TB-500 vs Thymosin Alpha-1
TB-500 and thymosin alpha-1 share a prefix and very little else. Thymosin alpha-1, generic name thymalfasin, is a 28-amino-acid peptide derived from prothymosin alpha, registered as a prescription immunomodulator in a number of countries and studied in more than thirty controlled human trials. TB-500 is the synthetic Ac-LKKTETQ fragment marketed as an analogue of thymosin beta-4, a 43-amino-acid actin-sequestering peptide. Both parent peptides were isolated from the same crude bovine thymus preparation, thymosin fraction 5, which is why a substantial older literature applies or measures the two side by side. Direct evidence therefore exists, unusually for this category: experiments have tested both in chick chorioallantoic membrane angiogenesis, human colonic lymphocytes, human monocyte-derived dendritic cells, rat glioma and spleen cultures, human sperm and rat hypothalamic tissue. Every one of them used full-length thymosin beta-4 rather than the seven-residue fragment sold as TB-500, and the most recent was published in 2007.
They have been compared directly.
Direct evidence exists, with two limits that govern how far it reaches. Every experiment used full-length thymosin beta-4 rather than the Ac-LKKTETQ fragment sold as TB-500, and all of it is in vitro or ex vivo immunology and endocrinology published between 1981 and 2007. Where the two peptides were applied to the same system, the results usually diverged. In the human mixed lymphocyte reaction thymosin alpha-1 enhanced both allogeneic and autologous proliferation while thymosin beta-4 suppressed it. On human monocyte-derived dendritic cells thymosin alpha-1 upregulated CD40, CD80 and MHC class I and II while thymosin beta-4 produced none of those effects. On human peripheral blood lymphocytes thymosin beta-4 reduced Fc alpha receptor expression and antibody-dependent cellular cytotoxicity while thymosin alpha-1 was inactive. Thymosin beta-4, but not thymosin alpha-1, stimulated luteinizing hormone-releasing factor secretion from superfused rat hypothalami, and thymosin alpha-1, but not thymosin beta-4, increased human sperm penetration rates. Both peptides converged in a small number of experiments: both potentiated the antigen-presenting capacity of macrophages, both suppressed thymidine incorporation into human colonic lamina propria lymphocytes, and both enhanced angiogenesis in the chick chorioallantoic membrane. Several assays returned nothing for either peptide, including interleukin-6 release from rat glioma and spleen cells and direct adrenal corticosteroid production. The remainder of the literature that engages both consists of radioimmunoassay and ELISA studies of endogenous serum concentrations in humans, cattle, pigs, rats and monkeys, immunohistochemical localisation in brain and thymus, structural and mass-spectrometric characterisation, and thymosin-family reviews. No study in this group examined tissue repair, and none reported a clinical endpoint in patients.
The 51 studies that tested both
- 01Animal in vivo2001
Effect of thymosin peptides on the chick chorioallantoic membrane angiogenesis model
Koutrafouri V, et al. · Biochim Biophys Acta · chick chorioallantoic membrane in vivo angiogenesis assay; prothymosin alpha, thymosin alpha-1, parathymosin alpha, thymosin beta-4, thymosin beta-10 and thymosin beta-9 applied in parallel, with phorbol ester and hydrocortisone as positive and negative controls
Thymosin beta-4, prothymosin alpha and thymosin alpha-1 enhanced angiogenesis, while thymosin beta-10, thymosin beta-9 and parathymosin alpha inhibited it. When mixtures of thymosin beta-4 and thymosin beta-10 were applied together, the promoting effect of thymosin beta-4 was reduced. The beta-thymosin tested was the full-length peptide, not the TB-500 fragment.
- 02In vitro1990
Thymosin alpha 1 and thymosin beta 4 modulate human colonic lamina propria lymphocyte function
Elitsur Y, et al. · Immunopharmacology · lamina propria lymphocytes isolated from 18 human colon specimens and cultured in the presence or absence of thymosin alpha-1 and thymosin beta-4
Both peptides suppressed thymidine incorporation into lamina propria lymphocytes. Neither altered thymidine incorporation in cells stimulated with phorbol ester and ionomycin, and neither altered ornithine decarboxylase activity in concanavalin A-stimulated cells. The authors suggested that protein kinase C rather than calcium flux or the ornithine decarboxylase pathway might be involved.
- 03In vitro2007
Thymosin-alpha1 modulates dendritic cell differentiation and functional maturation from human peripheral blood CD14+ monocytes
Yao Q, et al. · Immunol Lett · human peripheral blood CD14-positive monocytes purified by magnetic separation and differentiated into immature dendritic cells with GM-CSF and interleukin-4, then exposed to thymosin alpha-1, thymosin beta-4 or thymosin beta-10
Thymosin alpha-1 significantly upregulated CD40, CD80 and MHC class I and class II molecules on immature dendritic cells and reduced antigen uptake by approximately 30 percent. Thymosin beta-4 and thymosin beta-10 did not produce these effects on the same cells.
