Surgery – Diagnostic testing – Sensitivity of skin to allergens or radiation
Reexamination Certificate
2000-06-20
2002-11-12
Lacyk, John P. (Department: 3736)
Surgery
Diagnostic testing
Sensitivity of skin to allergens or radiation
C206S569000
Reexamination Certificate
active
06478749
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns a skin test for determining the immune status against human papilloma viruses.
2. Description of the Related Art
Human papilloma viruses (HPV) are closely connected with malignant carcinomas of the anogenital tract, especially the neck of the uterus, the vulva, the penis and the anal duct. “High-risk” HPV types such as HPV 16 transform keratinocytes by means of the viral oncoproteins E6 and E7 contained therein by inactivating tumor suppressor proteins. It is assumed that the two oncoproteins E6 and E7 cooperatively contribute to the immortalizing (Hawley-Nelson, EMBO J., 8, 3905 (1989)).
The cancer cells transformed by HPV express the viral proteins E6 and E7 even in advanced tumor stages. It is assumed that a spontaneous or vaccination-induced immune reaction against these proteins could result in a regression of tumors caused by HPV. Until now, patients showing a spontaneous regression of their disease have not been examined due to the fact that examinations of the cellular defensive reaction in vitro are extremely time-consuming and, nevertheless, show a relatively low sensitivity. The role of the cellular immunological response in the case of vaccinations against HPV associated lesions is unclear.
Skin tests are partly already used in the clinical field in allergiology and for infectious diseases (mainly for clarifying tuberculosis in the form of the known TINE test).
There was, however, practically no specific application for virological questions or for cancer research until now.
Skin tests are also an excellent means for scientific questions and suitable for rapidly and practicably detecting complex cellular immune reactions in vivo. A skin test for examining the cellular immune reaction against “high risk” HPV is already known in prior art. This first application of the skin test for determining an immune reaction against a cancer associated virus was carried out with the coat protein L1 of the “high risk” HPV type 16 (utility model G9106105.9) and thereafter applied in animal models.
There is also a model for the skin test for the mouse; the immune reaction to a transplanted antigen was tested in this case (Mc Lean et al., J. Gen. Virol. 74, 239-245 (1993)).
This known skin test did not detect the humoral immunological response to an HPV infection. In contrast to the cellular defense, the detection of the humoral immune reaction can be carried out relatively easily in the laboratory by means of serological tests. It is considered to be proven that antibodies against three-dimensionally intact structures of the virus coat proteins can neutralize papilloma viruses (Christensen et al. J Gen Virol 75, 2271 (1994)). Antibodies against the early proteins E6 and E7 are associated with malignant tumors of the neck of the uterus (Jochmus-Kudielka et al. J. Natl. Cancer Inst. 81, 1698 (1989)).
A prophylactic vaccination with “virus like particles” consisting of coat proteins would preventively reduce an HPV infection and the risk of cancer associated therewith. The humoral immunological response against HPV, however, does not play a role with respect to the regression of already existing lesions. The serology has therefore an epidemiological significance.
In summary, the experiments with animal models and female patients show that cellular immune reactions against viral proteins are detectable by skin tests. As a result of the data, it can be assumed that an immune reaction against the coat protein L1 is not associated with regression, as in advanced lesions intact virus particles cannot be formed any more. Thus, the transforming virus proteins E6 and E7 are the probable goal of a “healing” immune reaction. These tumor antigens are thus potential candidates for the development of a vaccine if, in addition to the prophylactic effectiveness, a ctherapeutic effectiveness is to be achieved by virus coat proteins. It is assumed that such a vaccination causes an activation of cytotoxic T cells and T helper cells against persistently infected genital lesions.
However, an in vivo test for detecting the success of such a vaccination against E6 and/or E7 by means of the cellular defensive reaction of the immunological system as a reaction to the vaccination has not been known until now.
SUMMARY OF THE INVENTION
Therefore, the object to be solved by the invention is to provide a test by means of which the immune status against E6 and/or E7 proteins of papilloma viruses can easily be detected in vivo. According to the invention, this object is solved by providing the diagnosis kit for skin tests according to independent claim
1
and the process for carrying out a skin test according to independent claim
10
. Further advantageous embodiments and aspects of the invention are evident from the dependent claims and the description.
