Method for preparing reference serum for anticardiolipin antibodies diagnosis in quantitative microprecipitin test for syphilis

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to preparing diagnostic products. The method is implemented by intratesticular infections of rabbits producers of 3.0-3.5 kg with pathogenic Nichols strain T. Pallidum pallidum. 7-8 days after the infection, the animals are additionally twice intravenously immunised with purified treponema proteins ("ОПТ"-antigen) recovered from "КСТ"-antigen of cultural Treponema Palladium in dosage 0.023 g, every 7-8 days. It is followed with exsanguination 30 days after the infection. The prepared serums are analysed for anticardiolipin antibodies titre in quantitative cardiolipin antigen microprecipitation test.

EFFECT: method allows increasing anticardiolipin antibodies titre, standardising a procedure of quantitative cardiolipin microprecipitation test for syphilis, and halving the findings analysis time.

2 ex

 

The invention relates to biotechnology, namely, to obtain diagnostic products, and can be used in the production of diagnostic sera to control the quantitative reaction of microprecipitation with cardiolipin (CRMP) for syphilis.

The invention solves the task of organizing the production of inexpensive diagnostic serum for monitoring results CRMP TO syphilis.

When syphilis immunity is significantly different in nature from immunity in other infectious diseases of humans and animals. The disease is accompanied by the secretion of two kinds of antibodies: non - anticardiolipin (reagin) and specific - protivoradarnyh. The reagents react in vitro with cardiolipin antigen (diphosphatidylglycerol)extracted from muscle bovine hearts, and are identified in the reaction of complement fixation (RAC - Wasserman), quantitative reaction microprecipitation with cardiolipin (CRMP), flocculation reaction for the rapid diagnosis of syphilis (EDS). The reagents are produced and determined in the serum of all patients with syphilis, but does not have a protective effect against infection, but their presence together with antitreponemal antibodies speaks about the disease of syphilis and the presence in the organism vegetative forms of pathogenic T. Pallidum pallidum (syphilis). With ecificatio protivosemnye antibodies (IgY and IgM) produced under the influence of the protein antigens of the causative agent of syphilis. Recovered from infection treatment can again be infected and become ill. Immunity in syphilis is a "non-sterile" - "infectious" and is characterized by cellular and humoral protective reactions causing the formation of a primary chancre, a generalization of infection on the background of the production in the blood of the patient both types of antibodies (Ochozias Ed. by V.N. Pokrovsky. Medical Microbiology. - M.: GEOTAR-MED, 2001, s-434, Aeacarotiwk, Saubion. Medical Microbiology, immunology and Virology. - SPb.: Spec. Lit., 2002, s-478).

Currently syphilis acquired epidemic spread in both developed and developing countries. The leading role in combating the spread of infection is timely diagnosis, however, industrial production of the domestic budget control standardized diagnostic products for syphilis for use in serological laboratories of different levels established enough.

A method of obtaining protevoepilepticescoe diagnostic control sera for RAC (Pharmacopeia "Serum diagnosis of syphilis control, positive, dry, RSC FS 42-12 sun-91 approved by the Pharmacopoeia Committee of the USSR Ministry of health 04.07.91 year). The disadvantage of this method is the high cost serum, links the data with low credits anticardiolipin antibodies (from 1:12 to 1:15 to drying and 1:10 after drying serum) and use in this regard in the production of whole blood sera of rabbits with experimental syphilis large number of rabbits-producers to obtain the required quantities of drug release.

Closest to the claimed invention is a method for control sera for the diagnosis of syphilis in RAC (RF Patent No. 2185856 "Method of production control sera for the diagnosis of syphilis". Pozharskaya V.O., Gurtovoy E.A., ALEXANDER Ermolov Publ. 27.07.2002 bull. No. 21). The method is carried out by intratesticular infected rabbits weighing 3.0 to 3.5 kg pathogenic strain Nichols T. Pallidum pallidum, after 7-8 days after infection, animals twice with an interval of 7-8 days subjected to immunization intravenous cellular structures treponemes (CRP-antigen) of the cultural pale treponemes (CBT) with subsequent bleeding of animals within 30 days after infection. Biomass pale treponemes are grown on the artificial thioglycolic environment from the full set of three strains antigenic groups with the subsequent disintegration of cells by ultrasound, by centrifugation, separation of intact treponem, by centrifugation of the supernatant liquid, sedimentation walls treponem and supernatant (RF Patent No. 2141339 "Method of production of antigens from culture pale treponemes". Pozharskaya V.O. Publ. 20.11.99, bull. No. 32). Ways which can improve the average titers anticardiolipin antibodies in RAC with a dilution of 1:15 to 1:40 in the blood bled animals.

