L. A. Zakharova

New approach to study of T cellular immunity development: parallel investigation of lymphoid organ formation and changes in immune proteasome amount in rat early ontogenesis.

The expression pattern and distribution of proteasome immune subunits LMP7 and LMP2 in the developing rat spleen and liver as well as the periarterial lymphoid sheath formation were investigated. LMP7 and LMP2 were detected by immunoblotting in the spleen on the 21st embryonic day and during the first postnatal days in equal amounts. Their levels increased by the 8th and 18th postnatal days. Double immunofluorescent labeling the spleen cells revealed LMP7 and LMP2 in T and B lymphocytes localized in the red pulp in embryogenesis. Few T lymphocytes were discovered in periarterial zones on the 8th postnatal day. T lymphocytes filled these zones and formed lymphoid sheaths by the 18-19th day. In the liver, LMP7 and LMP2 were revealed by the 17-19th postnatal day. Immunofluorescent analysis showed their presence in hepatocytes at this period. The data suggest that T cell-mediated immune response in relation to hepatocytes is possible beginning from 18th to 19th postnatal day.

Ontogenesis of rat immune system: Proteasome expression in different cell populations of the developing thymus.

Immune proteasomes in thymus are involved in processing of self-antigens, which are presented by MHC class I molecules for rejection of autoreactive thymocytes in adults and probably in perinatal rats. The distribution of immune proteasome subunits LMP7 and LMP2 in thymic cells have been investigated during rat perinatal ontogenesis. Double immunofluorescent labeling revealed LMP7 and LMP2 in thymic epithelial and dendritic cells, as well as in CD68 positive cells - macrophages, monocytes - at all developmental stages. LMP2 and LMP7 were also detected by flow cytometry in almost all thymic CD90 lymphocytes through pre- and postnatal ontogenesis. Our results demonstrate that the immune proteasomes are expressed in all types of thymic antigen presenting cells during perinatal ontogenesis, suggesting the establishment of the negative selection in the thymus at the end of fetal life. The observation of the immune proteasome expression in T lymphocytes suggests their role in thymocyte differentiation besides antigen processing in thymus.

Pattern of MHC class I and immune proteasome expression in Walker 256 tumor during growth and regression in Brattleboro rats with the hereditary defect of arginine-vasopressin synthesis

Dynamics of the expression of MHC class I, immune proteasomes and proteasome regulators 19S, PA28, total proteasome pool and proteasome chymotrypsin-like activity in Walker 256 tumor after implantation into Brattleboro rats with the hereditary defect of arginine-vasopressin synthesis was studied. The tumor growth and regression in Brattleboro rats were accompanied by changes in the proteasome subunit level unlike the tumor growth in WAG rats with normal expression of arginine-vasopressin gene. In the tumor implanted into Brattleboro rats the immune proteasome level was maximal between days 14 and 17, when the tumor underwent regression. Conversely, the expression of proteasome regulators tended to decrease during this period. Immune proteasomes are known to produce antigen epitopes for MHC class I to be presented to CD8+ T lymphocytes. Enhanced expression of immune proteasomes coincided with the recovery of MHC class I expression, suggesting the efficient presentation of tumor antigens in Brattleboro rats.

Walker 256 tumor growth in rats with hereditary defect of vasopressin synthesis

Stable deceleration of Walker 256 tumor growth was detected in Brattleboro rats with vasopressin synthesis defect in comparison with normal WAG rats. In contrast to continuous tumor growth typical of rats, the growth of this tumor in Brattleboro rats was negligible and was observed during the first 15–18 days after transplantation, after which the tumor regressed and disappeared. The effect was age-dependent and was more pronounced in old animals. Repeated injection of Walker 256 cells does not lead to tumor development, which attested to direct involvement of the immune system in the detected phenomenon.

