thymic-factor--circulating and Autoimmune-Diseases

The manuscript will provide an in-depth and critical review of the nomenclature, biochemistry, biological properties, and a summary of published and on-going clinical trials with all reported thymic preparations, including both partially purified thymic factors (e.g., thymosin fraction 5, thymostimulin) as well as purified and synthesized thymic peptides (e.g., thymosin alpha 1, thymulin). Particular emphasis will be placed on which thymic peptides should be categorized as true hormones. In addition, the comparative biochemistry and biological activity in animals will be summarized and contrasted for all the currently available thymic factors. The effects, in vitro of thymic factors, on peripheral blood lymphocytes isolated from normal donors and patients with primary immunodeficiency disorders, autoimmune disorders, and neoplastic disorders will also be reviewed. Finally, a detailed critical summary of the clinical trials performed with each of the thymic preparations will be presented with an emphasis on treatment of patients with cancer.

Topics: Amino Acid Sequence; Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Autoimmune Diseases; Biological Assay; Cell Differentiation; Epithelium; Humans; Immunologic Deficiency Syndromes; Immunotherapy; Neoplasms; T-Lymphocytes; Terminology as Topic; Thymectomy; Thymic Factor, Circulating; Thymopoietins; Thymosin; Thymus Extracts; Thymus Gland; Thymus Hormones

The epithelial cells of the thymus synthesize at least 30 different polypeptides: the thymic hormones. The structure of 4 of them is well known. They are named thymosin alpha 1, thymopoietin, thymulin and thymic humoral factor. Biological functions and secretion regulation of thymic hormones are described as well as the interactions between brain, thymus and endocrine glands. Blood levels and clinical usefulness of thymic hormones are reviewed in different congenital or acquired immunodeficient states and in autoimmune diseases.

Topics: Acquired Immunodeficiency Syndrome; Autoimmune Diseases; Humans; Immunologic Deficiency Syndromes; Peptide Fragments; Thymalfasin; Thymic Factor, Circulating; Thymopentin; Thymopoietins; Thymosin; Thymus Extracts; Thymus Hormones

Topics: Animals; Autoimmune Diseases; Growth Inhibitors; Humans; Immunity; Immunologic Deficiency Syndromes; Interferons; Interleukin-1; Interleukin-2; Lymphotoxin-alpha; Neoplasms; Thymic Factor, Circulating; Thymosin; Thymus Hormones; Transfer Factor

Even though thymulin was isolated, sequenced and characterised some 20 years ago and later identified as a thymic hormone involved in immunomodulation, much more work is still required to further understanding of the mechanisms of action(s) of this peptide. Since the observation, by a semiquantitative bioassay, of diminished levels of thymulin in immunodeficiency and autoimmune disease, new data obtained by radioimmunoassay have not only confirmed previous observations but also demonstrated that thymulin plays a role in the interaction between the immune system and the neuro-endocrine system. In this paper we give an up to date account of recent developments in research into the role of thymulin in immunomodulation.

Topics: Amino Acid Sequence; Animals; Autoimmune Diseases; Humans; Immune System; Molecular Sequence Data; Thymic Factor, Circulating

The author studied the effect of immunostimulating (thymalin) and immunodepressive agents (glucocorticoids) on the state of the immune system in 25 patients with idiopathic autoimmune cytopenias. It was established that the treatment favoured correction of disorders of the immune system characteristic of this kind of pathology. The proposed scheme is recommended for clinical employment in patients with idiopathic autoimmune cytopenias.

Topics: Adjuvants, Immunologic; Adult; Anemia, Hemolytic, Autoimmune; Autoantibodies; Autoimmune Diseases; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunity; Immunosuppressive Agents; Male; Middle Aged; Neutropenia; Purpura, Thrombocytopenic, Idiopathic; Thymus Hormones

Age-related features of structural and cytochemical changes in the brain cortical neurons were investigated in offspring of rats which were neurosensitized and received a course of timalin treatment during gestation. Course treatment with the drug prevented the development of dystrophic changes in cortical neurons, their death and decrease in cell density within the cortical layers. Timalin acted positive in terms of increase in protein content of the cellular nucleus and especially in the cytoplasm. These effects were more pronounced in aged animals. Possible mechanism of timalin action in neurosensitized mothers is discussed.

