Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1994-04-18
1998-11-03
Schwadron, Ronald B.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 72, 435975, 435 772, 435 792, 435 793, 435 794, 435 795, 435331, 435332, 436506, 436536, 436811, 436820, 530300, 530324, 530325, 530326, 530327, 530328, 530401, 5303879, 5303882, 5303891, 530868, 5303911, G01N 3353, G01N 33564, C07N 14435, C07N 1618
Patent
active
058306676
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR92/00639, filed Jun. 16, 1992.
BACKGROUND OF THE INVENTION
The present invention relates to peptide fragments derived from human cytochrome P450 IID6 (formerly called cytochrome P450 dbl), to anti-peptide fragment antibodies and to their applications in the diagnosis of autoimmune hepatitis and more particularly in the differential diagnosis between autoimmune hepatitis and other chronic hepatitides of viral origin, such as hepatitis C or hepatitis B.
DESCRIPTION OF THE BACKGROUND
Autoimmune hepatitis, in particular in children, is an inflammatory disease which progresses into cirrhosis and hepatic insufficiency, which generally responds to an immunosuppressive treatment and is characterized by the presence of high non-organ-specific autoantibody titres.
Two subgroups have been defined, as a function of the autoantibody present in the serum: anti-smooth muscle antibody (anti-SMA) and anti-liver-kidney-microsome antibodies (anti-LKM), called hereinafter anti-LKM antibodies.
The antigen recognized by the anti-LKM antibodies is a protein with a molecular weight of 50 kDa, which is present at a relatively high concentration in the endoplasmic reticulum. Several studies suggest that this antigen corresponds to a protein of the cytochrome P450 family (WAXMAN B. J. et al., Gastroenterol. 1988, 95, 1326). This was confirmed by screening a rat liver cDNA library in the presence of an anti-50 kDa protein antibody, purified by affinity from an LKM-positive serum. Both constitutive forms of cytochrome P450, belonging to the subfamily IID 1 and 2 (rat db1 and db2), have been identified, as the antigens recognized by the anti-LKM antibody (GUEGUEN M. et al., J. Exp. Med., 1988, 168, 801).
Other studies (GUEGUEN M. et al., Biochem. Biophys. Res. Commun., 1989, 159, 542; ZANGER U. M. et al., Proc. Natl. Acad. USA, 1988, 27, 8256; MANNS M. P. et al., J. Clin. Invest., 1989, 83, 1066) have shown that cytochrome P450 IID6 is a protein recognized, in human liver, by the anti-LKM antibody.
Several methods for assaying anti-LKM antibodies have been proposed:
a first method of detection of these antibodies has been described in RIZZETTO et al., 1973, Clin. Exp. Immunol., 15, 331, and has especially been used for the diagnosis of liver diseases associated with the production of anti-LKM antibodies in children (MAGGIORE et al., J. Pediatrics, 1986, 108, 3, 399-404: Liver-disease associated with anti-liver-kidney microsome antibody in children); this method consists in detecting the said antibodies (serum) by indirect immunofluorescence on rat liver and kidney sections.
The sera are considered as positive for the anti-LKM antibodies when they react at a minimal dilution of 1:100 with the cytoplasm of hepatocytes and proximal renal tubules, whereas no coloration is obtained in the distal tubules.
However, this indirect immunofluorescence method has the major disadvantage of not being very sensitive and of thereby causing false negatives which can direct the clinician towards a wrong diagnosis and thereby disorient him with respect to the clinical signs observed.
Furthermore, the interpretation of the results obtained is generally difficult and is limited to specialist laboratories.
Other tests have therefore been proposed; there may be mentioned especially:
an RIA test (Clin. Exp. Immunol., 1984, 57, 600-608: Detection of liver-kidney microsomal auto-antibodies by radioimmunoassay and their relation to anti-mitochondrial antibodies in inflammatory liver diseases), which has the general disadvantages of RIA tests (especially difficulty of obtaining and handling labelled reagents);
ELISA tests;
in J. Ped. Gastoenterol. Nutr. 1988, 7, 816-822 (Detection of anti-endoplasmic reticulum antibody-positive autoimmune hepatitis in children, using an ELISA technique), the Authors (K. PARADIS, A. DIB, JC. HOMBERG, O. BERNARD, D. ALAGILLE and F. ALVAREZ) have described an ELISA method of detection using, as antigen, a preparation of rat liver microsomes.
This technique proved more sensitive than indirect
REFERENCES:
patent: 5106726 (1992-04-01), Wang
Hurtenbach et al., J. Exp. Med., 177:1499-1504, 1993.
Gonzalez et al., Nature, 331: 442-446, 1988.
Yamamoto et al., Eur. J. Immunol, 23: 1105-1111, 1993.
Godins, Chapter 3, from: "Monoclonal Antibodies: Principles and Practices", pp. 59-103, Academic Press, 1986.
Waldmann, Science, 252:1657-62, 1991.
Harris et al., TIBTECH, 11: 42-44, 1993.
Edginston, Bio/Technology, 10: 383-389, 1992.
Proceedings of the National Academy of Sciences of USA. vol. 85, Nov. 1988, Washington US, pp. 8256-8260; U.R. Zanger et al.: "Antibodies against human cytochrome P450dbl in autoimmune hepatitis type II".
Biochemical and Biophysical Research Communications, vol. 159, No. 2, Mar. 15, 1989, Duluth, Minnesota, US; pp. 542-547; M. Gueguen et al; "Anti-Liver kidney microsome antibody type I recognizes human cytochrome P450dbl".
The Journal of Clinical Investigation, vol. 88, No. 4, Oct. 1991, New York, pp. 1370-1378; M.P. Manns et al: "LKM-1 Autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 Monoxygenase".
Institut National de la Sante et de la Recherche Medicale-INSERM
Schwadron Ronald B.
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