to their sense of taste. This was thought to be due to one of the chemicals used in the preparation of the cells.

What do the results tell us?

The results of the trial firstly show that it is possible to collect and identify the EBV-targeting T cells from the majority of people with progressive MS and grow them in the laboratory.

They also tell us that the treatment appears safe. The findings have been published in the scientific journal JCI Insight. It is a potentially encouraging results for people living with primary and secondary progressive MS. However, it is important to be mindful that this was a very small study that was first and foremost designed to identify any safety issues with the treatment. It is too small, and not designed with the gold-standard placebo controlled, blinded, design to identify whether the treatment was truly effective.

However, the clinical signs of improvement noted in this study are encouraging. In particular, one important observation was that the strength of the EBV-targeting response noted in the preparation of the cells in the laboratory prior to treatment did seem to match with the clinical outcomes. The six participants with a strong reaction to EBV showed clinical improvement, whereas only one of the four participants with a weak reaction to EBV showed clinical improvement of symptoms but not disability.

What’s next?

Professor Khanna is now collaborating with biotechnology company Atara Biotherapeutics to conduct a bigger, randomised controlled (double blind) trial of another ‘off-the-shelf’ version of this treatment – you can learn more about this trial here.

This phase I trial was funded through a grant to Professor Rajiv Khanna and Professor Michael Pender in a partnership between MS Research Australia and MS Queensland and other philanthropic support to QIMR Berghofer Medical Research Institute.

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Ilmoitin aikaisemmin, että tulokset olivat ATA-188 tutkmuksesta, mutta olivat adoptive immunotherapy tutkimuksesta, joka perustuu potilaan omiin soluihin.
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