The skin test according to the invention can also be used for detecting spontaneous regressions of papilloma virus carcinoma precursors (CIN).
In a further aspect, the skin test according to the invention can also be used in the field of research in order to examine mechanisms in the regression of lesions caused by HPV.
REFERENCES:
patent: 91 06 105 (1991-07-01), None
patent: 91 06 105.9 (1991-11-01), None
patent: 0 386 734 (1990-09-01), None
patent: 0 451 550 (1991-09-01), None
Viscidi et al., Int J. Cancer, Serologic Response in HPV-Associated Invasive Cervical Cancer, 55(5):780-4, Nov. 11, 1993.*
Park et al., HPV-16-related proteins as the serologic markers in cervical neoplasia, Gynecol Oncol 1998, Apr.; 69(1):47-55.*
Medline, Washington, D.C., USA; Abstract No. 91073133, see abstract, XP002090517 & M. Muller et al, “Identification of seroreactive regions of the human papillomavirus type 16 protein E4, E6, E7 and L1” Journal of General Virology, Bd. 171, 1990, Seiten 2709-2717, Oxford UK.
K. Seedorf, T. Oltersdorf, G. Krämmer and W. Röwekamp, Identification of Early Proteins of the Human Papilloma Viruses Type 16 (HPV 16) and Type 18 (HPV 18) in Cervical Carcinoma Cells, The EMBO Journal vol. 6 No. 1 pp. 139-144, 1987.
Oltersdorf T., K. Seedorf, W. Rowekamp and L. Gissman, Identification of Human Papillomavirus Type 16 E7 Protein by Monoclonal Antibodies, Journal of General Virology 68(Pt 11) pp. 2933-2938, Nov. 1987 (Abstract Only).
Pamela Hawley-Nelson, Karen H. Vousden, Nancy L. Hubbert, Douglas R. Lowy and John T. Schiller, HPV16 E6 and E7 proteins cooperate to immortalize Human Foreskin Keratinocytes, The EMBO Journal vol. 8 No. 12 pp. 3905-3910, 1989.
Ingrid Jochmus-Kudielka, Achim Schneider, Rüdiger Braun, Rainer Kimmig, Ursula Koldovsky, Karl Eduard Schneweis, Klaus Seedorf, Lutz Gissmann, Antibodies Against the Human Papillomavirus Type 16 Early Proteins in Human Sera: Correlation of Anti-E7 Reactivity With Cervical Cancer, Journal of the National Cancer Institute, Aug. 31, 1989.
Martin Müller, Heinrich Gausepohl, Guy de Martynoff, Rainer Frank, Robert Brasseur and Lutz Gissman, Identification of Seroreactive Regions of the Human Papillomavirus Type 16 Proteins E4, E6, E7 and L1, The Journal of General Virology (1990), 71, 2709-2717.
R. Höpfl, M. Sandbichler, N. Sepp, K. Heim, E. Müller-Holzner, B. Wartusch, O. Dapunt, I. Jochmus-Kudielka, J. Ter Meulen, L. Gissmann, P. Fritsch, Skin Test for HPV Type 16 Proteins in Cervical Intraepithelial Neoplasia, The Lancet, vol. 337, p. 373, Feb. 9, 1991.
Cornelia S. McLean, Jane S. Sterling, Justine Mowat, Anthony A. Nash and Margaret A. Stanley, Delayed-type Hypersensitivity Response to the Human Papillomavirus Type 16 E7 Protein in a Mouse Model, Journal of General Virology (1993), 74, pp. 239-245.
Reinhard M. Höpfl, Neil D. Christensen, Michael G. Angell and John W. Kreider, Skin Test to Assess Immunity Against Cottontail Rabbit Papillomavirus Antigens in Rabbits with Progessing Papillomas or After Papilloma Regression, The Society for Investigative Dermatology, Inc., 1993, pp.227-231.
Neil D. Christensen, Reinhard Höpfl, Susan L. DiAngelo, Nancy M. Cladel, Susan D. Patrick, Patricia A. Welsh, Lynn R. Budgeon, Cynthia A.
Burns Doane , Swecker, Mathis LLP
Lacyk John P.
Medigene Aktiengesellschaft Gesellschaft fur Molekularbiologisch
Wingood Pamela
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