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Biomedical subjects

A L Goldstein

Publications and source records attributed to A L Goldstein.

At least 127 records · Page 7Linked to original sources
PubMed1985

Heterogeneity and age dependency of human thymus reticulo-epithelium in production of thymosin components.

The specific compartmentalization of intrathymic lymphoid cells in different steps of T-cell maturation and the involvement of thymosin components in these steps prompted us to evaluate the localization of epithelial cells synthesizing various thymosin components. Thymosin fractions 5 and 6 were found in epithelial cells throughout the thymus cortex and medulla. Thymosin alpha 1 and beta 4 were observed in subcapsular and perivascular epithelial cells, and thymosin alpha 1 was observed in the medullary epithelium. Thymosin alpha 7 was exclusively found in Hassall's corpuscles and adjacent epithelial cells. We conclude that the organ localization of epithelium synthesizing different thymosin components is associated with the organ localization of intrathymic T-cell maturation steps. The involution of the human thymus, starting during the third decade of life, has been related to the age-dependency of thymus humoral factors in the circulation. However, quantitative data on humoral factor synthesizing epithelial cells are lacking. We found a strong intensity of thymosin fraction 6 expression by epithelium in thymus tissue from donors in the early postnatal period (2-4 months of age) and from all four donors aged 20-30 years. This phenomenon was paralleled by a high number of thymosin fraction 6 positive cells per unit area.

Adolescent↗
PubMed1985

Thymosin fraction 5 causes increased serum corticosterone in rodents in vivo.

In these studies it was found that i.p. injection of thymosin fraction 5 (TF5) caused a dose-dependent increase in serum corticosterone in male Swiss Webster mice and in male Wistar rats. The maximum responses were seen at 1 and 2 hr, respectively. There was no effect on serum corticosterone in mice when Thymosin alpha 1 (a 28 amino acid peptide isolated from TF5) was injected i.p. at doses up to 100 micrograms. The steroidogenic effects of TF5 were seen only when the basal levels of serum corticosterone were low (less than 80 ng/ml). In studies in which the baseline levels in the animal colony were elevated (greater than 80 ng/ml), there were no steroidogenic effects, or they were minimal. These results suggest that some component of TF5 may influence pituitary adrenal function.

Animals↗
PubMed1985

A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer.

A randomized trial was performed in 42 postradiotherapy patients with non-small cell lung cancer to determine whether the administration of synthetic thymosin-alpha 1 by either a loading dose or a twice-weekly schedule could accelerate the reconstitution of thymic dependent immunity. The radiotherapy-induced immunosuppression was characterized by an absolute T cell lymphopenia and by impaired T cell function in lymphoproliferative assays. Placebo-treated patients did not show any improvement in T cell numbers or function over 15 weeks of serial immune monitoring, and exhibited gradual depressions of helper T lymphocyte percentages. Patients treated with thymosin by the loading dose regimen exhibited a normalization of T cell function (p = 0.04), whereas patients treated with the twice-weekly schedule maintained normal helper T cell percentages (p = 0.04). Thymosin treatment was associated with significant improvements in relapse-free and overall survival, which was most pronounced for patients with nonbulky tumors. Thymosin-alpha 1 exhibits schedule-dependent immune restorative and homeostatic properties. Large scale Phase III trials are indicated to definitively establish the impact of thymosin therapy in lung cancer patients treated with radiotherapy.

Adjuvants, Immunologic↗
PubMed1984

Immunoreactive thymosin alpha 1 is associated with murine T-cell lymphomas.

Growth of murine spontaneous and transplanted AKR T-cell lymphomas results in marked elevations of serum immunoreactive thymosin alpha 1. Thymosin alpha 1 is one of the peptide hormones believed to be secreted primarily by the thymic epithelium. This elevation, however, is not mediated by the thymus but rather, seems to be directly associated with the tumor cells. Growth of a B-cell lymphoma does not generate elevated immunoreactive thymosin alpha 1 in the serum, thus, a thymosin alpha 1-like peptide is selectively associated with these T-cell lymphomas. The possible relationship between expression of T-leukemia viruses and alpha 1 expression is discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Immunochemical studies on thymosin: radioimmunoassay of thymosin beta 4.

