Papers by Allan Goldstein
Lymphokine research, 1989
Incubation of human peripheral blood monocytes (PBM) with a partially purified thymic preparation... more Incubation of human peripheral blood monocytes (PBM) with a partially purified thymic preparation, thymosin fraction (TF5), results in a dose dependent production of an interleukin-1 (IL-1)-like factor. The biological activity of this factor can be blocked by anti-IL-1 alpha, but not by anti-IL-1 beta which neutralizes bacterial induced IL-1 activity. Studies with further purified TF5 fractions show that this activity is not due to the well-characterized peptide, thymosin alpha 1 (T alpha 1), but rather a new thymosin peptide(s) isolated from a more basic fraction. Intraperitoneal injection of TF5 also induces the expression of a membrane-bound IL-1 (mIL-1) on mouse peritoneal cells. This study provides the first evidence that TF5 can influence macrophage activity directly by enhancing IL-1 production. This observation may help explain the mechanism by which TF5 modulates immune responses. These results also point to a more selective role for thymic hormones, growth factors and cyto...
Proceedings of the National Academy of Sciences, 1992
Thymosin beta 4 (beta 4) is a 5-kDa polypeptide originally identified in calf thymus. Although nu... more Thymosin beta 4 (beta 4) is a 5-kDa polypeptide originally identified in calf thymus. Although numerous activities have been attributed to beta 4, its physiological role remains elusive. Recently, beta 4 was found to bind actin in human platelet extracts and to inhibit actin polymerization in vitro, raising the possibility that it may be a physiological regulator of actin assembly. To examine this potential function, we have increased the cellular beta 4 concentration by microinjecting synthetic beta 4 into living epithelial cells and fibroblasts. The injection induced a diminution of stress fibers and a dose-dependent depolymerization of actin filaments as indicated by quantitative image analysis of phalloidin binding. Our results show that beta 4 is a potent regulator of actin assembly in living cells.
The Journal of Immunology
Prior scanning electron microscope studies have indicated that T (thymus derived) lymphocytes app... more Prior scanning electron microscope studies have indicated that T (thymus derived) lymphocytes appear “smooth” while human B (thymus independent) lymphocytes appear “hairy” with numerous microvilli covering their surfaces. A recent report (24) has raised some doubt as to the validity of classifying lymphocyte subpopulations on this purely morphologic basis. We have examined lymphocytes taken from congenitally athymic “nude” mice (lacking T cells) and compared them with those taken from normal littermates and CBA/J mice (both having T cell populations). We have determined that there are no distinguishable differences between teh distribution of surface morphologies of lymphocytes from animals either with or without T cells. Our studies indicate that the classification of T and B cells, based on cell surface features, requires more than just finding out whether or not the cells are smooth or hairy.
The Journal of Immunology
Evidence is presented that T cell impairment appears to be specifically related to the pathogenes... more Evidence is presented that T cell impairment appears to be specifically related to the pathogenesis of experimental amyloidosis. This conclusion is based on the finding that thymosin administration improves T cell function as measured by mitogen stimulation of spleen cell suspension and at the same time reduces the incidence and severity of amyloid disease in casein-treated mice.
Proceedings of the National Academy of Sciences, 1986
The expression of interleukin 2 receptors (IL-2R) is a critical step leading to normal lymphocyte... more The expression of interleukin 2 receptors (IL-2R) is a critical step leading to normal lymphocyte proliferation. Since thymosin fraction 5 (TF5), a thymic hormone preparation, enhances lymphoproliferative responses of human cells, we examined the effects of TF5 on the expression of IL-2R on mitogen-stimulated human lymphocytes. TF5 significantly increased the percentage and antigen density of cells expressing IL-2R after stimulation with an optimal concentration of phytohemagglutinin (PHA) when the cells from the same donor exhibited suboptimal responses to PHA alone. The same effect was observed with a suboptimal PHA concentration and with OKT3 monoclonal antibody stimulation. Thymosin alpha 1, a synthetic polypeptide originally isolated in its native form from TF5, was also able to increase IL-2R expression in response to PHA, suggesting that it is the active species in TF5. The enhancement of IL-2R expression was paralleled by increased proliferative responses. Increased IL-2R ex...
