Sunday, January 31, 2016

Differential Toxicity of Antibodies to the Prion Protein

Differential Toxicity of Antibodies to the Prion Protein
 
Regina R. Reimann , Contributed equally to this work with: Regina R. Reimann, Tiziana Sonati
 
Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Tiziana Sonati , Contributed equally to this work with: Regina R. Reimann, Tiziana Sonati
 
Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Simone Hornemann, Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Uli S. Herrmann, Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Michael Arand, Affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
 
⨯ Simon Hawke, Affiliation: Vascular Immunology Laboratory, Department of Pathology, University of Sydney, Camperdown, Australia
 
⨯ Adriano Aguzzi * E-mail: adriano.aguzzi@usz.ch
 
Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland
 
⨯ Differential Toxicity of Antibodies to the Prion Protein Regina R. Reimann, Tiziana Sonati, Simone Hornemann, Uli S. Herrmann, Michael Arand, Simon Hawke, Adriano Aguzzi PLOS x Published: January 28, 2016 DOI: 10.1371/journal.ppat.1005401
 
Abstract Antibodies against the prion protein PrPC can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-related toxicity, yet a subsequent study contradicted these findings. We have reported that several antibodies against certain epitopes of PrPC, including antibody POM1, are profoundly neurotoxic, yet antibody ICSM18, with an epitope that overlaps with POM1, was reported to be innocuous when injected into mouse brains. In order to clarify this confusing situation, we assessed the neurotoxicity of antibodies D13 and ICSM18 with dose-escalation studies using diffusion-weighted magnetic resonance imaging and various histological techniques. We report that both D13 and ICSM18 induce rapid, dose-dependent, on-target neurotoxicity. We conclude that antibodies directed to this region may not be suitable as therapeutics. No such toxicity was found when antibodies against the flexible tail of PrPC were administered. Any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects.
 
Author Summary The human prion disease, Creutzfeldt-Jakob disease (CJD), is a progressive neurodegenerative syndrome. Although far less prevalent, CJD shows many molecular and clinical similarities to Alzheimer's disease, such as the buildup of protein aggregates in the brain and the absence of effective treatments. Many attempts at immunotherapy for Alzheimer’s disease are being reported in specialized journals and in the lay press, and have been linked to strong hopes for a cure. The same therapeutic strategy appears plausible for Creutzfeldt-Jakob disease, and indeed, there are some encouraging preclinical studies. However, there have also been reports that antibodies against the prion protein (PrPC) can also wreak damage on the brain. We have gathered evidence that various antiprion antibodies vary not only in their efficacy but also in their potential to induce serious untoward effects. In a dose-escalation study, we report that all antibodies against a set of epitopes in the globular domain of the prion protein display acute neurotoxicity. These issues need to be carefully assessed before considering any clinical studies involving human subjects.
 
 
Alzheimer-type brain pathology may be transmitted by grafts of dura mater
 
26/01/2016 By Karl Frontzek, et al.:
 
 
Original article | Published 26 January 2016, doi:10.4414/smw.2016.14287
 
Cite this as: Swiss Med Wkly. 2016;146:w14287
 
Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting
 
 
MY comment as follows ;
 
Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
 
07 02:27 AM
 
Terry S. Singeltary Sr. said:
 
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
 
2015-12-07 02:27 AM
 
Terry S. Singeltary Sr. said: re-Evidence for human transmission of amyloid-? pathology and cerebral amyloid angiopathy Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
 
 
I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.
 
First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.
 
Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.
 
where have we all heard this before? it’s been well documented via the BSE Inquiry. have they not learned a lesson from the last time?
 
we have seen this time and time again in England (and other Country’s) with the BSE mad cow TSE Prion debacle.
 
That ‘anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.
 
The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ? who got pooled extracts injected from thousands of cadavers ? were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.
 
That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find ? alarming? is pathetic.
 
Sounds like the journalists had it right in the first place: ‘Alzheimer,s may be a transmissible infection? in The Independent to ? You can catch Alzheimer’s? in The Daily Mirror or ? Alzheimer’s bombshell" in The Daily Express
 
if not for the journalist, the layperson would not know about these important findings.
 
where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?
 
when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.
 
to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimer?s, the price of poker goes up drastically.
 
so, who makes that final decision, and how many more decades do we have to wait?
 
the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?
 
Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.
 
FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.
 
in my opinion, it?s one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.
 
greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it?s bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.
 
my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer?s of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.
 
I kindly wish to remind the public of the past, and a possible future we all hopes never happens again. ...
 
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer?s and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]
 
 
 
 
Terry S. Singeltary Sr. Bacliff, Texas USA 77518
 
snip...see Singeltary comment ;
 
 
Subject: 1992 IN CONFIDENCE TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION REMAINS OPEN
 
BSE101/1 0136
 
IN CONFIDENCE
 
CMO
 
From: . Dr J S Metiers DCMO
 
4 November 1992
 
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
 
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised the public sensitivity of these findings and intend to report them in their proper context. 'This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.
 
2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed". As the report emphasises the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.
 
what are the implications for public health?
 
3. The route 'of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.
 
1
 
92/11.4/1.1
 
BSE101/1 0137
 
4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required’’ before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.
 
J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 llllYc!eS 2 92/11.4/1.2
 
 
>>> The only tenable public line will be that "more research is required’’ <<<
 
>>> possibility on a transmissible prion remains open<<<
 
O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?
 
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
 
*** Singeltary comment PLoS ***
 
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
 
Posted by flounder on 05 Nov 2014 at 21:27 GMT
 
 
Sunday, November 22, 2015
 
*** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis Abstract
 
Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 °C or autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans.
 
Purchase options Price * Issue Purchase USD 511.00 Article Purchase USD 54.00
 
 
 
Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery.
 
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC. Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
 
Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.
 
 
Friday, January 10, 2014
 
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
 
Greetings Friends, Neighbors, and Colleagues,
 
 
Thursday, January 14, 2016
 
Preventable Tragedies: Superbugs and How Ineffective Monitoring of Medical Device Safety Fails Patients REPORT
 
how can it be, HOW CAN IT BE $$$ not a word about CJD GSS FFI VPSPR TSE Prions that I saw...absolutely crazy, WE ARE MISSING THE BIGGER PICTURE!
 
how many victims that will never be reported ???
 
 
Sunday, January 17, 2016
 
Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease
 
 
Saturday, December 12, 2015
 
CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT DECEMBER 14, 2015
 
 
Tuesday, January 26, 2016
 
Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting
 
 
Tuesday, January 26, 2016
 
Alzheimer-type brain pathology may be transmitted by grafts of dura mater
 
 
 Terry S. Singeltary Sr. Bacliff, Texas
 
 
Sunday, January 31, 2016
 
Differential Toxicity of Antibodies to the Prion Protein

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