[Immunomodulators and some aspects of their clinical use].
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Biomedical subjects
Publications and source records attributed to B V Pinegin.
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Prolonged clinico-immunological observation of 85 patients with definite multiple sclerosis (MS) was performed in order to elucidate the connections between the clinical and immune state. A battery of immunological investigations was performed, including estimation of T-cell subpopulations in blood and cerebrospinal fluid (CSF); proliferative responses of circulating lymphocytes to mitogens, recombinant interleukin-2 (rIL2) and myelin basic protein levels in different culture conditions; levels of immunoglobulin (Ig) in sera and CSF, and of Ig production in vitro; indices of IL2 synthesis and IL2 sensitivity; production of prostaglandin E2 and tumour necrosis factor (TNF) alpha by monocytes and levels of beta-endorphin in sera and supernatants phytohaemagglutinin of (PHA)-activated cells. Clinical observation was performed periodically using Kurtzke scales and was supplemented by repeated recording of evoked potentials and magnetic resonance imaging. Initial investigations showed specific differences between patients with MS and the control groups (donors and patients with other neurological disorders of the same age). Correlative and regressive analyses showed no association between immunological and clinical parameters at the initial investigation, although immunological indexes were inter-related, and indicated specific alterations in immunoregulation in MS. Retrospective analysis revealed associations between the clinical status of patients with MS and their previous immune status. Evidence of cell activation--including a decreased percentage of circulating cells with differential antigens, lower cell mitogen-induced proliferative responses in vitro, with restoration following the addition of autoserum, greater IL2 sensitivity, and increased TNF-alpha production by macrophages--often predicted the clinical manifestation of deterioration. It is proposed that the immunopathological process in MS has a number of stages with characteristic features, and that progression from one stage to another can be subclinical. No single immunological index can be used to determine stage. Only systemic alterations reflect the real situation, whilst every patient has some abnormalities. A system of clinico-immunological monitoring could severe as the basis for a new approach to the dynamic treatment of MS.
The paper reports the results of ribomunil trial in chronic bronchitis (CB) patients who suffered from frequent exacerbations. The drug was found to act primarily on a phagocytic component of the immunity and local immunity of the respiratory mucosa. Because of its vaccine-like effect, ribomunil administration is most beneficial in CB remission. Ribomunil treatment results in reduction of the number and duration of CB exacerbations, of the scope of antibacterial therapy.
In this study, synthetic peptides that copy conserved regions of the HIV-1 envelope proteins gp120 and gp41 were tested for their impact on the chemotaxis of leukocytes and neutrophils from HIV-1-infected individuals, while neutrophils from HIV-1-infected patients were tested for their effect on the chemotaxis of neutrophils from healthy donors. The synthetic peptides (corresponding to the 251-272-amino acid sequence of gp120 and the 584-618-amino acid sequence of gp41) were capable of specifically inhibiting the formyl peptide-induced chemotaxis of cells from HIV-1-infected patients, and such inhibition was observed both with a total leukocyte population and with pure neutrophils. The migration of neutrophils from healthy donors was specifically inhibited in the presence of either of the synthetic peptides of HIV-1 envelope proteins after their incubation with neutrophil supernatants obtained from HIV-1-infected individuals. As shown by ELISA tests, the neutrophil supernatants from HIV-1-infected individuals contain antibodies to a recombinant env-1 protein that might be one of the reasons for the specific arming of neutrophils from HIV-1-infected persons.
In this study myelin basic protein (MBP) was tested for its effect on chemotaxis of human peripheral blood leukocytes (PBL) and neutrophils from multiple sclerosis (MS) patients. MBP appeared to inhibit specifically the formyl-methionyl-leucyl-phenylalanine (FMLP)-induced chemotaxis of both the total leukocyte population and neutrophils. In comparison, no inhibition of chemotaxis was observed in healthy donors and patients with other neurological diseases. From MS patients we collected neutrophil supernatants obtained by incubation of the cells in a serum-free medium at 37 degrees C for 60 min and evaluated their effect on chemotaxis of neutrophils from healthy donors. Chemotaxis of healthy donor neutrophils was inhibited specifically in the presence of MBP after treatment with these supernatants, presumably relating to the presence of immune complexes on the surface of neutrophils from MS patients. Those complexes can be eluted into the incubation medium and coat healthy donor neutrophils, thus arming them specifically.
