A method of treating leukemia with autoimmune manifestations induced in the experiment

 

(57) Abstract:

The invention relates to medicine, in particular to the immunological treatment of autoimmune diseases and leukemia autoimmune manifestations in the experiment. The proposed method is based on the induction of synthesis of antiidiotypic antiautorun antibodies in the patient's body, which is achieved by immunization with the relevant autoantibodies and immune receptors of lymphocytes, pre-allocated on the immunosorbents carrying antigens that serve as targets for autoimmune reactions the patient body, and attached to an inert carrier. table 1.

The invention relates to medicine, in particular to the immunological treatment of autoimmune diseases and leukemia with autoimmune manifestations.

For the treatment of autoimmune diseases, immunological methods are used only passive immunization introduction antilimfocitarnyi immunoglobulins.

Along with the obvious success of therapy of autoimmune diseases, it can be noted from immunological methods the following disadvantages: lack of or insufficient selectivity effects, which is the cause of the de diseases; the necessity of using heterologous donor material may cause such infections, blood-borne, as hepatitis, HIV, etc. as well as additional immunization of the patient and donor proteins.

For the treatment of hematological malignancies with autoimmune manifestations (acute and chronic leukemia, lymphosarcoma) was tested several ways immunological effects: passive immunization with serum or lymphocytes of patients in remission, as well as antibody preparations against leukemia" antigens; passive therapy antiadiotipiceskih antibody (monoclonal) against immunoglobulins produced by tumor cells B-lymphocytes. C. M. Burgholzer and co-authors was proposed method of regulation of specific immunity" with leukaemia. The method consists in the re-introduction of large quantities of immunoglobulins isolated from native serum of patients.

However, the above-mentioned methods of immunotherapy was ineffective and not currently in use. All these methods involve the use of drugs that do not have sufficient immunogenicity upon administration to patients.

The advantages of the proposed method consist in the following:

1. Immunization with autoantibodies leads to Skopelitis suppression of isolated clones of autoimmune lymphocytes instead of total immunosuppression induced by cytostatics and antilimfocitarnyi immunoglobulins. Therefore, the method of treatment is specific and gentle, and safe for the patient. 2. Use as therapeutic drugs materials from the patient (according to the principle: each person is his own donor) excludes: 1) the possibility of Contracting hepatitis, HIV and other 2) the possibility of complications with the introduction of materials from animals (antilimfocitarnyi globulins) and any exogenous donor materials. The versatility of the proposed method of treatment offers the possibility of treatment of immunodeficiencies and diseases associated with transplantation immunity. The method of treatment, offered by us, allows to increase the efficiency and safety of treatment of patients with autoimmune diseases and leukemia autoimmune manifestations. Patients subjected to active immunization isolated from them by autoantibodies and receptors of autoimmune lymphocytes, which leads to the synthesis in the body opredelyaemye the method is as follows. Treatment is preceded by a preparation of antibody-sorbents designed for separation and accumulation of autoimmune factors (antibodies, receptors of immune lymphocytes) from materials taken from the patients. Such immunosorbents are a specific set of antigens that are targets of autoimmune reactions the patient directed against lymphocyte blood cells and bone marrow. To prepare antigen-sorbents using lymphocytes of patients with chronic lymphomatosum, tumor cells of patients with acute lymphoblastic leukemia, platelet donors (thrombocytopenia), erythrokaryocytes liver of human embryos (partial krasnocletocnaya aplasia). By treatment of cells with detergents get solubilization membrane antigens of cells and coniugium them with separate or oxidized cellulose. Patients will receive the following materials: serum, lymphocytes promptly removed spleen, and/or lymphocytes drained from the thoracic duct (lymph). Serum secrete circulating immune complexes and immunoglobulins by precipitation with polyethylene glycol (mol. wt. 6000), and lymphocytes prepared drug solubilizing membranacei-elution prepared materials on columns with antigen-sorbents. Selected antibodies (eluate) sterilized by ultrafiltration and coniugium with inert carrier sterile fine suspension of oxidized cellulose (SOTS sorbent), which dramatically increases the immunogenicity of materials. After verifying the sterility of the obtained conjugates (autoimmunogenic) is administered to the patient subcutaneously at intervals of 7 Nam in doses of 100 to 150 mg of protein per 1 kg of body weight. After 4 weeks impose the same material in a soluble form (without sorbent) at a dose of 200 μg per 1 kg of This cycle is repeated after 3-4 months with appropriate indications (signs of relapse and/or the appearance of antibodies). Monitoring and evaluation of the clinical and immunological efficacy of immunotherapy carried out initially in the hospital, and then in the outpatient setting within two years. The proposed method was experimentally tested in numerous series of experiments more than 900 mice with retroviral leukemia Rausher, as well as in mice and rabbits with autoimmune partial krasnocletocnaya aplasia of the bone marrow.