According to the MOH orders No. 87 dated 26.03.2001, "On improving the serological diagnosis of syphilis" (subsection 2.1. Appendix No. 1) and No. 327 dated 25.07.2003, "On approval of the Protocol for the management of patients with Syphilis (based on guidelines of clique "Treatment and prevention of syphilis". M.: 1999) in the complex serological reactions (DAC) for syphilis entered the test CRMP-FOR the purpose of monitoring the presence and dynamics of changes in the titles anticardiolipin antibodies (reagin) for diagnosis of syphilis serological laboratories at all levels: regional, provincial, district, and also to monitor the effectiveness of specific treatment of syphilis infection in conjunction with the test reaction of haemagglutination (DSA) - treponemal syphilis. However, control serum for the diagnosis anticardiolipin antibodies in CRMP TO syphilis is not available and you want them daily titration before setting CRMP-according TO the same order of the Ministry of the Russian Federation No. 87 dated 26.03.2001, (p.4-6), which doubles the time of arming and recording the results of the analyzed serum for syphilis in this reaction.

The aim of the invention is the possibility of organizing industrial production control sera for the diagnosis anticardiolipin antibodies in CRMP TO syphilis and reduce the time for setting reactions in serological laboratory is oriah all levels twice, as well as lowering production costs by increasing titers anticardiolipin antibodies by immunization of rabbits with experimental syphilis purified proteins treponemes (OPT)obtained from CRP CBT, and a corresponding decrease in the number of animals used-producers.

This goal is achieved by the fact that rabbits weighing 3.0 to 3.5 kg intratesticular infect pathogenic strain Nichols T. Pallidum pallidum. After 7-8 days after infection, animals also twice with an interval of 7-8 days subjected to immunization intravenous dose is 0.023 g of purified proteins treponemes (OPT)obtained from CRP CBT, then on 30-31 days after infection, animals bleed, get the serum, define captions anticardiolipin antibodies in CRMP TO standardise, bottled and dried finished product.

WHOLESALE-antigen for immunization of rabbits with experimental syphilis is obtained from CRP-antigen by releasing it from the General group antigens (RF Patent No. 2156467 "enzyme Immunoassay system for the detection of antibodies to syphilis". Designed by MV, Ermolov CENTURIES, Pozharskaya V.O., Talbuk VP Publ. 20.09.2000, bull. No. 26).

In relation to the above prototype-the inventive method has the following distinctive features.

Additional immunization after exposure of rabbits pathogenic strain is icols So Pallidum pallidum is the OPT-antigen double-dose is 0.023 g, which leads to a higher level of increase in the titer of antibodies to non-specific cardiolipin antigen as a complement binding (RAC)and precipitins (CRMP-K).

If the prototype immunization CRP-antigen positive (4+) titles to anticardiolipin antigen in RAC detected in a dilution of 1:40, and in CRMP-in a dilution of 1:8, for the proposed method (immunization OPT-antigen) titles anticardiolipin antibodies in RAC detected in a dilution of 1:50-1:60, and in CRMP-in a dilution of 1:32-1:40.

The obtained results show that the OPT-antigen significantly increases the titer is not only complimentative antibodies, but precipitins that justifies its use in obtaining positive control sera for setting CRMP TO syphilis.

According to the requirements of the monograph produced dry control positive sera with cardiolipin antibody in the RAC should be positive not lower than 1:10 dilution.

According to the Ministry of health of the Russian Federation No. 87 of 26.03.01, "On improving the serological diagnosis of syphilis" (subsection 2.1. Annex 1 page 2 p.1, p.4-6) in preparation in laboratories positive control sera daily titration in quality control are positive sera at dilutions less than 1:8.

The possibility of practical use of the proposed method is confirmed by examples of specific performance.