Topics: Adjuvants, Immunologic; Animals; Atrophy; Autoantibodies; Autoimmune Diseases; Brain; Cerebral Cortex; Female; Immunity, Maternally-Acquired; Neurons; Pregnancy; Rats; Thymus Hormones

The thymic epithelium, a major component of the thymic microenvironment, is a heterogeneous tissue bearing distinct monoclonal antibody-defined subsets. Among these, KL1+ cells represent a mouse medullary subpopulation characterized by high mol wt cytokeratin expression. Given the fact that thymic epithelial cells (TEC) express glucocorticoid receptors and that glucocorticoid hormones are known to modulate the expression of keratins, we decided to study the in vivo effects of hydrocortisone on KL1+ cells in normal and autoimmune mice. Within 24 h after a single injection of this steroid we observed a significant increase in the number of KL1+ cells. Interestingly, this effect was reversible and was no longer detected 7 days after treatment. Parallel studies analyzing the effects of hydrocortisone on the secretion of thymulin, a chemically defined thymic hormone revealed a transient decrease in serum levels of this hormone, but with different kinetics than the effects on KL1+ cells. Ontogenetic studies showed that the responsiveness of TEC to hydrocortisone, in terms of high mol wt cytokeratin expression, appeared late in fetal life and disappeared in aging animals. Importantly, aging, but also young adult, autoimmune mice were not responsive. In vitro experiments using a mouse TEC line confirmed the data observed in vivo demonstrating that the increase in KL1+ cells is a direct effect of hydrocortisone on TEC. The bulk of the data presently reported demonstrates that glucocorticoid hormone can act on TEC modulating the expression of both secretory and cytoskeletal protein families.

Topics: Aging; Animals; Atrophy; Autoimmune Diseases; Cell Count; Dose-Response Relationship, Drug; Epithelium; Hydrocortisone; Immunoblotting; Keratins; Kinetics; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NZB; Molecular Weight; Thymic Factor, Circulating; Thymus Gland

A colony of dogs was obtained by the mating of a female German Shepherd Dog crossbred and a male Belgian Shepherd Dog crossbred, both with systemic lupus erythematosus (SLE). The colony also contained 16 dogs representing F1, F2, and F3 generations. Ten colony dogs had circulating antinuclear antibodies, and 5 of the 10 had clinical signs of SLE. Two F3-generation females had signs of severe SLE. Two dogs had antibodies to extractable nuclear antigen, notably 1 dog had antibodies to Smith (Sm) antigen and 1 had antibodies to Sjogren syndrome A (SSA) antigen. Thymulin (serum thymic factor associated with zinc) titers were generally low in the descendants, but fluctuations were detected within the same dog. In vitro response of lymphocytes from these colony dogs to concanavalin A was maximal for lower mitogenic concentrations, compared with response of lymphocytes from 10 healthy dogs. The suppressive lymphocyte activity in 6 autoimmune colony dogs was diminished in comparison with the activity in 5 nonautoimmune colony dogs and 6 healthy dogs.

Topics: Animals; Antibodies, Antinuclear; Autoimmune Diseases; Disease Models, Animal; Dog Diseases; Dogs; Female; Lupus Erythematosus, Systemic; Lymphocyte Activation; Male; Pedigree; T-Lymphocytes; Thymic Factor, Circulating

We studied the effect of a low dose cyclophosphamide (CY) treatment on the clinical course of experimental autoimmune encephalomyelitis (EAE) in rats from three resistant or low-susceptible strains: Fischer, Brown-Norway, PVG, and the F1 hybrid between the two former strains. Treatment with 40 mg/kg two days before immunization resulted in a marked potentiation of EAE development in Fischer and PVG rats, but not in BN rats or F1(BN X F) hybrids. The effect of the CY treatment was a short period of severe lymphoid cell depletion with an increase in the quotient between T cells reacting with w3/25 monoclonal antiserum and such reacting with ox-8 antiserum, indicating a relative reduction in suppressor/cytotoxic cell counts. Treatment of Fischer or PVG rats, after CY treatment, for five days with thymic hormone factor (THF) normalized T cell ratios and restored the rats to a state of low susceptibility. It is concluded that Fischer and PVG rats have an EAE suppressive mechanism dependent on CY-sensitive suppressor lymphocytes, while there may be other mechanisms of resistance to EAE in BN rats.

