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We pioneered the theory (Nature, 1974) that hyperproduced interferons (cytokines) can bring autoimmune diseases (AD) and neutralizing these cytokines can be therapeutic. In 1975 we first performed successful anticytokine therapy using anti-IFN-alpha antibodies in patients with rheumatoid arthritis (RA). In 1989 we proposed also treating AD including AIDS by removing TNF-alpha and IFN-alpha. Our theory has been widely confirmed: injections of IFN-alpha and -gamma can exacerbate AD, while antibodies to IFN-alpha and -gamma and TNF-alpha can be therapeutic. Anti-IFN-gamma may be a universal treatment for Th1 AD. We had good results using anti-IFN-gamma to treat RA, multiple sclerosis (MS), transplant rejection, alopecia areata, vitiligo, psoriatic arthritis, psoriasis and others. For Th1/Th2 diseases, antagonists to cortisol could prevent the Th1-Th2 shift and allow treatment as a Th1 disease. Anticytokine therapy can also be therapeutic in many neuropsychiatric diseases. Every disturbance of homeostasis may lead to cytokine disturbance. IL-10 may restore homeostasis by inhibiting the production of certain Th1 cytokines and could be used to treat some embryonic disturbances and AD including MS., (Copyright 2002 Elsevier Science Ltd.)

Aim: Objective evaluation of the effectiveness and tolerance of antibodies to interferon-gamma (TNF-gamma) vs those to tumor necrosis factor-alpha (TNF-a) and placebo in patients with rheumatoid arthritis (RA)., Material and Methods: A double blind randomised controlled trial of effectiveness and tolerance of anticytokine antibodies was conducted in 30 patients with active RA. The drugs were given i.m. for 5 consecutive days. The results were assessed on day 7 and 28., Results: Antibodies to both cytokines produced a marked therapeutic effect in RA, much greater than placebo effect. Improvement by day 7 was achieved in 9, 7 and 2 patients on anti-TNF-a, anti-INF-g and placebo, respectively. By day 28 in 8, 8 and 0 patients, respectively. Tolerance of anticytokines was good. Significant differences between the results of treatment with anti-INF-g and anti-TNF-a were not found., Conclusion: Administration of antibodies to INF-a proved ineffective and well tolerated method in the treatment of severe RA resistant for a number of standard basic drugs. Anti-IFN-a holds great promise when used in combination with classic antirheumatoid drugs, primarily with methotrexate.

Aim: Investigation of efficacy of antibodies ot interferons in rheumatoid arthritis (RA) versus relevant efficacy of the tumor necrosis factor (TNF), comparison of the above cytokines in monotherapy and combined treatment., Materials and Methods: An open controlled randomized trial of clinical benefit and tolerance of anticytokine antibodies was performed in a group of RA patients at stage II, III and IV (1, 20 and 4 patients, respectively). The activity degree II and III was in 10 and 15 patients, respectively. All the patients had articular functional insufficiency of the second degree. 21 patients failed previous therapy with basic drugs including immunodepressants., Results: The anticytokine antibodies proved to be highly effective in RA. Positive changes in teh disease activity were achieved early after the end of the 5-day course in 88% of patients. The most definite immediate therapeutic effect was noted in usage of TNF antibodies both in monotherapy and in combination with other anticytokines. Long-term effect was the best in patients given antibodies to interferon gamma. Interferon-alpha antibodies produced weaker effect. The combined treatment had no advantages over the monotherapy., Conclusion: A significant therapeutic effect of antibodies to interferon-gamma is indicative of an important role of this cytokine in RA pathogenesis. Anticytokine antibodies are promising as a component of combined therapy of patients with resistant RA.

The results and methods of treatment in 26 patients showing posttraumatic osteomyelitis of long tubular bones with antistaphylococcal plasma are described. This is a preliminary report, but it is believed that intramedullary, intravenous and local administration of antistaphylococcal plasma neutrolizes staphylococci in the wound and blood, produces a greater reactivity of the body and proves to be a rather effective measure in combating against staphylococcal infection in osteomyelitis.

The possibility of quantitative determination of human leukocyte interferon using FITC-labeled anti-interferon antibody was studied. Anti-interferon immunoglobulin of high specific activity was obtained as a result of long-term immunization of a donkey with human leukocyte interferon preparation and subsequent fractionation and immunoadsorption steps. This immunoglobulin was labeled with FITC and then used for titration of human leukocyte interferon by the fluorescence inhibition immunoassay. The titres of different preparations of human leukocyte interferon in the immunoassay were comparable with the titres of the same preparations detected by the inhibition of a cytopathic effect of VSV.

C57BL/6 mice were immunized once with leukemic cells L 1210; (CBAXC57BL/6) F1 mice were immunized once with leukemic cells L 1210 and P-388. These animals were injected intraperitoneally for 8 days (including the day of immunization) with 0.4 ml each of allogeneic or syngeneic interferon-containing serum; as to control animals, they received the same amount of normal serum from the intact mice. The interferon-containing serum was obtained from the (CBAXC57BL/6) F1 mice 24 hours after the intraperitoneal injection of 2 mg of tilorone hydrochloride. Some of the samples of the interferon-containing serum were subjected to the 48-hour dialysis against the physiological saline. The interferon titer in the serum was 512-1500 units/ml. The sera from mice were tested in the microcytotoxic test against leukemic cells 9-10 days after the immunization. A distinct stimulation of the cytotoxic activity of the sera from mice given the interferon-containing serum was observed. Syngeneic interferon-containing serum caused a more marked immunity-stimulating effect than allogeneic serum.