Thymosin beta 4, a peptide with hormonal-like properties first isolated from the thymus gland, can be measured in serum using a newly described radioimmunoassay. The radioimmunoassay utilizes an antibody raised in rabbits against synthetic thymosin beta 4 conjugated by glutaraldehyde to keyhole limpet hemocyanin. A 125I-tyrosine-C13 analogue of the biologically active C-terminal fragment is used as the radioactive tracer. The radioimmunoassay is sensitive in the nanogram range and no cross-reactivity with common serum proteins is demonstrable. High performance liquid chromatography of serum samples indicates that two thymosin beta 4 cross-reactive species are present in human serum. Levels in serum range from 450 to 1100 ng/ml and decline with age.

Amino Acid Sequence↗
PubMed1984

Specific antibody synthesis in vitro. II. Age-associated thymosin enhancement of antitetanus antibody synthesis.

A decline in T cell function accounts for many of the observed age-related deficient immune responses. Specific antibody response to many antigens requires T cell cooperation, and deficient antibody response to such antigens has been demonstrated with aging. In an effort to assess the potential reconstitutive capacity of Thymosin Fraction 5, in vitro antitetanus antibody production was measured in tetanus toxoid booster-immunized young and old volunteers. 22 young and 12 old volunteers were immunized with tetanus toxoid and plasma antitetanus antibody and in vitro lymphocyte production of antitetanus antibody was measured. Plasma antitetanus antibody response was significantly greater in the young. In vitro antitetanus antibody synthesis was negligible prior to immunization and peaked in cultures established 1 week after immunization from both young and old. When Thymosin Fraction 5 was added to the cultures, however, there was a dose-related enhancement of antibody synthesis in 7 of 10 from the group of elderly volunteers, but only 3 of 12 from the younger group. Our data indicate that specific antibody response is deficient in the elderly, but can be enhanced in vitro by thymosin. A future clinical trial of thymosin as an adjuvant to active immunization for the elderly is warranted.

Adjuvants, Immunologic↗
PubMed1984

Estrogen and thymic hormone interactions in the female mouse.

This study showed that there are relationships between thymic and adrenal/ovarian endocrine actions. A 4 mg/kg dose of thymosin fraction 5 (TSN5) advanced vaginal opening and elevated estrogen levels. Single estradiol benzoate (EB) injections decreased thymus weight and caused a transient reduction in circulating plasma levels of thymosine alpha 1 (TSN alpha 1), a peptide component of TSN5. Circulating estrogen levels were elevated when TSN alpha 1 levels were undetectable. Also, TSN alpha 1 levels decreased with age and after a prolonged athymic state. The thymus was shown to involute after a single TSN5 injection, suggesting the existence of a negative hormonal feedback on the thymus. Additionally thymectomy at 3 days of age was shown to delay vaginal opening while thymectomy at 30 days of age failed to produce any significant effect on reproductive maturation. Although much research is still needed, our results provide additional evidence of a relationship between the endocrine thymus and ovary.

Adrenal Glands↗
PubMed1984

Thymosin increases production of T-cell growth factor by normal human peripheral blood lymphocytes.

The in vitro incubation of phytohemagglutinin-stimulated peripheral blood lymphocytes with thymosin results in a marked and reproducible increase in production of T-cell growth factor, which is dose dependent and most pronounced in the first 24 hr of culture. Incubation of lymphocytes with thymosin alone failed to induce any production of T-cell growth factor. The biological activity of thymosin fraction 5 cannot be attributed to the activity of thymosin alpha 1, one of the well-characterized peptide components of fraction 5. These data provide the basis for (i) a potential mechanism for the in vivo immunorestorative effects of thymosin in primary and secondary immunodeficiencies and (ii) identification of an additional, but as yet undefined, immunoregulatory component of thymosin fraction 5.

Dose-Response Relationship, Drug↗
PubMed1984

Inverse correlation between age related abnormalities of T-cell immunity and circulating thymosin alpha 1 levels in haemophilia A.