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The functional activity of peripheral phagocytes were comparatively studied in 14 HIV-infected patients and 28 patients with chronic Herpes simplex viral infection. The two groups exhibited lowered adhesive capacity of phagocytes, impaired production and excretion of active oxygen metabolites. In addition, the patients with chronic Herpes simplex infection showed much elevated levels of myeloperoxidase and acid phosphatase, which indicated its compensatory pattern. The HIV infected had no enhanced enzymatic activity. One cannot rule out that these differences in the functional activity of phagocytes are associated with different effects of viral peptides on the cellular wall of phagocytes.
The authors studied the immune status of 14 HIV-infected patients, 6 of whom had lymphadenopathy, 4 were diagnosed as having AIDS-related complex and 4, a full-blown AIDS. Analysis of laboratory findings showed that of predictive value are serum levels of immunoglobulin B, a CD4 cell count less than 200, reduced populations of CD20 and CD16 lymphocytes, and a depressed response to pokeweed mitogen. Based on the clinical manifestations and laboratory results, three stages characterizing the immune system in HIV infection have been identified.
The impact of oral administration of heat-killed bifidobacteria, lactobacteria, enterococci and bacteroides on mouse resistance to experimental salmonellosis and content of immunoglobulin-synthesizing cells in the proper plate of the small intestine was studied. It was shown that the administration of the killed bifidobacteria, lactobacteria and enterococci increased the animal resistance to experimental salmonellosis infection and induced an increase in the content of immunoglobulin-synthesizing cells in the proper plate of the small intestine. The administration of the killed bacteroides had no such effect. Possible development of bacterial preparations with immunomodulating properties based on killed bifidobacteria, lactobacteria or enterococci is discussed.
Unlike hemocarboperfusion (HCP), plasmapheresis (PA) produces a long-term effect in the treatment of serious cases of rheumatoid arthritis. This explains why the rebound syndrome occurs in PA two times less frequently. The analysis of the immunomodifying action of both the treatments and comparison of their efficacy suggest the conclusion that long-term and complete remissions are associated with the immunosuppressive effects, while the development of exacerbations accompanies the immunomodifying effect. HCP stimulates the immune system, while PA can induce both stimulation and suppression. Therefore, HCP can be used as an adjuvant treatment of highly active rheumatoid arthritis before the basic therapy. In PA immunosuppressive effect, it may be used as an original treatment method.
Twenty-two females, 38 to 75 years of age, who underwent planned operation for chronic uncomplicated calculous cholecystitis were examined in the pre- and postoperative period. Postoperative pneumonia developed in 4 (13.4%) patients, no other complications occurred. Functional neutrophil activity was studied according to the following parameters: spontaneous and induced NBT test, myeloperoxidase activity, amount of cationic proteins, expression of Fc receptors, spontaneous and induced luminol-dependent chemiluminescence, neutrophil bactericidal action against H-thymidine-labelled Staphylococcus aureus (strain 209), amount of blood immunoglobulins, and the modulating effect of serum of patients on the chemiluminescence of neutrophils of healthy donors. The control group consisted of 35 volunteers whose ages ranged from 18 to 50 years. Basic differences were revealed between the indices of neutrophil activity in patients with an uneventful postoperative period and those of patients with infectious complications in the preoperative period which became much graver in the early postoperative period. This suggests that neutrophilic dysfunctions play a significant role in the development of postoperative infectious complications in this category of patients.
