thymalfasin and Immunologic-Deficiency-Syndromes

Thymosin alpha 1 (Ta1) is a peptide originally isolated from thymic tissue as the compound responsible for restoring immune function to thymectomized mice. Ta1 has a pleiotropic mechanism of action, affecting multiple immune cell subsets that are involved in immune suppression. Ta1 acts through Toll-like receptors in both myeloid and plasmacytoid dendritic cells, leading to activation and stimulation of signaling pathways and initiation of production of immune-related cytokines. Due to the immune stimulating effects of Ta1, the compound would be expected to show utility for treatment of immune suppression, whether related to aging or to diseases such as infection or cancer. Extensive studies in both the preclinical and clinical setting will be summarized in the subsequent sections. These studies have demonstrated improvements in immune system cell subsets and the potential of Ta1 for the treatment of a range of diseases.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Disease Models, Animal; Humans; Immunity; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Infections; Mice; Neoplasms; Thymalfasin; Thymosin; Vaccines

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: Adjuvants, Immunologic; Clinical Trials as Topic; Humans; Immunologic Deficiency Syndromes; Lung Neoplasms; Thymalfasin; Thymosin; Thymus Hormones

To investigate the immunological function of a yeast expression system for thymosin alpha1 (Talpha1).. A constructed Talpha1 yeast expression system was used to investigate the immunological function of orally administered Talpha1. Dried yeast containing three different concentration of Talpha1 was fed to normal Balb/c mice and other Balb/c mice whose immunities were inhibited in advance by cyclophosphamide. Synthesized Talpha1 peptide was used as positive control and dried yeast with empty plasmid was used as negative control. CD4(+) and CD8(+) levels were detected by flow cytometry assay. TNF-alpha, IFN-gamma, IL-2, IL-6 and IL-10 levels were detected by liquid chip.. In normal Balb/c mice or immune inhibition Balb/c mice, CD8(+) levels were significantly increased. Especially in immune inhibition Balb/c mice, CD8(+) levels in synthesized Talpha1 group (18.77%+/-4.72%), small dose group (13.48%+/-6.17%) and large dose group (22.74%+/-1.09%) were significantly higher than that in empty yeast control group (7.49%+/-2.14%).. Orally administered Talpha1 has its certain immunomodulatory function.

Topics: Administration, Oral; Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclophosphamide; Cytokines; Immunologic Deficiency Syndromes; Immunologic Factors; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Recombinant Proteins; Saccharomyces cerevisiae; Thymalfasin; Thymosin

Thymosin alpha1 is a biological response modifier that has been used clinically for the treatment of chronic hepatitis B viral infection. Both immunomodulatory and immediate intracellular mechanisms have been postulated to explain the effect of thymosin alpha1 on hepatocytes infected with hepatitis B virus (HBV). Here, we established a new animal model and the related suitable conditions to access the thymosin activity by means of measuring the production of neutralizing antibody against hepatitis B surface antigen (HBsAg). We proved that chemically synthesized thymosin alpha1 restored the T cell-mediated antibody production following its suppression in mice by 5-fluorouracil (5-FU), and found that thymosin alpha1 showed activity at a low dose of 30 microg/kg. Further studies utilizing the flowcytometric analysis showed that thymosin alpha1 at this dose accelerated the replenishment and maturation of thymocytes while the expression of Smoothened (Smo) of the Hedgehog (Hh)-signaling in CD4-CD8- thymocytes, the potent negative regulator of proliferative responses, was not affected. The restoration of some of the defects in the host defense systems may facilitate elimination of infectious agents, and the present study provides a novel model to define the restoration of T cell-mediated immune responses to hepatitis B virus in vivo.

Topics: Adjuvants, Immunologic; Animals; CD4-CD8 Ratio; Cyclophosphamide; Female; Flow Cytometry; Fluorouracil; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Mice; Mice, Inbred C3H; Organ Size; Stimulation, Chemical; T-Lymphocytes; Thymalfasin; Thymosin; Thymus Gland

In patients with primary immunodeficiencies the role of natural killer (NK)- and lymphokine (IL-2)-activated killer (LAK)-cells is not yet satisfactorily established. Using a clonogenic assay with K562 leukemia target cells, we studied their NK- and LAK-cell activity in vitro. Moreover, the effect of thymosin alpha 1 (T alpha 1) on LAK-cell activity was studied in 11 patients with different immunodeficiencies. The results were compared with data of healthy controls (n = 11) and cord blood samples (n = 6). Common variable immunodeficiency patients demonstrated a mean LAK-cell activity of about 65% of normal controls and cord blood samples. The moderately reduced LAK-cell activity was not affected by T alpha 1. In the immunodeficient other patients, low levels of LAK-cell activity with a mean value of 10% of normal controls were seen. The mean LAK-cell activity could be improved by T alpha 1: three patients showed an improvement of their LAK-cell activity up to 25-30% after T alpha 1 administration in vitro, but in one case T alpha 1 was without any effect. Analysis of the expression of the surface markers CD8, CD16, CD57 and CD8/CD57 revealed that only CD16 positive lymphocytes were significantly less in immunodeficient patients. We found a linear correlation between LAK-cell activity and CD8/CD57 double positive lymphocytes in all patients. Our results demonstrate that suppressed LAK-cell activity from immunodeficient patients can be individually improved by T alpha 1. Further in vivo studies should evaluate thymic peptide immunotherapy for individual immunodeficient patients.