Topics: Animals; Autoimmune Diseases; Cell Count; Cyclophosphamide; Disease Susceptibility; Encephalomyelitis; Rats; Rats, Inbred Strains; Spleen; Thymic Factor, Circulating

NZB mice, DBA/2 mice and reciprocal F1 hybrids between both strains were studied from birth to two months of age for the secretion of a serum thymic factor, thymulin (formerly named Facteur Thymique Sérique) and for spontaneous and antigen-induced immune responses: spontaneous splenic anti-2,4,6-trinitrophenyl (TNP) plaque-forming cells (PFC), spontaneous IgM serum levels, immune direct anti-sheep red blood cells (SRBC) PFC and immune serum antibody production to human gamma globulin (HGG) as well as susceptibility to tolerance induction by deaggregated HGG. An early decline of thymulin serum level was detected from two weeks of age both in NZB mice and F1 hybrids, the latter maintaining a level intermediate between that of both parental strains. Such a fall of circulating thymulin was associated to a decreased number of thymulin-secreting cells. F1 hybrids and NZB mice exhibited at two and three weeks of age spontaneous anti-TNP PFC in the spleen, and increased IgM serum levels as compared to DBA/2 mice. When immunized at birth with SRBC or at two weeks of age with HGG, NZB mice and F1 mice similarly exhibited a higher anti-SRBC antibody response, as measured 5 days later by PFC numbers, and a higher anti-HGG serum antibody production 2 weeks post-immunization, than age-matched DBA/2 mice. F1 hybrids tended to develop with age spontaneous and immune antibody responses lower than NZB mice but still much higher than DBA/2 mice. Conversely, after tolerization at birth with deaggregated HGG NZB mice but not the F1 hybrids produced higher titers of anti-HGG antibodies upon challenge than similarly tolerized DBA/2 mice. DBA/2 mothered and NZB mothered F1 hybrids did not differ for any parameter tested and no influence of the sex could be detected.

Topics: Animals; Antibody Formation; Autoimmune Diseases; Erythrocytes; Heterozygote; Immune Tolerance; Immunoglobulin M; Mice; Mice, Inbred NZB; T-Lymphocytes; Thymic Factor, Circulating; Thymus Gland; Trinitrobenzenes

We analysed the effect of nandrolone decanoate (ND) on functional and quantitative changes in immune cell populations, on survival, and on autoantibody production of female New Zealand Black (NZB) mice. Our results confirmed that, with increasing age, untreated NZB mice display a lower natural killer (NK) cell activity, an impaired T-cell function as evidenced by a reduced mitogen lymphoproliferative response, IL-2 production and generation of cytotoxic lymphocytes, a lower level of thymic serum factor (TSF), a reduced percentage of Thy-1+ cells; we also observed an increased incidence of mice with abnormally high levels of anti-DNA in the serum. In addition, we demonstrated an important defect in the IL-1 production by LPS-stimulated macrophages. ND administered to female NZB mice increased the survival time of the animals and reduced the anti-DNA titres. This favourable effect was associated with improved immune responses, especially those mediated by T cells; these included increased IL-2 production, complete recovery of cytotoxic T lymphocytes (CTL), a significant augmentation of the percentage of Lyt-2+ cells and enhanced TSF level. Moreover IL-1 production by macrophages returned to normal. These results suggest that ND acts on T-cell differentiation, either by a direct effect on thymic epithelial cells resulting in an increased TSF release, and/or via macrophage regulatory activity. The protective effect of ND may also be attributed in part to the higher number of Lyt-2+ (suppressor) T cells present in the spleen after treatment.