- 04In vitro1997
A novel thymosin peptide stimulates interleukin-6 release from rat C6 glioma cells in vitro
Tijerina M, et al. · Neuroimmunomodulation · rat C6 glioma cell cultures exposed to thymosin fraction 5, to seven HPLC-derived fractions of it, and to previously purified component peptides
Thymosin fraction 5 stimulated interleukin-6 release up to nine-fold over a 24-hour incubation, but the purified peptides tested, including thymosin alpha-1 and thymosin beta-4, had no effect on interleukin-6 release at any concentration examined. The activity tracked instead to two unidentified HPLC pools.
- 05In vitro1993
Thymosin stimulates interleukin-6 production from rat spleen cells in vitro
Attia WY, et al. · Immunopharmacology · rat spleen cell cultures with and without mitogen, exposed to thymosin fraction 5 and to purified component peptides
Thymosin fraction 5 stimulated interleukin-6 production from rat spleen cells, but the previously characterised peptides thymosin alpha-1 and thymosin beta-4 had no effect on interleukin-6 production either in the absence or in the presence of mitogen.
- 06In vitro1992
Thymosin alpha-1 enhances the fertilizing capacity of human sperm cell: implication in diagnosis and treatment of male infertility
Naz RK, et al. · Biol Reprod · human sperm penetration assay and acrosome reaction assays using synthetic thymosin alpha-1, synthetic thymosin beta-4 and antibodies raised against each
Thymosin alpha-1 significantly increased human sperm penetration rates, while thymosin beta-4 did not. Antibodies to both peptides bound predominantly to the acrosomal region and increased penetration rates up to 4.7-fold. Thymosin alpha-1 and the antibodies also enhanced spontaneous and calcium ionophore-induced acrosome reaction and acrosin release.
- 07In vitro1989
Thymosins alpha 1 and beta 4 potentiate the antigen-presenting capacity of macrophages
Tzehoval E, et al. · Immunopharmacology · in vitro antigen-specific, macrophage-dependent T-cell proliferation system
Both thymosin alpha-1 and thymosin beta-4 augmented the antigen-presenting capacity of macrophages, at concentrations the authors described as well within the physiological range of activity for peptide hormones. They proposed that activation of macrophages at the time of antigen presentation may be an initial step in thymosin-mediated regulation of immune function.
- 08In vitro1987
Immunoregulatory effects of fraction 5 thymus peptides. I. Thymosin alpha 1 enhances while thymosin beta 4 suppresses the human autologous and allogeneic mixed lymphocyte reaction
Baxevanis CN, et al. · Immunopharmacology · human autologous and allogeneic mixed lymphocyte reaction, with separate assessment of T4-positive and T8-positive subpopulations, using peptides isolated from calf thymus fraction 5
Thymosin alpha-1 enhanced both the allogeneic and the autologous mixed lymphocyte reaction, whereas thymosin beta-4 suppressed proliferative responses. The enhanced response to allo- and autoantigens under thymosin alpha-1 was attributed to T4-positive helper and inducer cells rather than T8-positive cells.
- 09In vitro1987
Effect of two thymosin fraction 5 polypeptides on human peripheral blood lymphocytes
Kokkinopoulos D, et al. · Immunopharmacol Immunotoxicol · human peripheral blood lymphocytes tested for Fc alpha receptor expression, antibody-dependent cellular cytotoxicity and sheep red blood cell rosette formation
Thymosin beta-4 significantly decreased Fc alpha receptor expression and antibody-dependent cellular cytotoxic activity and slightly increased rosette formation. In parallel experiments thymosin alpha-1 was inactive on the same parameters.
- 10In vitro1986
Solid phase synthesis of thymosin beta 9
Chandramouli N, et al. · Int J Pept Protein Res · solid-phase synthesis of thymosin beta 9 followed by terminal deoxynucleotidyl transferase and rosette inhibition bioassays alongside calf thymus fraction 5 and other thymosin peptides
Synthetic thymosin beta 9 was more active than calf thymus fraction 5 in the terminal deoxynucleotidyl transferase assay and comparable to thymosin beta-4. Neither thymosin beta-4 nor thymosin beta 9 was active in the rosette inhibition assay, in contrast to thymosin alpha-1.
- 11In vitro1985
Comparison of the effects of thymosin and other thymic factors on modulation of interleukin-2 production
Zatz MM, et al. · J Biol Response Mod · in vitro interleukin-2 production assays comparing thymosin fraction 5 with purified component peptides and with other thymic factors
Thymosin fraction 5 modulated interleukin-2 production, but the authors reported that the activity was not attributable to the two well-characterised component peptides thymosin alpha-1 and thymosin beta-4, and pointed instead to a further unidentified component of the fraction.