Nature medicine, 2017
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembran... more Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that f...
Clinical Immunology Newsletter, 1983
Clinical Immunology and Immunopathology, 1979
The in vitro effect of thymosin fraction 5, a thymic gland extract, on thymus-dependent lymphocyt... more The in vitro effect of thymosin fraction 5, a thymic gland extract, on thymus-dependent lymphocytes was studied in 12 patients with alcoholic hepatitis (AH) and in 18 patients with compensated alcoholic cirrhosis (CAC). The baseline number and proportion of spontaneous rosette-forming T lymphocytes were significantly reduced in AH as compared to the controls. No such decrease was seen in CAC. When the lymphocytes of patients with AH were incubated in the presence of thymosin fraction 5, the subsequent number and proportion of rosette-forming T lymphocytes showed a significant increase. There was no significant reponse to thymosin in CAC or in control subjects. There appears to be a subset of immature T lymphocytes in patients with AH that is responsive to exogenous thymic factors with subsequent activation of the capacity to form spontaneous rosettes.
ngiogenesis involves endothelial cell attachment; base- ment membrane degradation; and synthesis,... more ngiogenesis involves endothelial cell attachment; base- ment membrane degradation; and synthesis, migration, and proliferation. Because of the importance of angio- genesis in tissue formation, wound healing, and in pathologic con- ditions such as cancer, Wegener's granuloma, Takayasu's arteritis, systemic lupus erythematosus, and other autoimmune diseases, identification of factors influencing blood vessel formation is of major importance. We previously found that
Journal of immunology (Baltimore, Md. : 1950), 1979
The responses of lymphoid cells from the thymus, lymph nodes, and spleen of male and female BALB/... more The responses of lymphoid cells from the thymus, lymph nodes, and spleen of male and female BALB/c mice were evaluated to determine if sex-related variations in immune expression could be found. Immunologic assays used included blastogenic responses to mitogens, mixed lymphocyte responses, and direct and indirect measurement of plaque-forming cells against soluble and particulate antigens. The results indicated that responses of spleen cells from young adult female mice were higher than those of males in all comparative tests. Little or no differences between the sexes were observed in the mitogenesis of lymph nodes and thymuses. Newborn mice did not demonstrate the sex-associated immune differences. Among the weanling mice slight differences between male and female spleen cells responsiveness to mitogenic agents were observed.
Proceedings of the 1980 Laurentian Hormone Conference, 1981
Publisher Summary This chapter discusses the current status of the chemistry, biology, and clinic... more Publisher Summary This chapter discusses the current status of the chemistry, biology, and clinical applications of the well-defined thymic hormones. The first biologically active polypeptide to be isolated from among the highly acidic components of bovine thymosin fraction 5 has been termed thymosin α1. This peptide is highly active in amplifying T-cell immunity and is active in modulating the expression of terminal deoxynucleotidyl transferase. The ultimate application of the thymosins and other thymic hormones and factors in cancer treatment should be in providing a means of safely augmenting specific T lymphocyte functions in patients with diminished thymic-dependent immunity. In anergic cancer patients, thymic hormones may be of importance as an adjunct to conventional treatments by increasing T-cell function in response not only to tumor cells but also to pathogens, thus reducing the high incidence of infection that often accompanies cancer treatment.
