Thymulin (formerly FTS, from the French facteur thymique sérique — serum thymic factor) is a natural thymic hormone: a very short peptide of nine amino acids that works only when a zinc ion is attached to it. It was discovered in the 1970s as a substance circulating in the blood and helping T lymphocytes to mature. For over a decade it was a prominent candidate for an “immunity hormone”, but after 1987 human studies practically stopped. Today the literature on thymulin consists mainly of old biochemical papers, observations of blood levels in people with zinc deficiency, and more recent rodent experiments on pain and inflammation. This review explains what thymulin is, why zinc is a condition of its activity rather than an add-on, and how little is known about giving it to people.
What thymulin is
Thymulin is a hormone produced exclusively by the epithelial cells of the thymus — the organ where T lymphocytes are “trained”. It was described in the 1970s by the group of Bach and Dardenne, first as an activity in serum that could be measured in a cell-based test (the so-called rosette assay), and in 1977 it was characterised biochemically in the journal Nature. The name “thymulin” appeared in 1982, when the same group showed that the peptide exists in two forms: one without zinc, which is biologically inactive, and one with zinc, which works. Since then the name thymulin has meant precisely the complex of the peptide with zinc (FTS-Zn).
How it works — a hormone that stays silent without zinc
The most important thing about thymulin: zinc does not “support” its action, it switches it on. In the 1982 paper by Dardenne et al., both the synthetic and the natural peptide lost activity after treatment with a resin that captures metal ions, and the activity returned after zinc salts were added — best at a ratio of one ion per peptide molecule. Gastinel's 1984 study refined this: the nonapeptide binds exactly one zinc ion, strongly and depending on pH (below pH 6 binding disappears), and other metals — including copper, manganese and aluminium — compete with zinc for that site and weaken the biological activity in the test tube to the same extent. Active thymulin is thought to promote the differentiation of T lymphocytes both inside and outside the thymus — this was the basis of the interest in it as an “immunity hormone”.
Structure and origin
Thymulin is one of the shortest known peptide hormones: nine amino acids and a zinc ion. Studies used both the natural peptide and a synthetic one with the same sequence — in the 1982 paper the presence of zinc in the synthetic peptide was confirmed by atomic absorption spectrometry, and microanalysis revealed the metal in the epithelial cells of the thymus, that is, where the hormone is made. According to the review by Reggiani (2014), thymulin is produced only by thymic epithelial cells, its secretion is strongly controlled by the hormonal system, and thymulin itself acts on the pituitary — forming a two-way axis between the thymus and the endocrine system.
What was studied — cells and animals
The most interesting and most surprising animal thread concerns pain. The group of Safieh-Garabedian in Beirut showed in rats that very small, nanogram doses of thymulin given intraperitoneally (20–150 ng) lower the pain threshold to mechanical and thermal stimuli — that is, they heighten pain perception — while doubling the level of interleukin-1β in the liver; the effect was reversed by the tripeptide Lys-D-Pro-Val, an analogue of the α-MSH fragment known as KPV. A year earlier the same group had shown the opposite: in a model of local inflammation (endotoxin injected into the paw of rats and mice) high doses of thymulin reduced pain hypersensitivity in a dose-dependent manner. This is the origin of the term “biphasic dose dependence”: low doses sensitise, high doses relieve. Reggiani's review also describes attempts at gene therapy in mice born without a thymus (nude mice), where a vector carrying the gene of a thymulin analogue (metFTS) prevented some of the hormonal and reproductive abnormalities. All of this is animal data — none of these observations has been tested in humans.
Human data — blood levels, zinc and two old trials in rheumatoid arthritis
Human studies fall into two groups. The first is observation of levels. Fabris et al. (Lancet, 1984) found that people over 50 and most young people with Down's syndrome have markedly less active thymic hormone in their blood, yet simply adding zinc sulphate to their plasma restored the activity to the level seen in young, healthy people. The authors' conclusion: the thymus has not “failed”; what is missing is the zinc that would activate the molecules already present. Prasad et al. (1988) went further — in volunteers in whom a mild zinc deficiency was induced by diet, and in adults with sickle cell anaemia, serum thymulin activity fell and, after zinc repletion, returned to normal together with T-lymphocyte indices. Thymulin activity was recognised as a sensitive indicator of zinc deficiency in humans.
The second group is administration of the peptide to patients — and here there is one solid source. Amor, Dougados et al. (1987) reported two randomised, double-blind, placebo-controlled trials in patients with rheumatoid arthritis, comparing three dose levels of nonathymulin (synthetic thymulin). At the middle dose, overall improvement was found in 56% of patients versus 17% in the placebo group (p < 0.02), confirmed by four objective parameters, with minimal adverse effects — but without clear changes in immunological parameters. The trial is almost forty years old and has never been repeated on a larger scale. In PubMed we found no more recent randomised trial in which thymulin was given to people.
