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From: TSS ()
Date: August 17, 2005 at 7:07 am PST






(Open Session)

July 22, 2005

Gaithersburg Holiday Inn

2 Montgomery Village Avenue

Gaithersburg, Maryland

Proceedings By:

CASET Associates, Ltd.

10201 Lee Highway, Suite 180

Fairfax, Virginia 22030

(703) 352-0091

List of Participants:


What his data showed is that prion protein infectivity is only associated with the high molecular advance, not with the low molecular protein resistant forms such as the example he gives, GSS, which only generates the lower molecular weight forms. It was shown in animal experiment in transgenic animals that this does not cause the disease.

Therefore, what is the significance?


1: Transfusion. 2003 Dec;43(12):1687-94. Related Articles, Links

Similar levels of infectivity in the blood of mice infected with human-derived vCJD and GSS strains of transmissible spongiform encephalopathy.

Cervenakova L, Yakovleva O, McKenzie C, Kolchinsky S, McShane L, Drohan WN, Brown P.

Jerome H Holland Laboratory for the Biomedical Sciences, Red Cross, Rockville, MD 20855, USA.

BACKGROUND: The possible transmission of variant CJD (vCJD) through blood transfusion or use of plasma-derived products prompted this study comparing infectivity in murine models of vCJD and Gerstmann-Straussler-Scheinker (GSS) disease, a non-vCJD form of transmissible spongiform encephalopathy (TSE). STUDY DESIGN AND METHODS: RIII/Fa/Dk (RIII) or Swiss-Webster (Swiss) mice were inoculated intracerebrally (IC) with mouse-adapted strains of vCJD or GSS (Fukuoka-1) of similar infectivity. Groups of RIII mice were euthanized 17 weeks after inoculation (during the incubation period), and another 23 weeks after inoculation (when symptomatic). Blood was collected, separated into components, and inoculated into groups of healthy mice; brains and spleens from all mice were harvested and tested for the presence of PrPres by Western blot using 6H4 MoAb. RESULTS: Levels of 20-30 infectious doses per mL were present in buffy coat and plasma during both the incubation and symptomatic stages of disease; PLT pellet infectivity was lower (10 ID/mL) and RBCs were not infectious. The disease was transmitted more efficiently by IV than IC inoculation of plasma, but there was no difference observed with inoculation of buffy coat. The incubation period was shorter after IC inoculation of GSS- than vCJD-brain inocula. The amount of PrPres in spleens was similar for both TSE agents, but was slightly lower in brains of vCJD than GSS mice. CONCLUSION: Infectivity was detected in blood components of mice infected with a human-derived strain of vCJD during both the preclinical and clinical phases of disease in a similarly low range of concentrations as in mice infected with a human-derived nonvariant strain (GSS, Fukuoka-1). Other measures of virulence, including brain infectivity titers, incubation periods, and the accumulation of PrPres in spleens and brains, were also comparable in both experimental models.

PMID: 14641865 [PubMed - indexed for MEDLINE]


1: Brain. 1990 Dec;113 ( Pt 6):1891-909. Related Articles, Links

Spongiform encephalopathy transmitted experimentally from Creutzfeldt-Jakob and familial Gerstmann-Straussler-Scheinker diseases.

Baker HF, Duchen LW, Jacobs JM, Ridley RM.

Division of Psychiatry, MRC Clinical Research Centre, Harrow, Middlesex, UK.

A comparison was made of the effects of experimental intracerebral inoculation into marmosets of brain homogenates from a case of Creutzfeldt-Jakob disease (CJD) and from a member of the Wo. family with cerebral amyloid and spongiform encephalopathy--the Gerstmann-Straussler-Scheinker (GSS) syndrome. All the inoculated marmosets developed spongiform encephalopathy (SE) after incubation times of 20-23 months in the CJD group and 25-32 months in the GSS group. Subsequent passage from 1 affected animal in each group resulted in SE developing after 17 months incubation. In every animal inoculated with CJD or GSS material and in the 2 passage experiments the most severely affected region of the brain was the thalamus which in all cases was almost totally occupied by vacuoles. Other grey matter masses were less severely and less consistently affected. Vacuolation was observed in the cerebellar granule cell layer as well as in the molecular layer and the brain stem was finely vacuolated in all cases. There were only minor and inconsistent differences between the disease transmitted from CJD compared with GSS and some differences between the original transmissions and the SE caused by passaged inocula. Severe astrocytic gliosis accompanied the spongiform changes but no amyloid was identified in any of the marmosets with experimentally transmitted disease. The pathogenesis of the spongiform change in the thalamus was studied in a series of marmosets by light and electron microscopy 3-22 months after the intracerebral inoculation of CJD or GSS homogenates and was compared with controls. Dilated irregularly-shaped cisternae and the large complex vacuoles typical of SE, present in abundance after 18 and 22 months incubation, were considered most probably to be derived from cisternae of neuronal smooth endoplasmic reticulum.