Base for further research outlined above, is to standardize the used antigens CRP and OPT for dry weight (g) in 1 ml and injected rabbits producers with experimental syphilis, obtained by the standard technique after 7 and 14 days after infection with bleeding them for 30 days (the maximum time title anticardiolipin antibodies), were prepared serum by well-known methods and determined in her titles anticardiolipin antibodies in RAC and CRMP-K.

30 animals with experimental syphilis was injected intravenously on day 7 after infection 0,0115 g CRP-antigen, 14 day - 0,023 g CRP-antigen. In the blood serum of rabbits on a 30 day average titers anticardiolipin antibodies was in RSC - 1:40, CRMP-TO - 1:8 (RF Patent No. 2185856 "Method of production control sera for the diagnosis of syphilis". Pozharskaya V.O., Gurtovoy E.A., ALEXANDER Ermolov, publ. 27.07.2002, bull. No. 21).

Example No. 1. A control group. 30 animals with experimental syphilis was injected intravenously at 7 and 14 days after infection by 0,023 g CRP-antigen. In the blood serum of rabbits on a 30 day average titers anticardiolipin antibodies was in RSC - 1:43±2,1, CRMP-TO - 1:9±1,3. A mixture of sera obtained from 30 Krol the Cove, was the title anticardiolipin antibodies in RSC - 1:45, CRMP TO 1:10. Thus, the comparative titers obtained anticardiolipin antibodies in RAC and CRMP-IT was in 1,012 and 1.25 times more, respectively, and are the standard background for comparison put the same amount of OPT-antigen (0,023 g).

Example No. 2. The proposed method. 30 animals with experimental syphilis on the 7th and 14th day after infection were injected intravenously 0,023 g OPT-antigen. In the blood serum of rabbits on a 30 day average titers anticardiolipin antibodies was in RSC - 1:57±2,8, CRMP-TO - 1:36±3,8. A mixture of sera obtained from 30 rabbits, during the titration showed the titer anticardiolipin antibodies in RAC 1:55 in CRMP TO 1:34.

The obtained comparative results allow us to establish reliable P<0.01 increase in titer precipitating anticardiolipin antibodies. When immunization of rabbits with the OPT-antigen in CRMP TO the proposed method of immunization, which exceeded the titer of the control 3.4 times, while comparative titles anticardiolipin antibodies in RAC exceeded the control by a factor of 1.2, indicating that the higher activation production anticardiolipin antibodies in rabbits with experimental syphilis when introducing them to the OPT-antigen.

When the production release control sera standardization (bottling, drying), taking into account the production losses of up to 20%, required when entering the filling serum to have titles anticardiolipin antibodies in CRMP-brought to 1:10.

Received pilot series production release of the sera showed titers anticardiolipin antibodies in CRMP-in a dilution of 1:8. Given the title of precipitins in sera when setting CRMP, you can determine the level of dilution is 1:2 or 1:2,5, which significantly increases the volume of serum, providing a lower cost (reduction in the number of producers sera), and also halves the time of receipt of the results of research on syphilis in CRMP-K.

Control series production of the drug has been tested on the bases of the branch of the state unitary enterprise "NPO Microgen" MOH "Allergen" in Stavropol and Stavropol regional dermatovenerologic dispensary (serological laboratory).

Preparing to release the production of a series of positive control sera for the diagnosis anticardiolipin antibodies in CRMP TO syphilis and documentation to them for approval of the release of the drug.

Thus, the invention is feasible, its use in biotechnology will provide for the first time in the RF industry standard production budget control sera for CRMP TO syphilis, which will increase the efficiency of the control diagnosis of syphilis, and) is the communication time of receipt of the results of the study will reduce labor costs for production CRMP-on average 40-60%.

The method of obtaining control sera for the diagnosis anticardiolipin antibody in quantitative reaction microprecipitate for syphilis, including intratesticular infected rabbits weighing 3-3 .5 kg pathogenic strain Nichols T. Pallidum pallidum, bleeding animals, obtaining serum, determination anticardiolipin antibody in quantitative reaction microprecipitation with cardiolipin antigen, characterized in that the infected rabbits after 7-8 days additionally intravenously twice subjected to immunization purified proteins treponemes isolated from CRP-antigen cultural pale treponemes, the dose is 0.023 g with an interval of 7-8 days, the bleeding of animals carried out in 30 days after infection.



 

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