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Directorate-General for Health and Food Safety
Executive Summary
Question
The DG XXIV has asked the SCMPMD to provide it with comments on the following publication:
Pammer, J., Weninger, W. and Tschachler, E.: Human keratinocytes express cellular prion-related proteins in vitro and during inflammatory skin disease. American Journal of Pathology 153, 1353-1358, 1998.
Context of the question
The question is asked in the frame whether or not it is necessary to modify the policy regarding the use of hides and skins for the preparation of gelatine.
Answer
Pammer et al. unequivocally demonstrate the presence of PrPc in the skin. By this finding, they extent the range of tissues known to express PrPc. The theoretical possibility that skin contains also PrPSc, the pathologic form of the prion protein, or TSE infectivity in significant amounts is not supported by the majority of observations. However, crucial experiments as a search for PrPSc in the skin have not yet been performed. The methods are easily available. Until those studies are completed there is no sound justification for a change in policy regarding the use of hides and skins for the preparation of gelatine.
Assessment
After a discussion at the plenary meeting of the SCMPMD on 10 February 1999, the comments are summarised as follows:
1. The paper by Pammer et al. describes the detection of the cellular (non-pathogenic) form of the prion protein (PrPc) in the skin of humans, mainly in keratinocytes, but also in infiltrating mononuclear cells. The amount of PrPc is enhanced under certain pathological conditions of the skin (dermatitis, psoriasis, viral warts, squamous cell carcinomas). These findings are supported by in vitro studies on keratinocytes.
2. As it is generally accepted that the presence of PrPc is a prerequisite for the replication of TSE agents, the authors discuss two possible consequences of their finding: i) the TSE agent may enter the body via the skin; ii) the TSE agent may be transmitted via the skin to other individuals.
3. Although TSE agents can be transmitted by skin scarification (Taylor 1996) there is little epidemiological evidence that this route is of major importance. While some investigators believe that Kuru is transmitted through small injuries of the skin during the cannibalistic mourning rites (see 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.12) others argue that the oral route is of greater importance as this route is the established way of infection in bovine spongiform encephalopathy (BSE) and transmissible mink encephalopathy (TME). Also, epidemiological studies did not show that health care personnel with a high risk for skin injuries during invasive procedures (surgeons, neuropathologists) is at risk of acquiring CJD (Taylor 1996, van Duijn 1998).
4. While the presence of PrPc presents, at least theoretically, a site for entry of the TSE agent, it does not necessarily mean that there is also a site of PrPSc accumulation in diseased individuals. PrPc can be found in many tissues (Bendheim 1992, Horiuchi 1995), also in tissues in which TSE infectivity cannot be demonstrated (see table). Horiuchi concludes from his studies in sheep: "The tissue distribution of PrPc appears to be inconsistent with the tissues which possess scrapie infectivity, suggesting that factor(s) specific to certain cell types may be required to support multiplication of the scrapie agent."
5. Up to date, it is assumed that skin does not contain measurable amounts of infectivity (see table in the CPMP Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products). However, at least to the knowledge of the SCMPMD, there are no experiments published which are aimed to detect infectivity in skin. Especially, Hadlow (Eklund 1967, Hadlow 1974, Hadlow 1980, Hadlow 1982, Hadlow 1987) did not report on skin in his different studies with TSE infected mice, goats, sheep and minks. This may be partly due to the difficulty to prepare skin homogenates. In addition, there are no published reports which demonstrate the presence or the lack of PrPSc in the skin.
6. Pammer et al., seeking for a biological plausibility for the presence of PrPSc in the skin refer to the pruritus which is characteristic for scrapie infected sheep. However, unless the presence of PrPSc in the skin of those sheep is unequivocally shown, a neurological origin of this pruritus should be continued to be assumed.
7. Recent epidemiological studies (van Duijn 1998) show some unexplained correlation between the risk for CJD and contacts with skin and skin derivatives. While work with leather is obviously not a risk factor for CJD "contact with fur/leather other than through clothes" is. Also the use of fertilisers containing hoofs and horn seems to be a high risk factor for CJD, but detailed analysis shows that this correlation only holds for the years before 1985. As BSE was not existent or at least very limited before 1985 it is difficult to find a biological explanation for this observation.
8. Pammer et al. unequivocally demonstrate the presence of PrPc in the skin. By this finding, they extent the range of tissues known to express PrPc. The majority of observations seems to support the opinion that skin does not contain TSE infectivity in significant amounts. However, as there are still some open questions there is the need for studies investigating the presence of PrPSc, the pathologic form of the prion protein, in the skin. The methods are easily available. Until those studies are completed there is no sound justification for a change in policy regarding the use of hides and skins for the preparation of gelatine.
Table
Data from sheep with scrapie according to 1Horiuchi 1995 and 2Hadlow 1982. Infectivity was measured in mice as indicator animals. In a scrapie mouse model (Eklund 1967) infectivity could be found also in tissues like uterus, kidney and liver. In evaluating animal models all the considerations 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 (pp. 18-19) have to be taken into account.