Effect of prenatal infection of mice with bacterial endotoxin on the migration of neurons producing gonadotropin-releasing hormone

273 According to current concepts, the neuroendo crine and immune systems have a mutual regulatory influence on their formation and functioning in the pre and postnatal ontogeny [1, 2]. Due to the inter connection of these systems, the body responds by a protective reaction to different kinds of stress, includ ing infections. It is known that bacterial or viral infec tions of mother during early pregnancy may lead to the disturbance of brain development and functioning in the fetus both soon after birth and in later periods of life [1, 3]. After activation of the immune system of the mother with the bacterial endotoxin lipopolysaccha ride (LPS), stimulation of the synthesis and secretion of cytokines are observed. Production of proinflam matory cytokines exceeding physiological norm leads to preterm birth, various bone abnormalities, thymic atrophy, and impaired brain development during the prenatal period [4]. To present day, data on the effect of LPS on the reduction of reproductive performance of sexually mature individuals have been collected [5]. However, studies on the effect of prenatal infection on the development of the reproductive system of the fetus are practically absent. The key role in this process belongs to gonadotropin releasing hormone (GnRH), a neuropeptide synthesized in the hypothalamus. This hormone is known to be involved in the formation and functioning of both the reproductive and the immune systems of the body [6].

The role of serotonin in the immune system development and functioning during ontogenesis

In this study, we investigated the influence of serotonin on the development and functioning of T- and B-cell-mediated immunity during ontogenesis using the pharmacological model of serotonin depletion in rat fetuses. It has been demonstrated that prenatal serotonin deficiency resulted in a decrease in thymus and spleen weights, changes in their cellular composition, and long-lasting disturbances in cell-mediated and humoral immunity in postnatal ontogenesis. The data obtained suggest that serotonin may be considered a morphogenic factor in development of the immune system.

Evolution of adaptive immunity

The current state of the problem of emergence and evolution of adaptive immunity in different taxonomic groups of animals is analyzed. Special attention is given to the emergence and phylogenetic development of the lymphocyte, the key component of immune response, as well as to the evolutionary development of T- and B-cell immune systems, adaptive immune responses and their molecular regulators (cytokines), and antigen-recognition structures.

The morphogenetic effect of bacterial endotoxin lipopolysaccharide on the functioning of the reproductive system in rats

79 In the mammalian body, functioning of the repro ductive system depends on interaction of multiple neural, endocrine, immune, and behavioral processes. The regulatory effects of these systems are specifically important in the early period of ontogeny, which is the critical period of formation of the functions of the reproductive system [1]. The negative effect of immune stress on brain development in fetuses and its functioning in the later periods of life are known [2]. Infection of pregnant females with the bacterial lipopolysaccharide (LPS) endotoxin may be used as a model of immune stress, which induces in mothers and fetuses enhanced expression of cytokines repro gramming regulation of various systems of the fetuses for a long period of time [3].

The effect of catecholamine deficit on the development of the immune system in rats

68 Neuroendocrine control of functions of the immune system develops in prenatal ontogeny and operates during the whole life [1, 2]. In contrast to the late postnatal period, during early ontogeny, the neu roendocrine system performs not only regulatory, but also morphogenetic functions in the central nervous system and peripheral organs [3, 4]. The main signal molecules of these interactions are neurotransmitters and hormones of the hypothalamic–pituitary–adre nal system [5]. Among the regulators of development of different tissues in the fetus, catecholamines are of special interest. They are involved in cell differentia tion during the development of the secondary palate and kidneys [6]. The morphogenetic effects of cate cholamines on differentiation of peptidergic neurons are well known [7]. During the postnatal period, cate cholamines are important for normal functioning of the immune system [8]. Catecholamines can be syn thesized by lymphocytes and, probably, participate in autocrine and paracrine control of the immune response. In mature animals, administration of the catecholamine precursor L DOPA or inhibitors of catecholamine synthesis, respectively, increases or decreases the proliferative response of T and B cells of the thymus and the spleen to mitogens [9]. However, data on the role of catecholamines in the development of the immune system are sporadic.

Mechanisms of hypothalamic-pituitary and immune system regulation: The role of gonadotropin-releasing hormone and immune mediators

Different aspects of the reciprocal regulatory influence of systems producing the immune and gonadotropin-releasing hormone (GnRH) in pre- and postnatal ontogeny are discussed in this review. GnRH is a neurohormone synthesized by a small population of neurons located in the anterior hypothalamus, which regulates the secretion of gonadotropines in the anterior lobe of the pituitary gland and they finally regulate the synthesis of sex steroids. Particular attention is given to analysis of the data involving the role of thymic peptides and cytokines in GnRH-system regulation in the normal condition and in the case of inflammation development caused by endotoxines in adult animals. The main prospects of the studies involving the influence of proinflammatory cytokines on GnRH-neuron migration and differentiation in prenatal ontogenesis are also discussed.