- 12Animal in vivo1981
Modulation of terminal deoxynucleotidyl transferase activity by thymosin
Hu SK, et al. · Mol Cell Biochem · immune-suppressed mice given daily injections of thymosin fraction 5 or purified component peptides, together with in vitro incubation of normal murine thymocytes
Thymosin fraction 5 and thymosin beta 3 and beta 4 significantly increased terminal deoxynucleotidyl transferase activity in immune-suppressed mice compared with controls. In the in vitro system, thymosin fraction 5 and thymosin alpha-1 were highly active in decreasing the enzyme's activity in normal murine thymocytes after a 22-hour incubation.
- 13In vitro1981
Thymosin stimulates secretion of luteinizing hormone-releasing factor
Rebar RW, et al. · Science · superfused medial basal hypothalami from random cycling female rats, exposed to partially purified thymosin fraction 5 and to synthetic component peptides
Thymosin fraction 5 and synthetic thymosin beta-4 stimulated secretion of luteinizing hormone-releasing factor from the superfused hypothalami, whereas thymosin alpha-1 did not.
- 14In vitro1983
Thymosin peptides and lymphokines do not directly stimulate adrenal corticosteroid production in vitro
Vahouny GV, et al. · J Immunol · in vitro adrenal cell system tested with partially purified thymosin fraction 5 and with purified peptide components including thymosin alpha-1, thymosin alpha-7 and thymosin beta-4
Neither thymosin fraction 5 nor any of the purified peptide components tested, thymosin alpha-1 and thymosin beta-4 among them, had a direct steroidogenic effect on adrenal corticosteroid production in vitro.
- 15In vitro1990
Phytohemagglutin-stimulated human T cell: prothymosin alpha as an accessory signal
Cordero OJ, et al. · J Biol Regul Homeost Agents · phytohaemagglutinin-stimulated human peripheral blood mononuclear cells and purified T cells exposed to prothymosin alpha, thymosin alpha-1 and thymosin beta-4
The effects of prothymosin alpha and thymosin alpha-1 on peripheral blood mononuclear cells depended on the degree of cell stimulation, dose and preincubation time. Thymosin beta-4 had no effect on either cell type at any degree of stimulation, which led the authors to use it as a control peptide.
- 16In vitro1992
A hypothalamic activator of calmodulin-dependent enzymes is thymosin beta 4 (1-39)
Galoyan AA, et al. · Neurochem Res · purification of hypothalamic stimulators of calmodulin-dependent enzymes by reverse-phase HPLC, with identification by mass spectrometry and Edman microsequencing, tested against rabbit skeletal muscle myosin light chain kinase
The purified hypothalamic activator was identified as thymosin beta-4(1-39). Its stimulating effect on myosin light chain kinase basal activity was compared directly with that of thymosin alpha-1 and of thymosin beta-4(16-38).
- 17Human clinical1992
Serum levels of immunoreactive thymosin alpha 1 and thymosin beta 4 in large cohorts of healthy adults
Weller FE, et al. · Thymus · enzyme-linked immunosorbent assay of serum from 681 healthy adults aged 18 to 101 years
Immunoreactive thymosin alpha-1 occurred at a geometric mean of 540 pg/mL and immunoreactive thymosin beta-4 at 12.6 ng/mL. Neither differed by race or sex, and thymosin beta-4 showed a slight upward trend with increasing age. This is an assay of endogenous concentrations, and neither peptide was administered.
- 18Human clinical1993
Low periconceptional maternal serum thymosin alpha 1 levels are associated with blighted pregnancies
Kaufmann RA, et al. · Am J Reprod Immunol · serial preconceptual and first-trimester maternal serum assays by ELISA in 28 women with known ovulation dates who conceived
Thymosin alpha-1 levels in pregnancies that remained viable were significantly higher than in pregnancies that did not. Thymosin beta-4 was measured in the same samples. The study characterised endogenous concentrations of both peptides rather than administering either.
- 19Case report1993
Malignant thymoma associated with T-cell lymphocytosis. A case report with immunophenotypic and gene rearrangement analysis
Medeiros LJ, et al. · Arch Pathol Lab Med · single case of malignant thymoma with T-cell lymphocytosis, with immunophenotypic and gene rearrangement analysis and serum thymic peptide measurement
Serum thymosin alpha-1 was markedly elevated in the reported patient while thymosin beta-4 was decreased. Neither peptide was administered.
- 20Animal in vivo1991
The gonadotropin-releasing hormone agonist leuprolide affects the thymus and other non-reproductive systems of female rats
Blacker CM, et al. · Acta Endocrinol (Copenh) · female rats, including ovariectomised animals, treated with the gonadotropin-releasing hormone agonist leuprolide, with thymic and serum measurements
Thymosin alpha-1, but not thymosin beta-4, increased in leuprolide-treated ovariectomised rats. Leuprolide was the administered agent; both thymosins were measured as endogenous outcomes.
