[Immunity, aging and works of V.M.Dilman.]

The review, dedicated to the anniversary of the brilliant gerontologist, endocrinologist and oncologist Vladimir M. Dilman, provides a historical analysis of the hypotheses of immunocooperative interactions, which have been given a prominent place in his original concept of aging. The history of various T-cell populations and sub-populations is reviewed, and their functions are briefly analyzed in relation to age-specific changes in immunity. Also considered is the theory of inflammaging in the light of the concept of V.M.Dilman.

[Macrophages and Their Role in Destabilization of an Atherosclerotic Plaque].

The modern data on structure and the functional activity of macrophages are presented in the review. It is shown that they are the nonhomogeneous cell population. Two of their main subpopulations are presented as M1 and M2 phenotypes which perform opposite functions at inflammation development. The main attention in the review is paid to a role of macrophages in pathogenesis of atherosclerosis and, first, in formation of unstable atherosclerotic plaques which are the cause of the most severe complications of the disease. It is shown that main subpopulations of macrophages play different roles in formation of unstable and stable atherosclerotic plaques. Macrophages of M1 phenotype in the vascular wall carry out pro-atherogenic role and influence destabilization of an atherosclerotic plaque, while M2 macrophages perform atheroprotective function.

Mast cells and aging.

Mast cells (MC) are present in the skin and mucous membranes, lymphoid organs, intestine wall and brain, where they are located close to the blood and lymphatic vessels and nerve terminals. As a source of a large number of biologically active substances, many of which are released quickly into the environment as a result of degranulation process, mast cells play an essential role in the regulation of physiological processes in the tissues where they are present. Changing the MC population and activity in the tissues during aging is associated with age-related changes of the skin and mucous membranes, the development of central nervous system disorders such as itching, headache, joint and muscle pain, memory loss, attention deficits, depression, anxiety and depressive disorders, autism, Alzheimer's disease and multiple sclerosis.

[Declining mitogen-induced polyclonal activity of peripheral blood lymphocytes as an index of immunosuppression involved in different neoplasms].

Regulatory T cells are crucial for maintaining T cell tolerance to-self-antigens and autoimmune process prevention. They are known to be able to cut down in vitro autologous lymphocyte proliferation in mice. It is suggested that their increased levels are responsible for immunosuppression in human tumor growth. Our investigation was concerned with identifying the extent of mitogen-stimulated T- and B-cell concentration changes as well as phenotypic variation in peripheral blood lymphocyte level in lung, stomach, breast and colorectal cancer. It was found that malignancy involves reduced mitogen (PHA, ConA, PWM)-stimulated lymphocyte proliferation and enhanced peripheral blood CD25+-cell concentration which should be accounted for by regulatory T cell increase. However, both the extent of proliferation changes and CD25+-lymphoid cell concentration considerably depended on tumor localization, which might have an indicator of a varying degree of immunosuppression involved in different neoplasms.

[Effect of acetylcholine and C-reactive protein on regulation of anaphylactic shock in guinea pigs].

The investigation of acetylcholine-dependent regulation of the model anaphylaxic shock in guinea pigs showed that an increase in the concentration of endogenous acetylcholine in sensitized animals leads to an increase in the agonal shock period (by 15 +/- 1 min in the test and 3 +/- 1 min in the control) and abolishes shock in the pathochemical phase: anaphylactic index 0.4 +/- 0.02 in the test against 4 +/- 0.02 in the control). The injection of purified blood plasma proteins-IgG or C-reactive protein (CRP) preparations--decreased the anaphylactic reaction. The activation of cholinergic tone prior to shock induction is an effective means of preventing shock development. The acquired resistance decreased the response to repeated injections of horse serum. Animals protected from the shock (methacin 40 min and neostigmine 15 min prior to shock, or methacine plus IgG 40 min prior to shock) showed nearly normal PFCs. The effect of methacin was significantly influenced by simultaneously injected plasma proteins: IgG potentiated the broncholytic effect of methacin, while CRP abrogated it. The effective antishock therapy led to normalization of the antibody production activity of B-lymphocytes, while unprotected animals exhibited increased level of antibody production.

[Evaluation of the prolonged immunotropic effect of the potential antiparkinson agent himantane]. / Otsenka prolongirovannogo immunotropnogo éffekta gimantana--potsentsial'nogo protivoparkinsonicheskogo sredstva.

A prolonged immunotropic effect of himantane, a new potential antiparkinsonian drug with a multicomponent (including dopaminopositive) mechanism of action, upon the functional activity of splenic B-cells in mice was studied in comparison to the effect of a typical neuroleptic drug haloperidol. A single administration of himantane (10 mg/kg) stimulated the B-cell activity over a period of 21 days, while haloperidol (0.25 mg/kg) suppressed this activity for 14 days after administration. The results of experiments on the adjuvant arthritis (paw edema) model showed that a single administration of himantane in the same dose under these pathological conditions does not influence the immune response (B-cell activity) for 14 days and increases the number of antibody-forming cells only 21 day after injection. Himantane enhanced the model arthritis manifestations in the early stage and reduced them in the late stage. It was established that the pronounced effect of himantane on the activity of immunocompetent cells is probably related to the drug action upon the central mechanisms of immunoregulation (which is consistent with a prolonged effect observed upon a single administration). This immunotropic activity indicates that the drug may affect immunological mechanisms involved in the pathogenesis of Parkinson's disease.

[Combined use of an antihypoxic agent and a B-cell stimulator]. / Izuchenie vozmozhnostei sochetannogo primeneniia antigipoksanta so stimuliatorom B-kletok.

