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Directorate-General for Health and Food Safety
Question
DG XXIV has asked the SCMPMD to provide it with comments on the following publication:
Hill, AF, Butterworth, RJ, Joiner, S, Jackson, G, Rossor, MN, Thomas, DJ, Frosh, A, Tolley, N, Bell, JE, Spencer, M, King, A, Al-Sarraj, S, Ironside, JW, Lantos, PL, Collinge, J: Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353, 183-189, 1999
Context of question
The question is asked in the frame whether or not it is necessary to modify the policy regarding the use of blood and blood products.
Answer
The paper by Hill et al. (1999) extends an earlier paper (Hill 1997) by describing the presence of PrPSc in tonsils, spleen and lymph nodes of a number of nvCJD patients while this pathologic prion protein cannot be found in the same tissues of CJD and other patients or normal individuals. This finding has already been taken into account when the CPMP issued its opinion on measures with respect to blood products when one of the donors developed nvCJD. The CPMP position was also supprted by the SCMPMD. A change of this policy is not indicated on the basis of the new report by Hill et al. (1999).
Assessment
After a discussion at the plenary meeting of the SCMPMD on 10 February 1999, the comments are summarised as follows:
1. The paper of Hill et al. (1999) describes the finding that PrPSc, the pathologic form of the prion protein, can be consistently detected in tonsils, spleen and lymph nodes of patients (8 to 10 cases) with the new variant of CJD (nvCJD), but not in the same tissues of patients with different other forms of CJD, patients with other diseases (e.g. Alzheimer's disease) or normal controls.
2. This paper is an extension of an earlier report (Hill 1997), which has already been discussed in the OPINION ON THE RISK QUANTIFICATION FOR CJD TRANSMISSION VIA SUBSTANCES OF HUMAN ORIGIN adopted by the Scientific Committee on Medicinal Products and Medical Devices on 21 October 1998 (p. 14 and 25-26). This finding was also taken into account when the CPMP formulated his recall policy with respect to blood products when one of the donors subsequently developed nvCJD. This position was supported by the SCMPMD in its Opinion of 21 October 1998 (p. 27).
3. The data by Hill et al. also show that PrPSc seems to be associated with the follicular dendritic cells in the lymphatic tissues, and not with lymphocytes.
4. This association has also been described in a publication by Klein (1998). He also extends earlier studies (Klein 1997) demonstrating that the role of B lymphocytes in scrapie pathogenesis is most probably not of a direct, but of an indirect nature. The recent study demonstrates clearly that the promoting role of B lymphocytes does not depend on the production of PrPc, generally accepted to be a prerequisite for the propagation of TSE agents. These new findings shed some additional doubts on the usefulness of leukodepletion with respect to the theoretical transmission of CJD (SCMPMD Opinion p. 25-26).
5. Further studies have to focus on the role of the follicular dendritic cells in pathogenesis. The question as to how the TSE agents reaches these cells have also to be addressed.
References:
Hill, AF, Zeidler, M, Ironside, J, Collinge, J: Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy (letter). Lancet 349, 99-100, 1997
Hill, AF, Butterworth, RJ, Joiner, S, Jackson, G, Rossor, MN, Thomas, DJ, Frosh, A, Tolley, N, Bell, JE, Spencer, M, King, A, Al-Sarraj, S, Ironside, JW, Lantos, PL, Collinge, J: Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353, 183-189, 1999
Klein, MA, Frigg, R, Flechsig, E, Raeber, AJ, Kalinke, U, Bluethmann, H, Bootz, F, Suter, M, Zinkernagel, RM, Aguzzi, A: A crucial role for B cells in neuroinvasive scrapie. Nature 390, 687-690, 1997
Klein, MA, Frigg, R, Raeber, AJ, Flechsig, E, Hegyi, I, Zinkernagel, RM, Weissmann, C, Aguzzi, A: PrP expression in B lymphocytes is not required for prion neuroinvasion. Nature Medicine 4, 1429-1433, 1998
DG XXIV has asked the SCMPMD to provide it with comments on the following publication:
Hill, AF, Butterworth, RJ, Joiner, S, Jackson, G, Rossor, MN, Thomas, DJ, Frosh, A, Tolley, N, Bell, JE, Spencer, M, King, A, Al-Sarraj, S, Ironside, JW, Lantos, PL, Collinge, J: Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353, 183-189, 1999
Context of question
The question is asked in the frame whether or not it is necessary to modify the policy regarding the use of blood and blood products.