- 21Animal in vivo1989
Effect of GnRH agonists on the thymus in female rats
Ataya KM, et al. · Acta Endocrinol (Copenh) · female rats treated with gonadotropin-releasing hormone agonists, with thymic weight, organ weights and serum hormone measurements
Thymosin alpha-1 but not thymosin beta-4 increased in agonist-treated rats. Thymic weight correlated negatively with ovarian and uterine weights, relative adrenal weight, serum estradiol and luteinizing hormone, and positively with thymosin alpha-1.
- 22Animal in vivo1994
Porcine somatotropic regulation of thymic weight, thymosin beta 4, and insulin-like growth factors in lean and obese swine
Wise T, et al. · J Anim Sci · lean and obese swine, gilts and barrows, given porcine somatotropin by injection or by implant, with serial thymic and serum measurements
Thymosin beta-4 increased in a somatotropin dose-dependent manner and rose more in implanted than injected animals. Thymosin alpha-1 concentrations were higher in barrows than gilts but were unrelated to somatotropin dose. Temporal changes in thymosin beta-4 were not closely related to somatotropin, IGF-I or IGF-II.
- 23Animal in vivo1992
Developmental changes of serum thymosin alpha 1 and beta 4 in male and male castrated pigs: modulation by testosterone and human chorionic gonadotropin
Wise TH · Biol Reprod · boars and barrows followed developmentally, with human chorionic gonadotropin challenge and testosterone treatment
Thymosin beta-4 concentrations decreased with age in boars and barrows. Human chorionic gonadotropin challenge depressed thymosin alpha-1 and thymosin beta-4 in boars and thymosin beta-4 in barrows, and testosterone treatment depressed both peptides in barrows. The administered agents were gonadotropin and testosterone.
- 24Animal in vivo1991
Characterization of thymosin alpha 1 and beta 4 during the bovine estrual period: effects of elevated estradiol and progestin
Wise T, et al. · Biol Reprod · cattle sampled across the estrual period, including superovulated animals and animals with elevated estradiol and progestin
Thymosin beta-4 did not differ between control and superovulatory animals despite a tenfold increase in estradiol from the stimulated ovary. In a second experiment both thymosin beta-4 and thymosin alpha-1 increased as the estrual period progressed and decreased after the luteinizing hormone surge.
- 25Animal in vivo1990
Endocrine relationships of thymosin-alpha 1, thymosin-beta 4, and luteinizing hormone throughout the prepubertal period of development in heifers, ovariectomized heifers and ovariectomized heifers with estradiol implants
Wise T, et al. · J Reprod Immunol · control heifers (n=6), ovariectomised heifers (n=5) and ovariectomised heifers with estradiol implants (n=5), sampled through the prepubertal period from 266 days of age
Circulating thymosin alpha-1, thymosin beta-4 and luteinizing hormone were tracked to test for gonadal feedback on thymic secretion. Thymosin beta-4 concentrations did not differ between treatment groups. Estradiol implants, not the thymosins, were the administered intervention.
- 26Animal in vivo1989
Characterization of secretion of thymosin alpha 1 and thymosin beta 4 during prepuberty, estrus and pregnancy in the bovine female
Wolfe MW, et al. · Domest Anim Endocrinol · bovine females sampled during prepuberty, estrus and pregnancy
The study characterised endogenous secretion of thymosin alpha-1 and thymosin beta-4 across stages of ovarian function and pregnancy. Neither peptide was administered.
- 27Animal in vivo1991
Effects of PCB (Aroclor 1254) on non-specific immune parameters in rhesus (Macaca mulatta) monkeys
Tryphonas H, et al. · Int J Immunopharmacol · rhesus monkeys exposed to the polychlorinated biphenyl mixture Aroclor 1254, with non-specific immune parameters measured across exposure levels
A statistically significant exposure-related increase was observed for thymosin alpha-1 levels but not for thymosin beta-4 levels. The administered agent was the polychlorinated biphenyl mixture.
- 28Animal in vivo1990
Changes in circulating levels of neuroendocrine and thymic hormones during aging in rats: a correlation study
Goya RG, et al. · Exp Gerontol · young and old rats, with growth hormone, prolactin, thyrotropin and corticosterone measured in plasma and thyroid hormones and both thymosins measured in trunk serum
Growth hormone, thyroxine, thymosin alpha-1 and thymus weight showed a significant age-related reduction, whereas triiodothyronine, prolactin, corticosterone and thymosin beta-4 did not differ significantly between young and old animals.
- 29Human clinical1989
Modulation of thymosin alpha 1 and thymosin beta 4 levels and peripheral blood mononuclear cell subsets during experimental rhinovirus colds
Hsia J, et al. · Lymphokine Res · experimental rhinovirus challenge in volunteers, the first group comprising 18 subjects, with serial serum sampling and peripheral blood mononuclear cell subset analysis
Serum thymosin alpha-1 rose slightly by day 3 and significantly by day 5 after rhinovirus challenge, and serum thymosin beta-4 also rose significantly by day 5. Serum cortisol rose in parallel with thymosin alpha-1, but individual changes in the two were not directly related.