Evaluation of the effect of poviargol on the B cells of mice showed that the drug activity is retained for 21 h upon single injection. An analysis of the refractory period between the B-cell stimulant introduction and the administration of various antihypoxants showed that the most effective treatment is provided by poviargol injection 14 days before and antihypoxant (IEM-1875 preparation) 30 min before the hypoxia model induction. This regime, ensuring the best protection of experimental animals from hypoxia, can be of great importance and value in the prophylaxis of hypoxia in various pathological conditions.

[Immunotropic activity of a potential antiparkinson agent himantane]. / Immunotropnaia aktivnost' potentsial'nogo protivoparkinsonicheskogo sredstva gimantana.

N-(Adamant-2-yl) hexamethyleneimine hydrochloride (A-7, himantane), a new potential antiparkinsonian drug belonging to the class of aminoadamantyl derivatives, exhibits pronounced immunomodulant activity in a therapeutic dose of 10 mg/kg. A single intraperitoneal injection of himantane stimulated a high B-lymphocyte activity in mice over a period of 21 days. The drug inhibited the reaction of delayed hypersensitivity with respect to the Freund adjuvant, while enhancing the immediate reaction with respect to horse serum in guinea pigs. Himantane increased the functional (absorption) activity of macrophages in the peritoneal exudate, while not affecting superoxide anion production by the macrophages. These results suggest that the immunomodulant activity of himantane may produce a positive neuroprotective and symptomatic effects in the course of parkinsonism.

[The regulatory functions of pro-inflammatory cytokines and acute-phase proteins]. / Reguliatornye funktsii provospalitel'nykh tsitokinov i ostrofaznykh belkov.

The paper provides a brief review of recent basic studies made by the Department of Immunology, Institute of Experimental Medicine, Saint Petersburg. They show that with a panel of macrophage-like cell lines of varying maturation (P388D, THP-1, U937, HL-60), the ability to produce TNF alpha spontaneously and to synthesize TNF alpha in response to atherogenic low-density lipoprotein stimulation correlates with the degree of cell differentiation that can be in turn induced by agents such as phorbol myristic acetate. The TNF alpha molecular site responsible for the macrophage-activating action of TNF alpha was identified as peptide 123-131. The latter was demonstrated to be uninvolved in the cytotoxic activity of TNF alpha. In addition to its activating and modulating effects against neutrophils, monocytes, and lymphocytes, the acute-phase reactant C-reactive protein was found to be able to bind the antiinflammatory cytokines IL-4 and TGF beta.

[Atherogenesis and the acute-phase reaction of the liver]. / Aterogenez i reaktsiia "ostroi fazy" pecheni.

Data from literature are given on the role of "acute phase" proteins in inflammation and their connection with lipoproteins. Intensive production of acute phase proteins is shown to take place in modelling of experimental atherosclerosis. The hypothesis is proposed that allows to consider the acute phase reaction of the liver as a very important condition of modified lipoproteins formation acquiring autoantigenic properties.

[The regulation of blood neutrophil functions by C-reactive protein and serum amyloid P]. / Reguliatsiia funktsii neitrofilov krovi C-reaktivnym belkom i syvorotochnym amiloidom P.

The effect of C-reactive protein on oxygen metabolism and lysosomal activity of the human blood neutrophils was found to depend on its ability to conform and to render both the pro- and anti-inflammatory results. The serum amyloid P exerted mostly a consistent anti-inflammatory effect.

[The effect of interleukin-2 on interferon production by human lymphocytes and the importance of this test in autoimmune diseases]. / Izuchenie vliianiia interleikina-2 na produktsiiu interferona limfotsitami cheloveka i znachenie etogo testa pri autoimmunnykh zabolevaniiakh.

Interleukin-2 (IL-2) was demonstrated to induce interferon (IFN) production in the cultured lymphocytes from healthy donors and myasthenia gravis (MG) patients. Moreover, IL-2 enhanced lymphocytic IFN production in patients and healthy individuals in response to phytohemagglutinin and concanavalin A. However, in MG patients, IFN production in response to IL-2 alone or in combination with mitogens is several times lower than that in healthy donors. This lowered IFN production in MG patients is accompanied by much higher rates of lymphocytic proliferation and by considerably enhanced spontaneous lymphocytic production of C-reactive protein as compared with healthy individuals. This test may be of great value in establishing the diagnosis of an autoimmune disease, in defining its severity and in evaluating the efficiency of therapy.

[The influence of C-reactive protein and its subunits on the cytotoxic effect of tumor necrosis factor-alpha in relation to L929 fibroblasts]. / Vliianie C-reaktivnogo belka i ego sub''edinits na tsitotoksicheskii éffekt faktora nekroza opukholei al'fa v otnoshenii fibroblastov linii L929.

A study was made of the ability of purified human C-reactive protein (CRP) in pentameric (pCRP) and subunit (sCRP) form to induce the production of tumour necrosis factor alpha (TNF-alpha) in macrophage-like cell line P388D1, as well as the combined effects of CRP and recombinant human TNF-alpha on the proliferation of L929 cell line. Both pCRP and sCRP induced TNF production by P388D1 cells, pCRP was inhibitory per se for L929 cells, while sCRP was not, when present in cultures for 72 h without actinomycin D (AD). In the presence of AD, sCRP was inhibitory as well, even when the period of incubation was reduced to 18 h. The presence in CRP of melittin-like sequence known to be responsible for the activation of cellular phospholipases is shown herein. Together with literature data, indication that CRP does influence the catalytic activity of purified phospholipase D, suggests that CRP exerts effect on P388D1 and L929 cells via regulation of cell phospholipases. The results also indicate that TNF effects in vivo can be modulated in different ways by conformational variants of CRP, whose occurrence and ratio depend on a phase of inflammatory reaction.