Scandinavian Journal of Immunology, 1996
The adjuvant properties of Montanide CSA 720 were assessed in a comparison with alum. BALB/c mice... more The adjuvant properties of Montanide CSA 720 were assessed in a comparison with alum. BALB/c mice were immunized with recombinant HIV-1 gag protein p17 administered in either of the two adjuvants. The serum antibody response to p17 with Montanide CSA 720 appeared faster and reached a higher titre than with alum. The serum antibody response to p17 in Montanide CSA 720 was further characterized by a higher titre antibody directed against a 30 amino acid segment from the entire protein. The Montanide CSA 720 adjuvant was sufficiently strong to induce an antibody response against a weak synthetic peptide immunogen after two immunizations, while immunization with the peptide in alum generated no detectable serum antibody. The p17-specific proliferative response of splenocytes from animals immunized with recombinant protein in either adjuvant was similar.
Proceedings of the National Academy of Sciences, 1974
New Zealand Black (NZB) mice develop after 16 weeks of age an autoimmune and lymphoproliferative ... more New Zealand Black (NZB) mice develop after 16 weeks of age an autoimmune and lymphoproliferative disease which is a model for systemic lupus erythematosus and lymphoid malignancy in humans. At this age, the mice manifest a progressive decline in T lymphocyte (thymus-derived lymphocyte) functions and serum thymosin levels. Thymocytes from 8-week old NZB mice exhibit an abnormal DNA synthetic response when transplanted into lethally irradiated C57B1/6 recipients. DNA synthesis (measured as the incorporation of radioactively labeled 5-iodo-2′-deoxyuridine) is delayed in onset and still increasing 6 days after cell transfer. By contrast, 2-week old NZB thymocytes show a normal response which is rapid in onset and completed by day 6. NZB mice were injected with thymosin fraction 5 or with bovine serum albumin starting at 2 weeks of age. Thymocytes from 8-week old thymosin-treated mice showed a normal DNA synthetic response, whereas the albumin-treated controls showed the abnormal respons...
Proceedings of the National Academy of Sciences, 1981
Thymosin (fraction 5 and synthetic alpha 1 peptide) induced prothymocytes in mouse bone marrow an... more Thymosin (fraction 5 and synthetic alpha 1 peptide) induced prothymocytes in mouse bone marrow and spleen to express terminal deoxynucleotidyl transferase (TdT; DNA nucleotidylexotransferase; nucleosidetriphosphate:DNA deoxynucleotidylexotransferase, EC 2.7.7.31) or Lyt-1+, 2+, 3+ alloantigens (or both) after brief incubation in vitro. Three antigenic phenotypes were generated: (i) TdT+ Lyt+, (ii) TdT- Lyt+, and (iii) TdT+ Lyt-. The TdT+ Lyt+ phenotype was expressed by 80% of prothymocytes in bone marrow and 30% of prothymocytes in spleen from normal mice. The TdT- Lyt+ phenotype was expressed by 81% of prothymocytes in bone marrow from athymic mice. More than 80% of TdT+ bone marrow cells from normal and athymic mice expressed Lyt antigens after thymosin treatment. We interpret these observations as suggesting that (i) most TdT+ hemopoietic cells in normal and athymic mice are thymocyte progenitors; (ii) two independent lineages of prothymocytes exist, one that expresses TdT and an...
Proceedings of the National Academy of Sciences, 1970
Cells with the ability to recognize self antigens have been demonstrated in the thymus of the neo... more Cells with the ability to recognize self antigens have been demonstrated in the thymus of the neonatal mouse. The detection of these cells is based upon a newly described in vitro phenomenon termed the isogeneic lymphocyte interaction. This interaction is demonstrable by [ 14 C]thymidine uptake in cultures containing mixtures of neonatal thymus cells and adult spleen cells from the CBA strain of mice. The response observed in these mixtures has been shown to be almost entirely due to thymic cell proliferation. Other isogeneic lymphoid cells cannot replace adult spleen cells. Thymic isogeneic lymphocyte interaction activity increases sharply after birth, begins to decline within the first week of life and is lost by adulthood. It is suggested that the isogeneic lymphocyte interaction may represent an in vitro model for cognitory and discriminatory cellular events occurring routinely in vivo .