- 30Human clinical1988
Defective in vitro gamma interferon production and elevated serum immunoreactive thymosin beta 4 levels in patients with inflammatory bowel disease
Mutchnick MG, et al. · Clin Immunol Immunopathol · patients with inflammatory bowel disease and healthy controls, with in vitro gamma interferon production, T-cell subset proportions and serum thymic peptide levels measured
Serum thymosin beta-4 concentrations were significantly higher in all patient groups than in healthy controls, while serum thymosin alpha-1 levels were comparable across all study groups. Neither peptide was administered.
- 31Human clinical1986
Thymosin alpha 1 and thymosin beta 4 in serum: comparison of normal, cord, homosexual and AIDS serum
Naylor PH, et al. · Int J Immunopharmacol · radioimmunoassay of thymosin alpha-1 and thymosin beta-4 in the same serum samples across normal adults, cord blood, homosexual men and patients with AIDS
Both peptides were elevated in many individuals with AIDS, 57 percent for thymosin alpha-1 and 48 percent for thymosin beta-4. Individuals with AIDS-related immune dysfunction predominantly showed elevated thymosin alpha-1, 54 percent compared with 15 percent for thymosin beta-4.
- 32Human clinical1985
Modulation of thymosin beta 4 by estrogen
Suh BY, et al. · Am J Obstet Gynecol · radioimmunoassay of morning blood samples from 87 women in various clinical states, including premature ovarian failure, gonadal dysgenesis, castration and postmenopause
Basal thymosin alpha-1 concentrations were similar in all women sampled. Thymosin beta-4 was reduced in castrated women not receiving estrogen and reduced further in postmenopausal and castrated women on chronic estrogen therapy. Estrogen, not either thymosin, was the administered agent.
- 33Animal in vivo1990
Interleukin-2-dependent control of disease development in spontaneously diabetic BB rats
Zielasek J, et al. · Immunology · two sublines of spontaneously diabetic BB rats differing in disease development, with interleukin-2 as the administered intervention
Mean concentrations of both thymosin alpha-1 and thymosin beta-4 were between 140 and 200 percent higher in one subline than in the other. The thymosins were measured as endogenous markers rather than administered.
- 34In vitro1989
Localization of immunoreactive thymosin alpha 1 in astrocytes of normal human brain
Su YL, et al. · Ann Neurol · immunocytochemical examination of normal human brain using antiserum to thymosin alpha-1, with serial sections stained for thymosin beta-4 and glial fibrillary acidic protein in a double-staining technique
Antiserum to thymosin alpha-1 stained the cell bodies but not the processes of GFAP-positive astrocytes, while antiserum to thymosin beta-4 identified oligodendrocytes. The two peptides marked distinct cell populations in the same tissue.
- 35In vitro1986
Thymosin beta 4 is a shared antigen between lymphoid cells and oligodendrocytes of normal human brain
Dalakas MC, Trapp BD · Ann Neurol · immunohistochemical staining of normal human brain and lymphoid tissue with antisera to thymosin beta-4, thymosin alpha-1 and thymosin alpha-7
Immunoreactive thymosin beta-4 was demonstrated in the cell bodies and processes of a subset of interfascicular and satellite oligodendrocytes, and in macrophages, Langerhans cells of the skin and interdigitating cells of the thymus. Antisera to thymosin alpha-1 and thymosin alpha-7 did not react.
- 36In vitro1985
Heterogeneity and age dependency of human thymus reticulo-epithelium in production of thymosin components
Schuurman HJ, et al. · Thymus · immunohistological study of human thymus reticulo-epithelium across age groups, stained for individual thymosin components
Thymosin alpha-1 and thymosin beta-4 were both observed in subcapsular and perivascular epithelial cells, while thymosin alpha-1 alone was observed in the medullary epithelium, indicating heterogeneous production of the two peptides within one organ.
- 37In vitro1983
Demonstration of abnormalities in expression of thymic epithelial surface antigens in severe cellular immunodeficiency diseases
Haynes BF, et al. · J Immunol · thymic epithelium from three patients with severe cellular immunodeficiency diseases compared with age-matched normal thymic epithelium, using markers of human thymic epithelium and antibodies against thymosin alpha-1, thymopoietin and thymosin beta-4
Thymic epithelium from patients with severe combined immunodeficiency and Nezelof syndrome contained thymosin alpha-1, thymopoietin and thymosin beta-4 and expressed human Thy-1 antigen, while other thymic epithelial surface antigens were abnormally expressed.