References:
Bendheim, P.E., Brown, H.R., Rudelli, R.D., Scala, L.J., Goller, N.L., Wen, G.Y., Kascsak, R.J., Cashman, N.R., Bolton, D.C.: Nearly ubiquitous tissue distribution of the scrapie agent precursor protein. Neurology 42, 149,-156, 1992
Eklund, C.M., Kennedy, R.C., Hadlow, W.J.: Pathogenesis of scrapie virus infection in the mouse. Journal of Infectious Diseases 117, 15-22, 1967
Hadlow, W.J., Eklund, C.M., Kennedy, R.C., Jackson, T.A., Whitford, H.W., Boyle, C.C.: Course of experimental scrapie virus infection in the goat. Journal of Infectious Diseases 129, 559 567, 1974
Hadlow, W.J., Kennedy, R.C., Race, R.E., Eklund, C.M.: Virologic and neurohistologic findings in dairy goats affected with natural scrapie. Veterinary Pathology 17, 187,-199, 1980
Hadlow, W.J., Kennedy, R.C., Race, R.E.: Natural infection of Suffolk sheep with scrapie virus. Journal of Infectious Diseases 146, 657-664, 1982
Hadlow, W.J., Race, R.E., Kennedy, R.C.: Temporal distribution of transmissible mink encephalopathy virus in mink inoculated subcutaneously. Journal of Virology 61, 3235-3240, 1987
Horiuchi, M., Yamazaki, N., Ikeda, T., Ishiguro, N., Shinagawa, M.: A cellular form of prion protein (PrPC) exists in many non-neuronal tissues of sheep. Journal of General Virology 76, 2583-2587, 1995
Pammer, J., Weninger, W. and Tschachler, E.: Human keratinocytes express cellular prion-related proteins in vitro and during inflammatory skin disease. American Journal of Pathology 153, 1353-1358, 1998.
Taylor, D.M., McConnel, I., Fraser, H.: Scrapie infection can be established readily through skin scarification in immunocompetent but not immunodeficient mice. Journal of General Virology 77, 1595-1599, 1996.
van Duijn, C.M., Delasnerie-Lauprêtre, N., Masullo, C., Zerr, I., de Silva, R., Wientjens, D.P.W.M., Brandel, J.-P., Weber, T., Bonavita, V., Zeidler, M., Alpérovitch, A., Poser, S., Granieri, E., Hofman, A., Will, R.G.: Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993-95. Lancet 351, 1081-1085, 1998
Question
The DG XXIV has asked the SCMPMD to provide it with comments on the following publication:
Pammer, J., Weninger, W. and Tschachler, E.: Human keratinocytes express cellular prion-related proteins in vitro and during inflammatory skin disease. American Journal of Pathology 153, 1353-1358, 1998.
Context of the question
The question is asked in the frame whether or not it is necessary to modify the policy regarding the use of hides and skins for the preparation of gelatine.
Answer
Pammer et al. unequivocally demonstrate the presence of PrPc in the skin. By this finding, they extent the range of tissues known to express PrPc. The theoretical possibility that skin contains also PrPSc, the pathologic form of the prion protein, or TSE infectivity in significant amounts is not supported by the majority of observations. However, crucial experiments as a search for PrPSc in the skin have not yet been performed. The methods are easily available. Until those studies are completed there is no sound justification for a change in policy regarding the use of hides and skins for the preparation of gelatine.
Assessment
After a discussion at the plenary meeting of the SCMPMD on 10 February 1999, the comments are summarised as follows:
1. The paper by Pammer et al. describes the detection of the cellular (non-pathogenic) form of the prion protein (PrPc) in the skin of humans, mainly in keratinocytes, but also in infiltrating mononuclear cells. The amount of PrPc is enhanced under certain pathological conditions of the skin (dermatitis, psoriasis, viral warts, squamous cell carcinomas). These findings are supported by in vitro studies on keratinocytes.
2. As it is generally accepted that the presence of PrPc is a prerequisite for the replication of TSE agents, the authors discuss two possible consequences of their finding: i) the TSE agent may enter the body via the skin; ii) the TSE agent may be transmitted via the skin to other individuals.
3. Although TSE agents can be transmitted by skin scarification (Taylor 1996) there is little epidemiological evidence that this route is of major importance. While some investigators believe that Kuru is transmitted through small injuries of the skin during the cannibalistic mourning rites (see 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.12) others argue that the oral route is of greater importance as this route is the established way of infection in bovine spongiform encephalopathy (BSE) and transmissible mink encephalopathy (TME). Also, epidemiological studies did not show that health care personnel with a high risk for skin injuries during invasive procedures (surgeons, neuropathologists) is at risk of acquiring CJD (Taylor 1996, van Duijn 1998).
4. While the presence of PrPc presents, at least theoretically, a site for entry of the TSE agent, it does not necessarily mean that there is also a site of PrPSc accumulation in diseased individuals. PrPc can be found in many tissues (Bendheim 1992, Horiuchi 1995), also in tissues in which TSE infectivity cannot be demonstrated (see table). Horiuchi concludes from his studies in sheep: "The tissue distribution of PrPc appears to be inconsistent with the tissues which possess scrapie infectivity, suggesting that factor(s) specific to certain cell types may be required to support multiplication of the scrapie agent."
