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Thymic Peptides and Preparations: an Update

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Thymic Peptides and Preparations: an Update ¡ Archivum Immunologiae et Therapiae Experimentalis, 1999, 47¢ , 77–82 £ PL ISSN 0004-069X Review Thymic Peptides and Preparations: an Update ¤ O. J. Cordero et al.: Thymic Peptides ¦ ¨ § OSCAR J. CORDERO, A¥ LICIA PIÑEIRO and MONTSERRAT NOGUEIRA Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain Abstract. The possibilities of thymic peptides in human therapy are still being described. Here, we focus on their © general characteristics and on recent advances in this area. Key words: thymus; thymic peptides; preclinical investigation; therapeutic use; clinical trials. Thymic peptides, as well as a variety of other purified from porcine and human serum and from calf modulators (IL-1, IL-3, IL-6, GM-CSF) and cell-cell thymus, and named “facteur thymique serique”11. interactions, regulate the process known as thymic se- According to the classical criteria, TH is the unique lection by which pro-thymocytes become mature and peptide that can be recognized as a hormone. Its secre- functional T cells. tion by a subpopulation of thymic epithelial cells (TEC) Several polypeptides have been extracted, mainly is controlled by a pleiotropic mechanism involving its from young calves, and some of them have been suc- own levels and those of prolactine (PRL), growth hor- cessfully isolated and prepared synthetically (Fig. 1). mone (GH) through insulin growth factor 1 (IGF-1) se- The precise role of much of these factors purported to cretion, adrenocorticotropin (ACTH), thyroxin (T4), β- have intrathymic effects is still unknown, although endorphin and β-leukencephalin and IL-1α and β8. many of these compounds exhibit immunobiological Furthermore, reciprocal regulatory actions on the activity. On the basis of this fact, several clinical appli- hypothalamus-pituitary axis have been proposed, based cations of thymic peptides have been studied recently, on results suggesting that TH might modulate the se- revealing a promising new field in the development of cretion of ACTH, lutheinising hormone (LH) and therapeutic drugs, as positive results have been ob- PRL19, 21. In addition to this function as transmitter tained, i. e., on cancer and some immunodeficiencies. between the neuroendocrine and the immune system, TH exerts many other functions ranging from differen- tiation of immature thymocytes to immune modulation. Thymulin This is reflected by the fact that Crohn’s disease or acute lymphoblastic leukemia patients share Zn+2 and Thymulin (TH) is a nonapeptide that is biologically TH activity deficits. Likewise, people suffering myas- active only when it is coupled with zinc. Initially, it was thenia gravis show an impairment in both Zn+2 and TH, Abbreviation used: IL – interleukin, GM-CSF – granulocyte/macrophage-colony stimulator y factor, TEC – thymic epithelial cells, GH – growth hormone, IGF-1 – insulin growth factor-1, ACTH – adrenocorticotropin, T 4 – tiroxin, LH – lutheinising hormone, PRL – pro- lactine, TNF – tumor necrosis factor, PBMC – peripheral blood mononuclear cells, HIV – human immunodeficiency virus, IFN – inter- feron, NK – natural killer, HBV – hepatitis B virus, HBeAg – hepatitis Be antigen, AZT – azidodeoxithimidine/zidovudine, PHA – phy- tohemagglutinin. 2 – Archivum Immunologiae... 2/99 5 78 ¨ O. J. Cordero et al.: Thymic Peptides % but in this case an age-dependent mechanism also In addition to this possible function, THF-! γ2 re- seems to be involved24. stores immunocompetence and reduces metastasis in Recent data indicate that TH can be therapeutically tumor-bearing mice receiving anticancer immunother- effective in preventing the development of rheumatoid apy10. arthritis2. Likewise, its role in hyperalgesia is being in- Recently, a clinical trial has been developed which ! vestigated at the moment32, 33. concludes that THF-γ2 administered with zidovudine In rats immune to viral oncogene products, TH ( reduces the number of opportunistic infections in HIV augments suppressive effects on tumor development28. patients naive for antiretroviral therapy and it increases In the same way, the animal models of acute graft-ver- their survival time25. sus-host disease studied have shown that TH has a pro- tective effect in mice’s enteropathy; so, it has been re- Thymopoietin cently proposed as a possible therapeutic agent in acute © graft-versus-host disease after blood transfusion or Thymopoietin (TP) was isolated from calf thymus bone marrow transplantation in humans23. for its neuromuscular effects, but nowadays its immu- ) nomodulatory function is recognized too. Thymic Humoral Factor In spite of its abundant presence on thymocytes, TP appears in TEC, primary and secondary lymphatic tis- This crude extract was obtained from calf thymus, sues and in non lymphatic tissues (striated muscle, after which the octapeptide thymic humoral factor heart, small intestine and cerebellum). A role in the (THF)-! γ2 was isolated from it using chromatography. regulation of thymocyte differentiation