Mice susceptible lines were infected with virus leukemia of Rauser causing 100% mortality by 25-30 Nam after injection of the virus. The treatment was performed on the stage of rasierklingen 200 mg/kg); immunization with autoantibodies conjugated cellulose media (40 μg/mouse), 3 times, subcutaneously, every 7 days. As a result of experimental testing are obtained the following effects: long-term (>8 months) remission were achieved in more than 60% of the test animals. In the control without treatment 100% of the animals died by the end of the month, chemotherapy extends the life of animals is not more than 3 weeks.

Example 1. Test method for the treatment of autoimmune diseases was carried out on mice of BALB/c, artificially infected with the virus leukemia Rouser. 12-15 days after infection in mice took the serum. On a pre-prepared antigen-sorbents from selected serum autoantibodies: 1) to cells of leukemia Rouser; 2) histocompatibility antigen H-2 complex (sorbent from solubilizing activated T-lymphocytes of BALB/c; 3) to antigens in normal differentiation of lymphocytes in BALB/c mice. On 20-23 day mice were administered cyclophosphamide at a dose of 100-150 mg/kg of body weight. At 28, 35 and 42 day the mice were injected antibodies (autoantibodies) (1-3), conjugated with a sorbent suspension of oxidized cellulose at a dose of 15 μg of protein per mouse subcutaneously. Group IV received a mixture of antibodies 1-3. Control animals received only the CEC is the observation of the mice was carried out for 4 months by palpation determine the size of the spleen (1-2 times per week), hematological and immunological studies in the dynamics. The results of the experiment showed the following: All animals inoculated only with the virus, as well as the sorbent without autoantibodies, died to 35 Nam after infection. (28 8,5 Nam). Mice treated with cyclophosphamide, died to 58 Nam after infection (51,3 4,2). Mice treated with immunosorbents, had different life expectancy depending on the specificity of autoantibodies. The minimum life expectancy (75,6 8,4 Nam) noted in the group inoculated with antibodies to antigenic cells of leukemia Rouser. The maximum survival rate observed in the group immunized with the mixture of antibodies 1-3 (group IV). 11 mice from 12 to Exodus 4 months of observation were in this group in a state of complete remission. 1 mouse died of leukemia on day 104. In the serum of mice with remission detected antiidiotypic antibodies, neutralizing antibodies in the reaction immunofluorescence assay.

Example 2. The materials and test conditions similar to example 1. The results are presented for immunization autoantibodies in BALB/c mice infected with virus leukemia Rausher (BP) depending on the timing of the development of leukemia and influence representing immunization chemotherapy course for vigeveno the H-2 antigens of the major histocompatibility complex. From the results of the table shows that in the early stages (7 Nam after injection of the virus) vaccination with autoantibodies caused prolonged remission in 67% of mice. In the later stages similar effect was achieved only after a course of chemotherapy. The maximum effect was observed for the group immunized with the complex autoimmune antibodies OSCAR ecospecifier complex autoimmune reactions.

A method of treating leukemia with autoimmune manifestations induced in the experiment by immunotherapy, wherein the drug is administered autoantibodies and autoamtically "receptors" of autoimmune lymphocytes obtained by the selection of the patient's body using an immunosorbent, carrying a set of antigens "target" of this autoimmune process, and is attached to an inert carrier.

 

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