Publication Types:
Case Reports

PMID: 2276050 [PubMed - indexed for MEDLINE]

Infectivity in the blood of mice with a BSE-derived agent

D. M. Taylor, K. Fernie, H. E. Reichl, R. A. Somerville


The occurrence of variant Creutzfeldt-Jakob disease (vCJD) was first reported in 1996, and there is now convincing evidence that is caused by the bovine spongiform encephalopathy (BSE) agent. So far, 61 cases have been detected in the UK but it is unknown how many more will occur. PrPres, a disease-specific form of normal PrP protein, has been consistently detected in lymphoid tissues from cases of vCJD but not classical sporadic CJD.1 The healthcare industry has therefore been obliged to consider the possibility that the vCJD agent may be present in the blood of apparently healthy individuals incubating the disease. To minimize the risk of iatrogenic transmission, blood for transfusion in the UK is now leuco-depleted, and plasma-derived products are only manufactured from imported plasma.

Although there have been several reports of infectivity being detected in the blood of individuals with sporadic CJD, none of these stand up to rigorous scrutiny2. We can now report that the plasma of mice challenged with the 301V strain of mouse-passaged strain of BSE agent contains low levels of infectivity during the clinical stages of disease. The blood from 55 VM mice infected with the 301V mouse-passaged strain of BSE agent was collected aseptically by heart-puncture when they developed clinical neurological disease. The individual samples where pooled after their collection into citrate dextrose anticoagulant (10% v/v), and the plasma was drawn off after sedimentation. The plasma was injected intracerebrally into 48 VM mice (20µL per mouse) that were observed for up to 300 days for the development of clinical neurological disease. When such symptoms appeared, the affected mice were killed and their brains where examined histopathologically to confirm the presence of the spongiform encephalopathy that is pathognomonic for 301V in VM mice. Of the 48 mice injected, four became infected with 301V. The average incubation period was 208 days (SE+16.60) which is at the end of the dose-response curve for 301V in VM mice, and means that the plasma contained around five intracerebral ID50/mL.

In two studies where small amounts of scrapie infectivity were detected in mouse blood by bioassay, it was suggested that this might have originated from heart-muscle during the collection of blood by heart-puncture. This was speculative, however, and seems unlikely in view of the failure to detect scrapie infectivity in mouse blood by bioassay in the most extensive study of this type that has been carried out. Also, infectivity has not been detectable in heart-muscle of the nine sheep with natural scrapie3, or the four humans with sporadic CJD4 that have been investigated to date.

The data presented here relating to 301V should not be interpreted as a definitive representation of the situation in humans with vCJD. They do, however, add to the increasing evidence that low levels of infectivity can be detected in the blood of individuals with CJD-like diseases if the sensitivity of the assay systems is adequate. Somewhat similar levels of infectivity have been detected in the plasma of mice showing clinical signs after challenge with a mouse-passaged strain of Gerstmann-Straussler-Scheinker syndrome agent, although it was much more difficult to detect infectivity during the pre-clinical stage of disease.5 It is unknown at present whether infectivity can be recovered from the blood of 301V-infected mice during the pre-clinical phase of disease, and this may be an important question if (as seems likely) the pathogenesis 301V in mice and that of vCJD in humans are similar.

D. M. Taylor, Neuropathogenesis Unit
K. Fernie, Institute for Animal Health
H. E. Reichl, West Mains Road
R. A. Somerville, Edinburgh EH9 3JF, UK
And Haemosan GmbH
Kahngasse 20, A - 8045 Graz, Austria


Hill AF, Butterworth RJ, Joiner S et al. Investigation of variant Creutzfeldt-Jakob disease and other human Prion disease with tonsil biopsy samples. Lancet 1999; 353: 183-189
Brown P. Can Creutzfeldt-Jakob disease be transmitted by transfusion? Curr Opin Haematol 1995; 2: 472-477
Hadlow WJ, Kennedy RC, Race RE. Natural infection of Suffolk sheep with scrapie virus. J Infect Dis 1982; 146 : 657-664.
Asher DM, Gibbs CJ, Gajdusek DC. Subacute spongiform encephalopathies: slow infections of the nervous system. Microbiol Newsletter 1985, 7: 129-133.
Brown P, Cervenakova L, McShane LM et al. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion 1999; 39: 1169-1178.

Transmission of prion diseases by blood transfusion


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