The results of the study of the phagocytic element of immunity in cases of primary immunodeficiency, made with the use of a complex of functional tests, are presented. As shown in this study, in patients with definitely characterized phagocytic defect (chronic granulomatous disease) a decrease in all parameters under study, with the exception of phagocyte index, is observed. In patients with immunodeficient states of nonphagocytic nature moderate mosaic deviations of phagocytosis characteristics are noted. For further and more profound study of phagocytosis disturbances in such patients, it is expedient, in particular, to carry out studies in the activity of myeloperoxidaze and the intensity of oxygen-dependent metabolism. The use of the complex of methods used in this investigation has shown their high diagnostic value. It may be recommended for clinical practice under the condition of strict standardization of experimental techniques.
In four series of experiments human peripheral blood neutrophils were found capable of synthetizing the active forms of such enzymes as myeloperoxidase and acid phosphatase after stimulation with opsonized zymosan, and the optimum conditions for testing the synthetizing activity of neutrophils were established. The examination of 39 practically healthy donors revealed an approximate equilibrium between the synthesis of the active forms of the enzyme and its excretion from the cell after this cell was activated. Considerable changes in the enzymatic activity of peripheral blood neutrophils were found in patients with yersiniosis, chronic herpes, chronic bronchitis and AIDS-associated complex. The possibility of a deficient enzymatic activity in some patients was suggested.
A spectrophotometric method has been developed for measurements of myeloperoxidase activity in phagocytes, and conditions of measurements specified. Contribution of mononuclear cells to myeloperoxidase activity was found negligible, the major role here was played by neutrophils and eosinophils. Myeloperoxidase activity was found reduced in the patients with chronic granulomatous disease, agammaglobulinemia, and elevated in hyper-IgE-syndrome; this parameter was unchanged in ataxia telangiectasia and chronic dermatomucosal candidiasis.
The in vivo study of the influence of Kemantan on the growth of endogenous colonies in the spleen of sublethally (6 Gy) irradiated (CBA x C57BL/6J) F1 mice (mitostatic action) and on the capacity of transplanted lymphocytes of CBA mice for suppressing their multiplication (lymphotoxic action) was carried out. Besides the capacity of Kemantan for affecting the induction, formation and functioning of B-suppressors of antibody formation was studied. As revealed in this study, Kemantan in doses of 0.2-200 mg/kg did not produce a mitostatic and lymphotoxic effect and had no influence on the realization of the suppressing action of mature B-suppressors. In doses of 20 and 200 mr/kg Kemantan, injected to donors at the phase of the induction and accumulation of B-suppressors, abolished their formation.
The study of Kemantan on functionally alternative humoral immunity regulator cells: T-helpers and antigen-specific T-suppressors, including their induction, accumulation and functioning, was studied. Kemantan in doses of 0.2-200 mg/kg, introduced to the donors of T-helpers 2 days before they were taken, stimulated their activity 1.5- to 2-fold (with p less than 0.05). Kemantan had no influence on the functional activity of T-suppressors, as well as on their induction and accumulation.
The data on the state of cell-mediated immunity in patients with AIDS-related complex are presented. The synthetic peptide of membrane protein gp120 of HIV-1 was shown to inhibit leukocyte adhesion in persons under examination, as well as to have the tendency towards inhibiting the chemotaxis of migratory cells. The maximum effect was achieved at a peptide concentration of 10(-6) M. The data obtained in this investigation suggest the presence of specific cell-mediated sensitization to the fragment of protein gp120, detected by the adhesion inhibition test with the use of spectrophotometric techniques and the capillary evaluation of the chemotaxis of migrating cells, in patients with AIDS-related complex.
The data on the presence of factors blocking the reaction of E-rosette formation and leukocyte chemotaxis in the blood sera of patients with AIDS-related complex (ARC) and HIV-positive donors are presented. Most frequently the blocking of E-rosette formation coincided with the presence of a inhibiting effect on the migration capacity of leukocytes. This blocking activity was not linked with the presence of C-reactive protein in the circulation stream. The treatment of ARC patients with plasmapheresis and/or travolol was accompanied either by the disappearance of blocking activity or by the appearance of activity stimulating E-rosette formation.