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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4369.
Lessons from the blood of sheepBRISTOL INSTITUTE FOR TRANSFUSION SCIENCES
Blood from sheep in preclinical or clinical stages of prion diseases can efficiently transmit infectivity to healthy sheep, thereby providing a good animal model for the evaluation of interventions designed to minimize vCJD transfusion-associated transmission in humans.
These facts raise some very challenging questions. Is blood infective throughout the preclinical phase? The lower limit of the incubation period for vCJD from ingested food products is estimated to be approximately 12 years.4 The incubation period for transfusion-associated transmission of vCJD appears to be approximately 6 to 8 years.3 How efficient is this process? How many recipients of infected blood will develop the disease and after how long? In this issue of Blood, Houston and colleagues provide some answers to these questions by using a large animal model, which makes it possible to transfuse the same volume of blood that would be used for a whole blood donation in a human. Sheep comprising 3 different susceptible PrP genotypes were inoculated orally with BSE-infected cattle brain homogenate and subsequently used as blood donors when in either the preclinical or clinical stage of disease. The results show that blood from BSE-infected sheep halfway through the incubation period can cause clinical disease when transfused into another animal. If these data are relevant to the situation in humans, then it must be assumed that blood is potentially infective for at least 6 years prior to the appearance of clinical signs of vCJD in a donor. Four of 13 sheep receiving whole blood transfusions from infected animals at between 40% and 100% of the donor incubation period developed clinical disease, and 2 animals showed signs of PrPsc by immunohistochemistry. Transmission efficiency from whole blood in sheep of the PRNP genotype selected for these experiments is high! In this experiment, 2 animals were used as donors in the very early preclinical stages (12% and 22% of average incubation time to disease, respectively), and no disease transmission was observed in recipients of blood from these animals. In a parallel experiment, Houston et al examine the transfusion-associated transmission of scrapie and found disease transmission by blood taken from animals at approximately 34% of the incubation period. In this experiment, 4 animals that received blood earlier in the incubation phase failed to develop the disease. These experiments take a long time, but they provide a valuable animal model with which to assess the contribution of procedures designed to reduce the risk of vCJD transfusion to transmissions. Several measures to reduce the risk have already been taken (leukodepletion of blood for transfusion), and decisions on new measures (prion filtration, diagnostic testing) will have to be taken in the absence of data on efficacy obtained using this model. Nevertheless, it will be very important to use sheep to provide good data from which to make a retrospective assessment of these extremely expensive interventions and optimize the cost-benefit equation.
Footnotes
Conflict-of-interest disclosure: The author is a consultant and shareholder of D-GEN Ltd.
REFERENCES
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