- 38In vitro1987
On the molecular size of thymosins
Haritos AA, et al. · FEBS Lett · gel filtration and sedimentation equilibrium ultracentrifugation of prothymosin alpha, thymosin alpha-1 and related thymosin peptides
Prothymosin alpha and thymosin alpha-1 behaved as oligomers on gel filtration, a phenomenon previously reported for parathymosin alpha, thymosin beta-4 and thymosin beta-10. Sedimentation equilibrium ultracentrifugation showed thymosin alpha-1 to be a monomer of about 3000 relative molecular mass.
- 39In vitro2015
High-resolution mass spectrometry for thymosins detection and characterization
Cabras T, et al. · Expert Opin Biol Ther · top-down proteomic platform coupling high-performance liquid chromatography to LTQ-Orbitrap high-resolution mass spectrometry, applied to normal and pathological tissues and body fluids
Post-translational modifications of thymosin beta-4 and beta-10 were identified, including sulfoxide and lysine-acetylated derivatives and C-terminal truncated forms. Different proteoforms of prothymosin alpha, parathymosin alpha, thymosin alpha-1 and thymosin alpha-11 were characterised in the same analyses.
- 40In vitro1996
Development of specific anti-thymosin beta 10 antipeptide antibodies for application in immunochemical techniques
Leondiadis L, et al. · Peptides · synthesis of N-terminal and C-terminal fragments of thymosin beta 10 and production of antisera, tested for specificity and cross-reactivity against related thymosin peptides
All antisera raised against the thymosin beta 10 fragments or the intact molecule bound thymosin beta 10 with high specificity and showed minimal cross-reactivity with thymosin beta-4 isolated from bovine tissues or with synthetic thymosin alpha-1.
- 41Review2012
NMR structural studies of thymosin α1 and β-thymosins
Volk DE, et al. · Ann N Y Acad Sci · review of nuclear magnetic resonance structural work on thymosin alpha-1 and the beta-thymosins in different solvent environments
The report discussed current structural knowledge of thymosin alpha-1, noting its generic drug name thymalfasin, and set out similar structural properties for thymosin beta-4 and thymosin beta-9 across different environments.
- 42Review2016
Structures of Thymosin Proteins
Hoch K, Volk DE · Vitam Horm · structural biology review of prothymosin, parathymosin, thymosin alpha-1 and several beta-thymosins studied by circular dichroism, nuclear magnetic resonance and crystallography
The review described all thymosin proteins as short, highly charged and intrinsically unstructured under natural conditions, with structure inducible by charge neutralisation at low pH, zinc ions, organic reagents or interaction with natural binding partners.
- 43Review2007
beta-Thymosins
Hannappel E · Ann N Y Acad Sci · narrative review tracing thymosin beta-4 from thymic hormone candidate to actin-sequestering peptide to wound-healing cytokine
The review recorded that thymosin alpha-1, polypeptide beta-1 and thymosin beta-4 were all isolated from thymosin fraction 5 and tested for biological activity, and that none of the isolated peptides proved to be a thymic hormone. It dated the recognition of G-actin sequestration by thymosin beta-4 to 1990.
- 44Review2003
The thymosins. Prothymosin alpha, parathymosin, and beta-thymosins: structure and function
Hannappel E, Huff T · Vitam Horm · review of the thymosin field from its origin in 1965, covering the isolation of individual peptides from bovine thymosin fraction 5
The review described the isolation of polypeptide beta-1, thymosin alpha-1, prothymosin alpha, parathymosin and thymosin beta-4 from thymosin fraction 5, and concluded that none of the isolated peptides is a thymic hormone although each is a biologically important peptide with distinct intracellular and extracellular functions.
- 45Review2019
Thymosins in multiple sclerosis and its experimental models: moving from basic to clinical application
Severa M, et al. · Mult Scler Relat Disord · review of thymosin research in multiple sclerosis and its experimental models, based on a PubMed search without time constraints
The review examined thymosins as soluble hormone-like peptides that mediate immune and non-immune physiological processes and surveyed their emerging interest as therapeutics in inflammatory and autoimmune disease, covering both the alpha and beta families.
- 46Review1999
Homeostasis, thymic hormones and aging
Goya RG, Bolognani F · Gerontology · review of the thymic-pituitary axis and the immune-neuroendocrine network in relation to aging
The review collated reported activities of thymosin fraction 5, thymosin alpha-1 and thymosin beta-4 on beta-endorphin, adrenocorticotropic hormone, glucocorticoid, luteinizing hormone-releasing hormone and luteinizing hormone secretion across different animal and cell models.
- 47Review1999
The thymus-pituitary axis and its changes during aging
Goya RG, et al. · Neuroimmunomodulation · review of the bidirectional pituitary-thymic circuit and its progressive disruption with age, including the nude mouse as a model of thymus-dependent accelerated aging
The review summarised reported actions of thymosin fraction 5, thymosin alpha-1 and thymosin beta-4 on beta-endorphin, adrenocorticotropic hormone, glucocorticoid, luteinizing hormone-releasing hormone and luteinizing hormone secretion, alongside the hypophysiotropic actions of other thymic hormones.