5. Up to date, it is assumed that skin does not contain measurable amounts of infectivity (see table in the CPMP Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products). However, at least to the knowledge of the SCMPMD, there are no experiments published which are aimed to detect infectivity in skin. Especially, Hadlow (Eklund 1967, Hadlow 1974, Hadlow 1980, Hadlow 1982, Hadlow 1987) did not report on skin in his different studies with TSE infected mice, goats, sheep and minks. This may be partly due to the difficulty to prepare skin homogenates. In addition, there are no published reports which demonstrate the presence or the lack of PrPSc in the skin.
6. Pammer et al., seeking for a biological plausibility for the presence of PrPSc in the skin refer to the pruritus which is characteristic for scrapie infected sheep. However, unless the presence of PrPSc in the skin of those sheep is unequivocally shown, a neurological origin of this pruritus should be continued to be assumed.
7. Recent epidemiological studies (van Duijn 1998) show some unexplained correlation between the risk for CJD and contacts with skin and skin derivatives. While work with leather is obviously not a risk factor for CJD "contact with fur/leather other than through clothes" is. Also the use of fertilisers containing hoofs and horn seems to be a high risk factor for CJD, but detailed analysis shows that this correlation only holds for the years before 1985. As BSE was not existent or at least very limited before 1985 it is difficult to find a biological explanation for this observation.
8. Pammer et al. unequivocally demonstrate the presence of PrPc in the skin. By this finding, they extent the range of tissues known to express PrPc. The majority of observations seems to support the opinion that skin does not contain TSE infectivity in significant amounts. However, as there are still some open questions there is the need for studies investigating the presence of PrPSc, the pathologic form of the prion protein, in the skin. The methods are easily available. Until those studies are completed there is no sound justification for a change in policy regarding the use of hides and skins for the preparation of gelatine.
Table
| Tissue | Presence1 of PrPc | Scrapie infectivity2 |
| brain | + | + |
| spleen | + | + |
| lymph node | + | + |
| lung | + | - |
| heart | + | - |
| kidney | + | - |
| skeletal muscle | + | - |
| uterus | + | - |
| adrenal gland | + | + |
| parotid gland | + | - |
| intestine | + | + |
| liver | - | - |
Data from sheep with scrapie according to 1Horiuchi 1995 and 2Hadlow 1982. Infectivity was measured in mice as indicator animals. In a scrapie mouse model (Eklund 1967) infectivity could be found also in tissues like uterus, kidney and liver. In evaluating animal models all the considerations 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 (pp. 18-19) have to be taken into account.
References:
Bendheim, P.E., Brown, H.R., Rudelli, R.D., Scala, L.J., Goller, N.L., Wen, G.Y., Kascsak, R.J., Cashman, N.R., Bolton, D.C.: Nearly ubiquitous tissue distribution of the scrapie agent precursor protein. Neurology 42, 149,-156, 1992
Eklund, C.M., Kennedy, R.C., Hadlow, W.J.: Pathogenesis of scrapie virus infection in the mouse. Journal of Infectious Diseases 117, 15-22, 1967
Hadlow, W.J., Eklund, C.M., Kennedy, R.C., Jackson, T.A., Whitford, H.W., Boyle, C.C.: Course of experimental scrapie virus infection in the goat. Journal of Infectious Diseases 129, 559 567, 1974
Hadlow, W.J., Kennedy, R.C., Race, R.E., Eklund, C.M.: Virologic and neurohistologic findings in dairy goats affected with natural scrapie. Veterinary Pathology 17, 187,-199, 1980
Hadlow, W.J., Kennedy, R.C., Race, R.E.: Natural infection of Suffolk sheep with scrapie virus. Journal of Infectious Diseases 146, 657-664, 1982
Hadlow, W.J., Race, R.E., Kennedy, R.C.: Temporal distribution of transmissible mink encephalopathy virus in mink inoculated subcutaneously. Journal of Virology 61, 3235-3240, 1987
Horiuchi, M., Yamazaki, N., Ikeda, T., Ishiguro, N., Shinagawa, M.: A cellular form of prion protein (PrPC) exists in many non-neuronal tissues of sheep. Journal of General Virology 76, 2583-2587, 1995
Pammer, J., Weninger, W. and Tschachler, E.: Human keratinocytes express cellular prion-related proteins in vitro and during inflammatory skin disease. American Journal of Pathology 153, 1353-1358, 1998.
Taylor, D.M., McConnel, I., Fraser, H.: Scrapie infection can be established readily through skin scarification in immunocompetent but not immunodeficient mice. Journal of General Virology 77, 1595-1599, 1996.
van Duijn, C.M., Delasnerie-Lauprêtre, N., Masullo, C., Zerr, I., de Silva, R., Wientjens, D.P.W.M., Brandel, J.-P., Weber, T., Bonavita, V., Zeidler, M., Alpérovitch, A., Poser, S., Granieri, E., Hofman, A., Will, R.G.: Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993-95. Lancet 351, 1081-1085, 1998