T-cell immunity and serum levels of thymosin alpha 1, beta 2-microglobulin, circulating immune complexes, serum immunoglobulin levels, antibodies to hepatitis surface or core antigen, and to cytomegalovirus, and Epstein-Barr virus were investigated in 51 patients with haemophilia A ranging in age from 2 to 52 years. All patients had received commercial U.S. lyophilized concentrates of antihaemophilic factor (AHF). The mean helper/cytotoxic-suppressor (OKT4/OKT8) ratio of 11 pre-adolescents (1.6 +/- 0.4 SE) was not significantly different from that of age matched normal controls. In contrast, the mean OKT4/OKT8 ratios of 13 adolescent (1.2 +/- 0.2 SE) and 23 adult (0.8 +/- 0.1 SE) haemophiliacs were significantly reduced. Abnormalities of lymphocyte mitogenic responses were found only in adult haemophiliacs. Nine individuals treated with commercial U.S. prothrombin complex concentrates for antibodies directed against AHF or for haemophilia B had normal mean OKT4/OKT8 values. The mean serum thymosin alpha 1 levels for each age category was similar to that of age matched controls; however, regression analysis revealed a significant relationship between elevated thymosin alpha 1 levels and decreased OKT4/OKT8 ratios in adult haemophiliacs (P = 0.012). Although the mean serum level of beta 2-microglobulin was significantly increased in the adult haemophiliac group, there was no correlation between OKT4/OKT8 ratios and any of the other serologic parameters studied.

Adolescent↗
PubMed1984

Immunologic studies of the acquired immune deficiency syndrome: relationship of immunodeficiency to extent of disease.

Immunologic and conventional laboratory studies were done in 135 previously untreated subjects including 28 (20.7%) symptom-free homosexuals and 74 (54.8%) with ARC and 33 (24.5%) with AIDS. More than half of all patients had abnormal percentages of lymphocytes, percentages of T3+ cells, percentage and absolute number of T4+ cells, percentage of T8+ cells, T4/T8 ratio, monocyte adherence, and serum thymosin alpha 1. Most immune variables worsened with progressive disease. Low lymphocyte 5'nucleotidase increased suppressor cell activity, and impaired IL-2 and alpha interferon production and response suggest diminished mature and increased immature peripheral blood and tissue T cells. These findings suggest approaches to staging, prognostication, and treatment for AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Antibody to human T-cell leukemia virus membrane antigens, beta 2-microglobulin levels, and thymosin alpha 1 levels in hemophiliacs and their spouses.

Recently, antibodies to human T-cell leukemia virus membrane antigens (HTLV-MA) and elevated levels of beta 2-microglobulin and thymosin alpha 1 have been found with high frequency in patients with the acquired immunodeficiency syndrome. Prospective studies of asymptomatic persons at high risk for this syndrome will ascertain whether any of these findings is a predictive marker for the disease. In this study, antibodies to HTLV-MA, beta 2-microglobulin levels, and thymosin alpha 1 levels were determined for a group of asymptomatic adult hemophiliacs and their wives. Five of thirty-nine hemophiliacs had HTLV-MA antibody, compared with none of 21 wives tested. The mean beta 2-microglobulin level for hemophiliacs was significantly higher than the control value (p less than 0.001), whereas the wives had a normal mean value. The mean thymosin alpha 1 values were normal for hemophiliacs and their wives; however, 3 of 22 hemophiliacs and 1 of 16 wives had abnormally high levels. Whether any of these abnormalities correlate with subsequent development of the acquired immunodeficiency syndrome will be ascertained by longitudinal follow-up of this population.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Thymosins: structure, function and therapeutic applications.

Using a partially purified preparation, thymosin fraction 5, we have documented that thymosin can correct many of the immunological deficiencies resulting from the lack of thymosin function in animal models and in humans. Ongoing studies indicate that there is a family of biologically active peptides within fraction 5 that act on T-cell subpopulations to maintain normal immunological reactivity. Several of these peptides have been purified to homogeneity. Two peptides, thymosin alpha 1 and beta 4, have been sequenced and chemically synthesized. Thymosin fraction 5 has been used in most clinical trials reported to date, including children with immunodeficiency disease and patients with autoimmune diseases and cancer. Most recently, the National Cancer Institute has initiated a number of Phase I and Phase II clinical trials with thymosin fraction 5 and synthetic alpha 1 as part of a new Biological Response Modifier Program. Preliminary results from two of these studies look encouraging.