and T lympho- " Both share the same properties, namely, to have stimu- cyte proliferation has been described; in the same way # latory effects on myeloid and erythroid hematopoietic it has been recently described as an inductor of human progenitor cells and to enhance lymphocyte prolifera- TEC proliferation20. tion and IL-2 production by spleen cells from neona- Many evidences – including its interaction with lami- ) 38 tally thymectomized mice or from immunocom- na B1 – suggest that it plays a nuclear role, probably $ $ promised patients’ lymphocytes9. in proliferation and cell cycle control9. % An antiviral effect can be proposed for THF-! γ2 in Thymopoietin has 49 amino acids and its biological & vivo, if we consider both that it diminishes murine cy- activity is comprised in the pentapeptide composed of tomegalovirus infection and also that it increases pro- residues 32 to 36, named Thymopentin (TP-5). Interes- ' duction of IL-2 and TNF-α in PBMC obtained from tingly, there is a thymopentin-like motif which seems patients with chronic hepatitis B. to account for the immunomodulatory activity of G- actin36. TP-5 is the only thymic peptide approved as a single ' , drug, and it is applied in the therapy of primary immu- A. Thymulin (FTS) - QAKSQGGSN nodeficiencies. Recently, a phase III trial showed that dose-intensi- B. Thymic humoral factor (THF) – it is an extract * . γ fied chemotherapy can be used safely and effectively B. 1. THF- 2 / on pre-treated patients of breast, gastric and small cell LEDGPKFL # 31 0 lung cancer, if TP-5 and G-CSF are used as support . C. Thymopoietin (TP) 1 In spite of its good immunostimulatory results, TP-5 GLPKEVPAVL TKQKLKSELV ANGVTLPAGE 2 MRKDVYVELY LQHLTALH has as disadvantage its limited half-life in plasma. At- C.1. TP-5 tempts to resolve this have taken different approaches. RKDVY Stabilized analogues of TP-5 via insertion of keto- D. Thymosins (T) methylene have been tested in vivo showing immuno- D.1. ProT3 α potentiating properties (induction of Thy-1.2 express- 4 SDAAVDTSSE ITTKDLKEKK EVVEEAENGR ion and stimulation of T cell proliferation) as well as DAPANGNANE ENGEQEADNE VDEEEEEGGE they exhibited disease remitting properties in two ani- EEEEEEEGDG EEEDGDEDEE AESATGKRAA mal models of arthritis12, 13, 37. Good results of pre- EDDEDDDVDT KKQKTDEDD 30 3 valence were also obtained by preparing liposomes or D.2. Tα1 + 4 7 SDAAVDTSSE ITTKDLKEKK EVVEEAEN embedding the drug in polymeric matrix microspheres . In atopic eczema, TP-5 has also shown convincing Fig. 1. The amino acid sequences of the thymic peptides results in many different trials, being safe and effective 5 ¨ O. J. Cordero et al.: Thymic Peptides 79 in the improvement of clinical symptoms. Nevertheless, Similar trials are being performed in Singapore, Tai- therapeutic benefits of TP-5 in this affection have not 8 wan and Japan22, due to the great sanitary problem that taken to general acceptance, a surprising fact if we con- HBV represents in Asian countries. In Taiwan, 33.3% sider that classical treatments have shown high adverse of patients lost DNA and seroconverted for HBeAg in 6 side effects6, 26. a 6-month treatment and 38.5% in a 12 month one, 8 whereas the control group only did it in 8.3%. Thymosins Phase III trials being undertaken at Singapore and ; Japan are refining the use of this drug, as far as the Thymosins were originally isolated from a partially ' dose-ranging efficacy and effectiveness in a broader © purified bovine thymic extract, “named” thymosin frac- group of patients. tion V (TF-V). TF-V showed immunostimulatory ac- The Italian National Research Council22 has also tivity, restoring abnormalities in thymic weight and in sponsored a pilot trial of combination therapy with Tα1 ' diseases as Di George syndrome. At least 30 peptides and IFN-α, being given to chronic hepatitis B patients. belonging to the α or β thymosins family can be ident- The data indicate a conversion rate to negative status ified by isoelectric focusing of TF-V; from them, thy- in 40% subjects. < 7 mosin α1(Tα1) and thymosin β4(Tβ4) retain the major Even more, in a US multicenter trial beneficial re- = 3 activity of the original fraction . sults on IFN-α/Tα1 combination therapy for the treat- Tα1 is a highly conserved 28 amino acid peptide ment of hepatitis C infection were reported. This ap- 8 which contains most of the activity of TF-V; it is a po- proach revealed higher efficacy than with the use of tent immunostimulator with a very important advant- IFN-α 2b or placebo alone in terms of biochemical, his- age, its low toxicity compared to other response modi- tological and virological end-treatment responses35. In * ! fiers as ILs or IFN-γ. In lymphocytes, it induces a previous pilot trial, Tα1 alone did not show any re- ' differentiation (as seen from Thy1/Lyt1 and Lyt2,3 ex- markable effect, suggesting a sinergism between Tα1 1 pression) increases responses to mitogens and enhances and IFN-α2b . production of antibodies and many cytokines (IFN-α, In HIV infection, the immune response has to be IFN-! γ, IL-2, IL-3, IL-4).
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