Topics: Adolescent; Adult; Antigens, CD; Child; Fetal Blood; Humans; Immunologic Deficiency Syndromes; Killer Cells, Lymphokine-Activated; Thymalfasin; Thymosin

Immunodeficient ageing (C57BL/10 x DBA/2)F1 mice were treated by a single injection of synthetic thymic hormones and 4 days later their thymus and spleen cells were assayed in vitro for T cell activities. A few nanograms of THF-gamma 2 were found to raise the frequency of mitogen-responsive T cells in thymus and spleen cell populations as well as the frequency of cytokine-producing splenic T cells, up to the levels observed in young mice. Moreover, injection of THF-gamma 2 was found to restore T cell growth factor (TCGF) production by mitogen-stimulated spleen cells. Also, the helper activity of spleen cells was enhanced by this treatment and increased with increasing the THF-gamma 2 dose over a wide range. Similarly, the effects of thymopentin and thymosin-alpha 1 on T helper cell activity increased with increasing the injected dose, but the efficiencies of THF-gamma 2 and thymopentin were, respectively, 400-fold and eight-fold greater than that of thymosin-alpha 1.

Topics: Aging; Amino Acid Sequence; Animals; Cells, Cultured; Female; Immunologic Deficiency Syndromes; Interleukin-2; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Molecular Sequence Data; Oligopeptides; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Thymalfasin; Thymopentin; Thymosin; Thymus Hormones

Thymosin fraction 5 polypeptides beta 4 and alpha 1 were tested for their ability to affect certain immunological parameters of human peripheral blood lymphocytes (PBL). PBL were cultured with various concentrations of the peptides for 24 hours. Thymosin beta 4 was found to induce a significant decrease in the expression of the Fc alpha receptors of PBL, as well as in their ability to express antibody dependent cellular cytotoxic (ADCC) activity. In addition, this peptide had the ability to increase the percentage of T4 lymphocytes in normal and immunosuppressed donors and to decrease the percentage of T8 positive cells in normal donors. Finally, beta 4 peptide caused a small increase in the capacity of peripheral blood lymphocytes to form sheep red blood cell (SRBC) rosettes (ER). In parallel experiments thymosin alpha 1 was found inactive. The results presented here indicate that thymosin beta 4 may be used as an immunoregulatory molecule in patients with immunodeficiencies.

Topics: Adjuvants, Immunologic; Antibody-Dependent Cell Cytotoxicity; Humans; Immunologic Deficiency Syndromes; In Vitro Techniques; Lymphocytes; Receptors, Fc; Receptors, IgG; Rosette Formation; T-Lymphocytes; Thymalfasin; Thymosin

A Hispanic infant girl with DiGeorge syndrome underwent successful bone marrow transplantation (BMT) at age 28 1/2 weeks. She had typical facies, a cardiac defect, hypoparathyroidism, severe T and B cell immunodeficiency, and low levels of facteur thymique serique (FTS). In vitro incubation of the peripheral blood lymphocytes with thymosin alpha 1 showed no increase in the number of T cells on two occasions. A fetal thymus for transplantation was not available, and further review of past experience with thymic cells or factors revealed inconsistent and incomplete responses. Because of the patient's worsening clinical and immunologic status, BMT was performed, with her histocompatible brother as donor. The patient has had a good clinical and immunologic response to BMT, with evidence of T cell engraftment, improved B cell function, and increased levels of serum FTS. This experience indicates that minimal thymic influence is necessary for successful BMT and that patients with DiGeorge syndrome with significant T cell deficiency may benefit from this treatment.

Topics: Adult; Age Factors; B-Lymphocytes; Bone Marrow; Bone Marrow Transplantation; DiGeorge Syndrome; Evaluation Studies as Topic; Female; Humans; Immunoglobulin G; Immunologic Deficiency Syndromes; Infant, Newborn; Leukocyte Count; Male; T-Lymphocytes; Thymalfasin; Thymic Factor, Circulating; Thymosin

Immunodeficient dwarfism in Weimaraner dogs was characterized by failure to grow, emaciation, growth hormone (GH) deficiency, decreased lymphocyte blastogenic responsiveness to mitogens, lack of thymus cortex, and recurrent infections usually resulting in death. Affected pups did not respond to conventional supportive therapy, but did respond to treatment with thymosin fraction 5. Response to therapy with bovine GH was monitored by clinical observation, histopathologic examination of thymic biopsy material, lymphocyte blastogenic responsiveness to nonspecific mitogens, and radioimmunoassay of thymosin alpha 1 concentration in the serum. Growth hormone therapy (0.1 mg/kg of body weight/dose, 14 doses) during a 1-month period in 2 immunodeficient dwarf pups resulted in clinical improvement and a marked increase in the thickness and cellularity of the cortex of the thymus. Immunodeficient dwarf pups were not deficient in serum thymosin alpha 1 before GH therapy. Growth hormone therapy was not associated with a consistent increase in serum thymosin alpha 1 concentration or lymphocyte blastogenic responsiveness to mitogens.

Topics: Animals; Dog Diseases; Dogs; Dwarfism; Female; Growth Hormone; Immunologic Deficiency Syndromes; Lymphocyte Activation; Thymalfasin; Thymosin; Thymus Gland

Topics: Adult; Homosexuality; Humans; Immunologic Deficiency Syndromes; Infections; Male; Sarcoma, Kaposi; Thymalfasin; Thymosin; Thymus Hormones