Topics: Aging; Animals; Antibodies, Antinuclear; Autoimmune Diseases; Cytotoxicity, Immunologic; DNA; Female; Interleukin-1; Interleukin-2; Killer Cells, Natural; Mice; Mice, Inbred NZB; Nandrolone; Nandrolone Decanoate; T-Lymphocytes, Cytotoxic; Thymic Factor, Circulating

Topics: Antibody Formation; Autoimmune Diseases; Cells, Cultured; Cytotoxicity, Immunologic; Humans; Killer Cells, Natural; Platelet Aggregation; Thymic Factor, Circulating; Thymosin; Thymus Hormones

In this study we have evaluated the action of two compounds, cyclosporin A (Cy A) and thymulin (FTS-Zn) in old (NZB X NZW) F1 male mice which develop severe autoimmune disease. Compared with control mice, thymulin and Cy A treated mice already showed by 2 weeks a dramatic diminution of their anti-DNA antibody level which remained low throughout the treatment period and persisted for 7 weeks afterwards. Renal specimens were studied by direct immunofluorescence in Cy A and thymulin treated mice. Glomerular deposits were decreased compared with control mice; these differences were particularly clearcut for IgG1 and IgG2 deposits. Finally, thymulin (FTS-Zn) and Cy A appeared to induce the same improvement of DNA titres and glomerulopathy in (NZB X BW) F1 mice.

Topics: Animals; Antibodies, Antinuclear; Autoimmune Diseases; Cyclosporins; DNA; Fluorescent Antibody Technique; Glomerulonephritis; Immunoglobulin G; Kidney Glomerulus; Male; Mice; Mice, Inbred NZB; Proteinuria; Thymic Factor, Circulating; Thymus Hormones

This study was concerned with the in situ localization of facteur thymique sérique (FTS) by immunoelectron microscopy in the thymus of normal C57BL mice and aged auto-immune SWAN mice. Normal young mice have anti-FTS antibodies fixed specifically on the floccular material present in the cytoplasmic vacuoles of epithelial cortical and medullary cells. In aged auto-immune SWAN mice the anti-FTS antibodies show an activity only in the granules present in the vacuoles or free in the cytoplasm of epithelial cells. The floccular material is not labelled by the same antibodies. FTS positive granules show a repetitive structure which is characteristic of crystalline protein formations. The presence of FTS in the granules of cells confirm the hypothesis of FTS storage in the cytoplasm of epithelial cells in vivo during the auto-immune process.

Topics: Animals; Antibodies; Autoimmune Diseases; Epithelium; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Rabbits; Thymic Factor, Circulating; Thymus Gland; Thymus Hormones; Vacuoles

Topics: Animals; Anti-Inflammatory Agents; Antibody Formation; Antibody-Producing Cells; Autoimmune Diseases; Disease Models, Animal; Female; Immunity, Cellular; Immunosuppressive Agents; Kidney Diseases; Lymphocyte Activation; Male; Mice; Mice, Inbred NZB; T-Lymphocytes; Thymic Factor, Circulating; Thymus Gland; Transplantation, Isogeneic

Topics: Animals; Autoimmune Diseases; Female; Fetus; Hematopoietic Stem Cells; Liver; Male; Mice; Mice, Inbred CBA; Pregnancy; Rosette Formation; Spleen; Thymic Factor, Circulating; Thymus Gland; Yolk Sac

Mice from three different strains (NZB, B/W, and Swan) which spontaneously develop a lupus-like disease and show a premature decline of their secretion of the circulating thymic factor, Facteur Thymique Sérique (FTS), were treated repeatedly with FTS and followed for the evolution of their autoimmune disease. The autoimmune sialoadenoitis (Sjögren's syndrome) appearing in NZB and B/W mice, evaluated here by a scintigraphic method, was completely prevented or even cured by FTS treatment. The increase in anti-erythrocyte autoantibody production was transiently delayed in aged NZB mice. Conversely, antiDNA antibody production either remained unaffected or was accelerated (in B/W mice) by FTS treatment. These results demonstrate that the restoration of the failing thymic secretion does influence autoantibody production, in a manner depending primarily on the autoantigen eliciting the autoimmune response. However, caution is urged in the application of this approach to human lupus without further studies.

Topics: Age Factors; Animals; Autoantibodies; Autoimmune Diseases; DNA; Erythrocytes; Female; Hormones; Mice; Mice, Inbred C57BL; Mice, Inbred NZB; Sjogren's Syndrome; Thymic Factor, Circulating; Thymus Hormones; Time Factors

Topics: Animals; Autoantibodies; Autoimmune Diseases; Cytotoxicity, Immunologic; Female; Fetus; Immune Tolerance; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Pregnancy; Rosette Formation; Spleen; T-Lymphocytes; Thymic Factor, Circulating; Thymus Gland; Thymus Hormones