Proceedings of the National Academy of Sciences, 1967
Proceedings of the National Academy of Sciences, 1966
In recent years, investigations involving thymic ablation and replacement by thymic grafts or ext... more In recent years, investigations involving thymic ablation and replacement by thymic grafts or extracts in several species have suggested a central role for the thymus gland in the maturation, proliferation, and immunological competence of the lymphocyte.1 Two major types of observations imply that the influence of the thymus is in part endocrine. The first is the in vivo effect of thymic extracts on lymphopoiesis, lymphocytosis, and immunological competence;2-ll the second is the effect of thymus grafts, enclosed in cell-impermeable Millipore diffusion chambers, on thymectomized animals.12-'4 Previous attempts to isolate and purify "thymic hormones" have been hampered by the lack of a satisfactory, rapid assay method. In two earlier publications, Klein, Goldstein, and White10' 11 have described the preparation of thymic extracts and an in vivo method for testing their biological activity. In this communication, we wish to report the preparation and partial purification from calf thymic tissue of a product which stimulates incorporation of H3-thymidine into mesenteric lymph node cells. The lymphocytopoietic factor, which we term thymosin, is active when administered in vivo, as well as when added directly to a lymphocyte suspension incubated in vitro. This in vitro activity has permitted the development of a new assay procedure for thymosin and has facilitated purification studies. Materials.-Animals: Used for the in vitro and in vivo experiments were 29-day-old male Swiss Webster CD1 mice, 8-10-week-old male Sprague-Dawley rats, and 8-10-week-old male New Zealand white rabbits. All animals received food and water ad libitum until sacrificed. Radioactive precursors: H3-thymidine (3.0 c/mmole) and H3-deoxycytidine (2.4 c/mmole) were purchased from Schwarz BioResearch, Inc. H3-uridine (1.8 c/mmole), C'4-lysine (222 mc/mmole), C'4-leucine (223 mc/mmole), and CL4-phenylalanine (333 mc/mmole) were purchased from New England Nuclear. Chemicals and reagents: Trypsin (2 X crystallized, salt-free), soybean trypsin inhibitor (5 X crystallized), RNase (5 X crystallized), bovine serum albumin, and the nucleosides used were all purchased from Nutritional Biochemicals Corp. Phytohemagglutinin in a powdered form was obtained from the Burroughs Wellcome Co. Pooled calf serum (sterile and filtered) was purchased from the Pentex Corp. Eagle's medium for spinner cultures (MEM, without phosphate and calcium) was purchased in powdered form from General Biochemical Corp. Phosphate was added to the powder during preparation of the medium. Bio-Gel P-10 (50-150 mesh) was purchased from Bio-Rad Laboratories. All other chemicals used in this study were of analytical or reagent grade and were used without further purification. Fractionation procedure: Figure 1 presents a diagram of the fractionation procedure. Fresh or frozen calf thymus, obtained from a local abattoir, was cleaned, defatted, and homogenized in 0.15 M NaCl (tissue: saline = 1:3) at 0-50C in a Waring Blendor. All isolation procedures were carried out in the cold. The homogenate was centrifuged at 1200 X g in an International refrigerated centrifuge at 0-50C for 15 min. The supernatant fluid was then centrifuged at 105,000 X g in a Spinco model L ultracentrifuge for 1 hr. The supernatant fluid was passed through glass wool to remove floating particulate material. The clear extract (fraction 1) was then treated by either of two procedures. In method 1, developed initially, the solution was added slowly with * This investigation was aided by grants from the Life Insurance Medical Research Fund (G-64-67), the American Cancer Society (P-68-G), the National Science Foundation (GB-2711), and the National Cancer Institute, National Institutes of Health, USPHS (CA-07470-03). t Supported by training grant provided by the USPHS (5T1-GM-563-05).
Proceedings of the National Academy of Sciences, 1965
Journal of Investigative Dermatology, 1999
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Papers by Allan Goldstein