Answer
The paper by Hill et al. (1999) extends an earlier paper (Hill 1997) by describing the presence of PrPSc in tonsils, spleen and lymph nodes of a number of nvCJD patients while this pathologic prion protein cannot be found in the same tissues of CJD and other patients or normal individuals. This finding has already been taken into account when the CPMP issued its opinion on measures with respect to blood products when one of the donors developed nvCJD. The CPMP position was also supprted by the SCMPMD. A change of this policy is not indicated on the basis of the new report by Hill et al. (1999).
Assessment
After a discussion at the plenary meeting of the SCMPMD on 10 February 1999, the comments are summarised as follows:
1. The paper of Hill et al. (1999) describes the finding that PrPSc, the pathologic form of the prion protein, can be consistently detected in tonsils, spleen and lymph nodes of patients (8 to 10 cases) with the new variant of CJD (nvCJD), but not in the same tissues of patients with different other forms of CJD, patients with other diseases (e.g. Alzheimer's disease) or normal controls.
2. This paper is an extension of an earlier report (Hill 1997), which has already been discussed in the OPINION ON THE RISK QUANTIFICATION FOR CJD TRANSMISSION VIA SUBSTANCES OF HUMAN ORIGIN adopted by the Scientific Committee on Medicinal Products and Medical Devices on 21 October 1998 (p. 14 and 25-26). This finding was also taken into account when the CPMP formulated his recall policy with respect to blood products when one of the donors subsequently developed nvCJD. This position was supported by the SCMPMD in its Opinion of 21 October 1998 (p. 27).
3. The data by Hill et al. also show that PrPSc seems to be associated with the follicular dendritic cells in the lymphatic tissues, and not with lymphocytes.
4. This association has also been described in a publication by Klein (1998). He also extends earlier studies (Klein 1997) demonstrating that the role of B lymphocytes in scrapie pathogenesis is most probably not of a direct, but of an indirect nature. The recent study demonstrates clearly that the promoting role of B lymphocytes does not depend on the production of PrPc, generally accepted to be a prerequisite for the propagation of TSE agents. These new findings shed some additional doubts on the usefulness of leukodepletion with respect to the theoretical transmission of CJD (SCMPMD Opinion p. 25-26).
5. Further studies have to focus on the role of the follicular dendritic cells in pathogenesis. The question as to how the TSE agents reaches these cells have also to be addressed.
References:
Hill, AF, Zeidler, M, Ironside, J, Collinge, J: Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy (letter). Lancet 349, 99-100, 1997
Hill, AF, Butterworth, RJ, Joiner, S, Jackson, G, Rossor, MN, Thomas, DJ, Frosh, A, Tolley, N, Bell, JE, Spencer, M, King, A, Al-Sarraj, S, Ironside, JW, Lantos, PL, Collinge, J: Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353, 183-189, 1999
Klein, MA, Frigg, R, Flechsig, E, Raeber, AJ, Kalinke, U, Bluethmann, H, Bootz, F, Suter, M, Zinkernagel, RM, Aguzzi, A: A crucial role for B cells in neuroinvasive scrapie. Nature 390, 687-690, 1997
Klein, MA, Frigg, R, Raeber, AJ, Flechsig, E, Hegyi, I, Zinkernagel, RM, Weissmann, C, Aguzzi, A: PrP expression in B lymphocytes is not required for prion neuroinvasion. Nature Medicine 4, 1429-1433, 1998