The treatment of cells L-1210 and MX-11 in vitro with interferon, prior to their injection to mice, caused an enhancement of specific humoral response and cytotoxic action of immune lymphocytes to Cr51 labelled target cells. The injecting of mice with allogeneic interferon-containing serum against the background of immunization with L-1210 cells produces an enhancing effect upon the immune response. Much more marked enhancing effect was observed when using syngeneic interferon-containing serum. Short-term treatment of lymphocytes, being immune to L-1210 cells, with interferon in vitro leads to the increase of their specific cytotoxicity to Cr51 labelled cells. Pre-treatment of leukemic cells with interferon would enhance their sensitivity to specific antibodies. It is suggested to use an active immunization of acute leukemia patients with allogeneic leukemic cells pre-incubated in interferon in combination with the injection of interferon-containing donor plasma.

A single intraperitioneal injection of L 1210 cells preincubated in interferon or in "false interferon" was given to mice. These mice were sacrificed on the 10th day, and cytotoxicity of the sera against the L 1210 leukemic cells vas determined in the microcytotoxic test (modification of Terasaki's method). Leukemic cells treated with interferon before the immunization caused a more pronounced immune response in comparison with the cells treated under the same conditions with "false interferon". By the results of cytotoxic reaction immune response was enhanced 2-4-fold.

Sera from 35 patients suffering from autoimmune or allergic diseases such as bronchial asthma, lupus erythematosus, rheumatoid arthritis, Werlhoff disease (autoimmune form), hemorrhagic vasculitis and neurodermatitis and sera from 70 donors were examined for the presence of interferon. Interferon was found in the sera of 17 of the patients but not in any one of the donors' sera. It is suggested that anit-interferon immunoglobulins against human leucocyte interferon should be employed in the treatment of autoimmune or allergic diseases because of the positive clinical results that were obtained. The different hypotheses describing the role of interferon in immunity and allergy are discussed.

Anticoli (anti-Escherichia) plasma has been obtained from donors immunized with viable Escherichia oral vaccines, prepared from Str-d mutants of E. coli. Anticoli plasma has an therapeutic effect against diseases of Escherichia etiology.

Human peripheral blood lymphocytes were subjected to the action--at first of phitohemagglutinin (PHA) and then of 9, 10-dimethyl-1,2-benzanthracene (DMBA) in various concentrations. Lymphocytes subjected to the action of PHA and then of the DMBA (in a dose of 0.5 gamma/ml) continued to divide during the whole observation period (14 days). The action of DMBA on the intact lymphocytes not only failed to induce their division, but also eliminated their sensitivity to the subsequent action of PHA at least for several days. The results obtained are discussed from the aspect of general oncogenesis theory put forward earlier.

A research study and discussion of antiinterferon immunoglobulin in the treatment of rheumatoid arthritis and systemic lupus erythematosus, and its possible value in the treatment of allergic diseases, autoimmune diseases and other diseases where it is presumed there may be an autoimmune genesis.

The possibility of quantitative determination of human leucocyte interferon using FITC-labeled antiinterferon antibodies was studied. A highly specific antiinterferon immunoglobulin was obtained as a result of longterm immunization of a donkey with human leucocyte interferon followed by fractionation and immuno-absorbtion of immune plasma. This immunoglobulin was labeled with FITC and used for human leucocyte interferon assay in direct and indirect reactions of fluorescence immunoinhibition. The titres of different human leucocyte interferon preparations in this immunoassay were comparable with the titres of the same preparations detected by interferon inhibition of viral cytopathic effect.

Donkeys were regularly, at seven-day intervals, immunized subcutaneously with human leukocyte interferon (IF) with the activity of 1.6 X 103 U/10 ml. IF-neutralizing antibodies in the titre of 1:128-1:256 were detected in the animals' sera after 38-40 injections. As a result of continuing injections the titre of these antibodies increased considerably. The antibodies to the components of the system in which the IF was obtained were revealed in parallel. Donkey antiinterferon plasma was prepared by plasmapheresis and antiinterferon immunoglobulin (AIFIG) was released from the plasma by centrifugation using ammonium sulphate at 50% saturation. Contamination antibodies were removed from AIFIG by affin chromatography on combined immunosorbent.

L-1210 AND P-388 leukemic cells were incubated in three types of interferon, i.e. L-cell interferon and two types of lymphocyte interferon (induced in the lymph node lymphocytes of intact mice and the lymphocytes obtained on the 10th day after intraperitoneal injections of 5-10(7) L-1210 cells). "False" interferon obtained by the method analogous to that of obtaining L-cell interferon, excluding the viral induction, was used for control. Cells incubated in interferon proved to be more sensitive to the action of the cytotoxic antibodies than those treated with "false" interferon. Treatment of the cells with lymphocytic interferon induced on the lymphocytes of immune mice increased their sensitivity even more in comparison with the cells treated with interferon obtained from intact mice.

Mice F1(CBA X C57BL/6) were immunized intraperitoneally with a single injection of L-1210 cells preincubated in interferon or control "false" preparation. CBA mice were injected with MX-11 cells: similarly treated according to the same scheme. Injection of interferon-treated cells was accompanied by the enhancement of the cellular immune response. The greatest cytotoxic activity was possessed by the lymphocytes of mice to which M-11 cells were administered together with interferon in which the cells were formerly incubated.