- 48Review1985
Evidence that thymosins and other biologic response modifiers can function as neuroactive immunotransmitters
Hall NR, et al. · J Immunol · review setting out the case for thymic peptides and other biological response modifiers acting as signalling molecules between the immune and nervous systems
The paper cited thymosin alpha-1 and thymosin beta-4, alongside lymphocyte-derived adrenocorticotropic hormone, thyroid-stimulating hormone, beta-endorphin, interleukin 1 and interferon, as examples of molecules that may function as neuroactive immunotransmitters.
- 49Review1984
Thymosins: structure, function and therapeutic applications
Low TL, Goldstein AL · Thymus · review of thymosin structure, function and prospective therapeutic applications
The review recorded that two peptides of the thymosin family, thymosin alpha-1 and thymosin beta-4, had by then been sequenced and chemically synthesized, and set out the therapeutic applications under consideration at the time.
- 50Review1979
Current status of thymosin research: evidence for the existence of a family of thymic factors that control T-cell maturation
Low TL, et al. · Ann N Y Acad Sci · review of the evidence for a family of thymic factors controlling T-cell maturation, drawn from thymosin fraction 5 and its purified components
The review reported that thymosin beta 3 and beta 4 act on terminal deoxynucleotidyl transferase-negative precursor T cells to induce transferase-positive cells, while thymosin alpha-1 induces the formation of functional helper cells and the conversion of Lyt-negative cells to Lyt 1, 2 and 3 positive cells.
- 51Review2026
Peptide Therapies in Thyroid Health: Emerging Applications in Endocrine and Immune Modulation
Mazza AD · Integr Med (Encinitas) · narrative review of the mechanistic rationale for peptide interventions in thyroid biology, covering thymosin alpha-1, thymosin beta-4, BPC-157 and growth hormone secretagogues
The review reported that available data for these peptides consist primarily of preclinical investigations, mechanistic studies and early exploratory clinical reports rather than large randomised trials with thyroid-specific outcomes, that safety profiles vary across peptide classes, and that clinical use remains largely investigational.
Side by side.
| TB-500 | Thymosin Alpha-1 | |
|---|---|---|
| Evidence maturity | Early clinical | Approved drug |
| Studies cited here | 15 | 16 |
| Published 2023 or later | 8 | 11 |
| Newest paper | 2026 | 2026 |
| Sequence and origin | Synthetic seven-residue fragment, Ac-LKKTETQ, marketed as an analogue of thymosin beta-4, a 43-amino-acid endogenous actin-sequestering peptide that is widely expressed in human tissue. | A 28-amino-acid peptide derived from prothymosin alpha, originally isolated from thymic tissue and registered under the generic name thymalfasin. |
| Mechanism as described in the literature | Full-length thymosin beta-4 sequesters G-actin and promotes cell migration. Published biology also covers endothelial migration and angiogenesis, epicardial activation in cardiac repair, anti-fibrotic activity and inflammation resolution. | Acts largely through Toll-like receptor signalling on dendritic cells and monocytes, influencing T-cell differentiation, thymic output and cytokine balance. A 2026 mechanistic study described chaperoning of a microRNA ligand of TLR7. |
| Shared history in the literature | Thymosin beta-4 was isolated from thymosin fraction 5, a crude bovine thymus extract pursued as a source of thymic hormones. Its actin-binding function was only recognised in 1990. | Thymosin alpha-1 was isolated from the same fraction 5 preparation. Reviews of the field state that neither peptide turned out to be a thymic hormone in the original sense, which is why the shared literature is largely historical. |
| Size and character of the evidence base | A large preclinical literature on tissue repair, angiogenesis, cardiac regeneration and fibrosis, generated almost entirely with full-length thymosin beta-4 or its recombinant form rather than with the marketed fragment. | More than thirty controlled human trials, including a phase 3 randomised placebo-controlled trial in sepsis and multicentre randomised trials in necrotising pancreatitis and hepatitis B cirrhosis, together with several meta-analyses and a Cochrane review. |
| Human data | Completed randomised trials in healthy volunteers, severe dry eye and chronic venous ulcers, plus a 2025 report covering mice and patients with ST-segment elevation myocardial infarction. None addressed tendon, ligament or muscle injury. | A 1106-patient phase 3 trial reported 28-day mortality of 23.4 percent versus 24.1 percent with placebo in sepsis, and a 508-patient trial found infected pancreatic necrosis in 15.7 percent versus 18.1 percent with placebo. Positive results cluster in smaller and single-centre studies. |
| Evidence maturity | Early clinical. Phase 1 and phase 2 trials exist for thymosin beta-4, but no product is approved for musculoskeletal recovery, and the fragment sold as TB-500 has almost no independent pharmacology of its own. | Approved drug. Registered as a prescription immunomodulator in a number of countries, principally for chronic hepatitis B and as an adjuvant in sepsis and oncology, though not approved by the FDA or EMA. |
| Recency of primary research | Active. Animal and formulation studies of thymosin beta-4 in colitis, sepsis-associated kidney injury, corneal infection and endometrial regeneration were published in 2025 and 2026. | Active. A phase 3 sepsis trial, sepsis and pancreatitis meta-analyses, an acute-on-chronic liver failure trial and mechanistic dendritic-cell work were published between 2025 and 2026. |
| What the shared experiments actually tested | Full-length thymosin beta-4 in every case, and in one paper a truncated fragment of it. A PubMed search pairing the marketed TB-500 designation with thymalfasin returns no records at all. | Synthetic thymosin alpha-1, the same molecule registered as thymalfasin, so for this peptide the co-tested literature and the marketed product describe one substance. |
And what it does not.
