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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract
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