Amino Acid Sequence↗
PubMed1984

Suppressor cell responses in patients with rheumatoid arthritis: the effect of thymosin.

Peripheral blood lymphocytes (PBL) from patients with rheumatoid arthritis (RA) and age and sex-matched normal controls were compared in a Concanavalin A (Con A)-induced suppressor cell assay. Suppression induced by pre-incubation with Con A was significantly greater in PBL from RA patients than in PBL from normal controls. Preincubation with thymosin fraction 5, in the absence of Con A, also induced greater suppressor cell activity in PBL from normal controls. Preincubation with Con A and thymosin, simultaneously, induced suppression similar to that seen with Con A alone. These results suggest the presence of an immunoregulatory defect in RA, characterized by an excess of both Con A and thymosin-inducible suppressor cells, that may play a role in disease pathogenesis. The implications of these observations for immunotherapy of rheumatoid arthritis with thymosin are discussed.

Adult↗
PubMed1984

Restorative effects of thymosin polypeptides on purified protein derivative--dependent migration inhibition factor production by the peripheral blood lymphocytes of adult thymectomized guinea pigs.

Thymosin fraction 5 restored the capacity of peripheral blood lymphocytes (PBL) from thymectomized adult guinea pigs sensitized with purified protein derivative (PPD) to produce migration inhibition factor (MIF) as measured in an agarose droplet microassay with peritoneal exudate cells. PBL from sham-thymectomized and normal PPD-sensitized guinea pigs did not lose their capacity to make MIF in response to PPD and were unaffected by thymosin polypeptides. Splenic and lymph node lymphocytes of thymectomized guinea pigs retained their antigen responsivity , suggesting that thymectomy did not affect fully matured, localized memory cells, but caused an accumulation in the circulation of partially matured, antigen-sensitive lymphocytes that could release MIF only in the presence of thymic factors. Various thymosin polypeptides were tested in this system and only thymosin alpha 1, an acidic polypeptide of 28 amino acid residues, showed consistent activity. This polypeptide, which has a molecular weight of 3,108, did not inhibit macrophage migration by itself, but 10-1,000 ng/ml was able to completely restore the MIF-producing capability of PBL from thymectomized guinea pigs. A standardized method for pooling and cryopreserving guinea pig PBL was developed, allowing multiple assays to be performed with a single pool of cells. The specificity of this bioassay system has made it a useful tool in evaluating the thymosin alpha 1 activity present in various thymosin preparations, and in validating biological activity of thymosin alpha 1 preparations made by synthetic or recombinant DNA techniques.

Animals↗
PubMed1983

The thymus-adrenal connection: thymosin has corticotropin-releasing activity in primates.

Endotoxin-free thymosin fraction 5 elevated corticotropin, beta-endorphin, and cortisol in a dose- and time-dependent fashion when administered intravenously to prepubertal cynomolgus monkeys. Two synthetic component peptides of thymosin fraction 5 had no acute effects on pituitary function, suggesting that some other peptides in thymosin fraction 5 were responsible for its corticotropin-releasing activity. In agreement with these observations, total thymectomy of juvenile macaques was associated with decreases in plasma cortisol, corticotropin, and beta-endorphin. These findings indicate that the prepubertal primate thymus contains corticotropin-releasing activity that may contribute to a physiological immunoregulatory circuit between the developing immunological and pituitary-adrenal systems.

Adrenocorticotropic Hormone↗
PubMed1983

Isolation of thymosin alpha 1 from thymosin fraction 5 of different species by high-performance liquid chromatography.

High-performance liquid chromatography (muBondapak C18 column with 0.05% trifluoroacetic acid in acetonitrile as solvent system) was used to isolate thymosin alpha 1 (alpha 1) from thymosin fraction 5 (f5) of various species (calf, pig, sheep and mouse). Each of the f5 preparations gave a protein peak similar in retention time to bovine thymosin alpha 1. This peak coincided with the immunoreactive peak determined by a radioimmunoassay for alpha 1. Chromatographic analysis of fresh thymus tissue extracts using a high-performance liquid chromatographic similar system did not reveal a detectable protein peak or immunoreactive peak at the alpha 1 position. Our results suggest that alpha 1 may be synthesized in a precursor form in animal tissues.

Animals↗