Unusually for this category, experiments that applied both compounds within one design do exist, and they agree on one point: the two peptides behave differently. Thymosin alpha-1 enhanced the mixed lymphocyte reaction and dendritic cell maturation where thymosin beta-4 did not or did the opposite, thymosin beta-4 stimulated luteinizing hormone-releasing factor secretion where thymosin alpha-1 did not, and several assays returned nothing for either. None of that establishes a comparative ranking for any marketed use, because all of it is in vitro or ex vivo immunology and endocrinology published between 1981 and 2007, and because the beta-thymosin tested was the full-length 43-residue peptide rather than the seven-residue fragment sold as TB-500. Away from those experiments the two evidence bases barely intersect. Thymosin alpha-1 has more than thirty controlled human trials, whose largest and most rigorous, a 1106-patient phase 3 study in sepsis, was null. Thymosin beta-4 has completed human trials in dry eye, venous ulcers and cardiac ischaemia, but none in the musculoskeletal indications for which TB-500 is sold.
Common questions.
- Have TB-500 and thymosin alpha-1 ever been tested in the same experiment?
The peptide sold as TB-500 has not been. What has been tested alongside thymosin alpha-1 is full-length thymosin beta-4, the 43-residue parent peptide, in roughly sixteen in vitro and ex vivo experiments published between 1981 and 2007. A PubMed search pairing the TB-500 designation with thymalfasin returns no records. That distinction matters because the marketed fragment, Ac-LKKTETQ, has almost no pharmacology of its own, and its equivalence to the full-length peptide has not been demonstrated in published work.
- Why does so much older research measure both peptides at once?
Both were purified from thymosin fraction 5, a crude bovine thymus extract prepared in the 1960s to restore thymic function in immunodeficient animals and patients. Investigators isolated individual peptides from that fraction and tested each for the activities the whole extract showed. Reviews of the field record that none of the isolated peptides turned out to be a thymic hormone in the original sense, which is why the two peptides appear together mainly in historical immunology, endocrine assays and structural work rather than in modern therapeutic studies.
- Did the shared experiments show one peptide to be stronger than the other?
They showed divergent rather than ranked activity. Thymosin alpha-1 enhanced the human mixed lymphocyte reaction and upregulated dendritic cell maturation markers while thymosin beta-4 did not. Thymosin beta-4 reduced Fc alpha receptor expression and antibody-dependent cellular cytotoxicity on human lymphocytes while thymosin alpha-1 was inactive. Thymosin beta-4 alone stimulated luteinizing hormone-releasing factor secretion from rat hypothalamic tissue, and thymosin alpha-1 alone raised human sperm penetration rates. Both potentiated macrophage antigen presentation, and both were inactive in several other assays.
- Where does thymosin alpha-1 stand with regulators, and TB-500?
It is registered as a prescription immunomodulator in a number of countries, principally for chronic hepatitis B and as an adjuvant in sepsis and oncology, but it is not approved by the FDA or EMA. Its trial record is substantial and mixed: a 1106-patient phase 3 trial in sepsis found no mortality benefit, a 508-patient trial in necrotising pancreatitis found no reduction in infected pancreatic necrosis, and the pooled meta-analytic signal in sepsis disappears when analysis is restricted to high-quality multicentre trials.
- Do the shared papers say anything about tissue repair or recovery?
No. Not one of the publications that engages both compounds examined tendon, ligament, muscle or wound healing. The experiments that applied both are immunology and endocrinology assays, and the remainder are serum assays of endogenous concentrations in humans and livestock, immunohistochemical localisation in brain and thymus, structural and mass-spectrometric characterisation, and thymosin-family reviews. The tissue repair literature for thymosin beta-4 and the clinical trial literature for thymosin alpha-1 developed separately and have never been compared.
For research purposes only. Not for human consumption, diagnosis, treatment, or prevention of any condition. Nothing on this page is medical advice, and no comparison here should be read as a recommendation of either compound.