Safety and the limits of the evidence
What is known about the safety of thymulin in humans comes from the rheumatoid arthritis trials of the 1980s: adverse effects were described as minimal. There are no data on prolonged administration, on healthy volunteers, or on people with autoimmune diseases other than rheumatoid arthritis. The biphasic effect on pain — heightening at small doses — has been shown only in rodents, but it is a signal that “less” does not necessarily mean “gentler”. The biochemical work shows that activity depends on the availability of zinc and that other metals compete with it for the site in the molecule; whether this matters in a living organism is unknown, because nobody has studied it. The biggest limitation is simple: the clinical literature broke off four decades ago, and the newer knowledge comes from a single centre studying pain in rats. We deliberately give no methods of use and no doses.
The wider context — thymic peptides and zinc
Thymulin belongs to the same group of thymic peptides as thymosin alpha-1, but their fates diverged completely: thymosin alpha-1 went through large randomised trials and was approved as a medicine in many countries, while thymulin stayed in the laboratory. The zinc thread links it to the wider knowledge of immunity in older people — the observations of Fabris and Prasad were one of the arguments that zinc deficiency weakens T lymphocytes. An interesting bridge to another compound in our encyclopaedia is the tripeptide KPV: it was an analogue of KPV that reversed, in rats, the pain hypersensitivity caused by small doses of thymulin.
Summary
Thymulin is a nine-amino-acid thymic hormone that works only as a complex with zinc — without the metal it is inactive, and other metals compete with zinc for its place. In humans its blood activity falls in zinc deficiency and returns after repletion, as documented in the 1980s. The only studies in which the peptide was given to patients are two small randomised trials in rheumatoid arthritis from 1987, with a favourable but never replicated result. The data on analgesic and anti-inflammatory action, including the biphasic dose dependence, come exclusively from rodents. The state of the evidence is therefore weak: well-understood biochemistry, and no contemporary clinical literature at all.
Sources
- Amor B, Dougados M, Mery C, et al. Nonathymulin in rheumatoid arthritis: two double blind, placebo controlled trials. Annals of the Rheumatic Diseases. 1987;46(7):549–554. PMID: 3310925. DOI: 10.1136/ard.46.7.549. pubmed.ncbi.nlm.nih.gov/3310925
- Prasad AS, Meftah S, Abdallah J, et al. Serum thymulin in human zinc deficiency. Journal of Clinical Investigation. 1988;82(4):1202–1210. PMID: 3262625. DOI: 10.1172/JCI113717. pubmed.ncbi.nlm.nih.gov/3262625
- Fabris N, Mocchegiani E, Amadio L, et al. Thymic hormone deficiency in normal ageing and Down's syndrome: is there a primary failure of the thymus?. Lancet. 1984;1(8384):983–986. PMID: 6143966. DOI: 10.1016/s0140-6736(84)92325-0. pubmed.ncbi.nlm.nih.gov/6143966
- Dardenne M, Pléau JM, Nabarra B, et al. Contribution of zinc and other metals to the biological activity of the serum thymic factor. Proceedings of the National Academy of Sciences of the United States of America. 1982;79(17):5370–5373. PMID: 6957870. DOI: 10.1073/pnas.79.17.5370. pubmed.ncbi.nlm.nih.gov/6957870
- Gastinel LN, Dardenne M, Pleau JM, Bach JF Studies on the zinc binding site to the serum thymic factor. Biochimica et Biophysica Acta. 1984;797(2):147–155. PMID: 6538097. DOI: 10.1016/0304-4165(84)90116-8. pubmed.ncbi.nlm.nih.gov/6538097
- Bach J, Bardenne M, Pleau J, Rosa J Biochemical characterisation of a serum thymic factor. Nature. 1977;266(5597):55–57. PMID: 300146. DOI: 10.1038/266055a0. pubmed.ncbi.nlm.nih.gov/300146
- Safieh-Garabedian B, Kanaan SA, Jalakhian RH, et al. Hyperalgesia induced by low doses of thymulin injections: possible involvement of prostaglandin E2. Journal of Neuroimmunology. 1997;73(1–2):162–168. PMID: 9058772. DOI: 10.1016/s0165-5728(96)00195-6. pubmed.ncbi.nlm.nih.gov/9058772
- Safieh-Garabedian B, Jalakhian RH, Saadé NE, et al. Thymulin reduces hyperalgesia induced by peripheral endotoxin injection in rats and mice. Brain Research. 1996;717(1–2):179–183. PMID: 8738269. DOI: 10.1016/0006-8993(95)01532-9. pubmed.ncbi.nlm.nih.gov/8738269
- Reggiani PC, Schwerdt JI, Console GM, et al. Physiology and therapeutic potential of the thymic peptide thymulin. Current Pharmaceutical Design. 2014;20(29):4690–4696. PMID: 24588820. DOI: 10.2174/1381612820666140130211157. pubmed.ncbi.nlm.nih.gov/24588820
For in-vitro laboratory research only. It is not a human medicine and is not for treatment.