Skip to main content
PMC home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1988 Feb;26(1):87–93. doi: 10.1007/BF00199853

A randomized trial to evaluate the immunorestorative properties of thymostimulin in patients with Hodgkin's disease in complete remission

A M Liberati 1, E Ballatori 2, M Fizzotti 1, M Schippa 1, L Cini 1, S Cinieri 1, M G Proietti 3, R Di Marzio 3, M Senatore 1, F Grignani 1
PMCID: PMC11038239  PMID: 3125973

Abstract

A total of 19 Hodgkin's disease (HD) patients (12 male, 7 female) aged 26–67 years, who had been in complete unmaintained remission for 6 months or more when the study was initiated, were randomly given 50 mg thymostimulin (TS) i.m. daily (G1) or every other day (G2) for 35 days. A third group (G3) was not treated. Then TS, at the same dose was administered twice a week for the following 22 weeks in patients both initially receiving loading or intermittent TS treatment. When compared with age-and sex-matched controls, as a group, the patients' circulating OKT+3, OKT+4, OKT+11and E-AETR+ cells were depressed (P<0.001 for both proportions and absolute numbers), whereas their OKT+8cell population was not. Following 5 weeks of daily TS administration, the proportions and numbers of all T cell fractions significantly increased in G1 patients (P<0.03 for all the comparisons tested), while following intermittent TS treatment (G2) only the proportions of OKT+3and OKT+11cells (P<0.03), but not of other T cell fractions, significantly increased. In addition, no significant changes in the absolute numbers of T cell fractions were observed in this group of patients. Furthermore, no spontaneous variations in the T cell pool size occurred in untreated patients. TS maintenance therapy did not produce any further improvement in the size of overall T cells and T cell subsets but sustained percentage and absolute numbers of these cells during administration and the absolute number of T cells even after discontinuation of therapy. The TS-induced improvement in the T cell pool was not associated with any change in the size of circulating non-T lymphocytes and monocytes. In vitro phytohemagglutinin-induced interleukin-2 (IL-2) and gamma-interferon (IFN-γ) synthesis was assessed in 11 patients (3 G1, 4 G2, and 4 G3). Although it was not statistically significant, a rise in IL-2 and IFN-γ production was observed in TS-treated patients, but not in untreated controls. TS failed to exert any effect on the serum circulating levels of neopterin, type I and II IFN, beta-2 microglobulin (B2-M) and immunoglobulins (Ig). TS can thus improve defective T cell frequences and numbers and may modulate IL-2 and IFN-γ production.

Keywords: Complete Remission, Maintenance Therapy, Absolute Number, Cell Subset, Untreated Patient

References

  • 1.Aiuti F, Ammirati P, Fiorilli M, D'Amelio R, Franchi F, Calvani M, Businco L. Immunologic and clinical investigation on a bovine thymic extract. Therapeutic applications in primary immunodeficiencies. Pediatr Res. 1979;13:797. doi: 10.1203/00006450-197907000-00001. [DOI] [PubMed] [Google Scholar]
  • 2.Bergesi G, Falchetti R. Caratterizzazione chimica e attivitá biologica di un nuovo estratto timico. Folia Allergol Immunol Clin. 1977;24:204. [Google Scholar]
  • 3.Chang TW, McKinney S, Liu V, Kung PC, Vilcek J, Le J. Use of monoclonal antibodies as sensitive and specific probes for biologically active human γ-interferon. Proc Natl Acad Sci USA. 1984;81:5219. doi: 10.1073/pnas.81.16.5219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Costanzi JJ, Gagliano RG, Delaney F, Harris N, Thurman GB, Sakai H, Goldstein AL, Loukas D, Cohen GB, Thomson PD. The effect of thymosin on patients with disseminated malignancies. Cancer. 1977;40:14. doi: 10.1002/1097-0142(197707)40:1<14::aid-cncr2820400105>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  • 5.Falchetti R, Bergesi G, Eshkol A, Cafiero C, Adorini L, Caprino L. Pharmacological and biological properties of a calf thymus extract (TP-1) Drugs Exptl Clin Res. 1977;3:39. [Google Scholar]
  • 6.Ford RJ, Tsao J, Kouttab NM, Sahasrabuddhe CG, Mehta SR. Association of an interleukin abnormality with the T cell defect in Hodgkin's disease. Blood. 1984;64:386. [PubMed] [Google Scholar]
  • 7.Fuchs D, Hausen A, Knosp O, Reibnegger G, Wachter H, Kofler M, Kosahowsky H, Huber Ch, Niederwieser D. Biochemical and clinical aspects of pteridines. Berlin, New York: Walter de Gruyter; 1983. Neopterin evaluation in patients suffering from pulmonary tuberculosis; p. 281. [Google Scholar]
  • 8.Gastl G, Aulitzky W, Tilg H, Nachbaur K, Troppmair J, Flener R, Huber Ch. A biological approach to optimize interferon treatment in hairy cell leukemia. Immunobiology. 1986;172:262. doi: 10.1016/S0171-2985(86)80107-3. [DOI] [PubMed] [Google Scholar]
  • 9.Goldstein AL, Low TLK, Thurman GB. Immunological approaches to cancer therapeutics. New York: Wiley; 1982. Thymosins and other hormone-like factors of the thymus gland; p. 137. [Google Scholar]
  • 10.Grinblat J, Schauenstein K, Saltz E, Trainin N, Globerson A. Regulatory effects of thymus humoral factor on T cell growth factor in aging mice. Mech Ageing Dev. 1983;22:209. doi: 10.1016/0047-6374(83)90077-5. [DOI] [PubMed] [Google Scholar]
  • 11.Hausen A, Fuchs D, Reibnegger G, Wachter H, Egg D, Günther R. Biochemical and clinical aspects of pteridines. Berlin, New York: Walter De Gruyter; 1983. Neopterin as index for activity of disease in patients with rheumatoid arthritis; p. 245. [Google Scholar]
  • 12.Huang KY, Kind PD, Jagoda EM, Goldstein AL. Thymosin treatment modulates production of interferon. J Interferon Res. 1981;1:411. doi: 10.1089/jir.1981.1.411. [DOI] [PubMed] [Google Scholar]
  • 13.Huber Ch, Fuchs D, Hausen A, Margreiter R, Reibnegger G, Spielberger M, Wachter H. Pteridines as a new marker to detect human T cells activated by allogeneic or modified self major histocompatibility complex (MHC) determinants. J Immunol. 1983;130:1047. [PubMed] [Google Scholar]
  • 14.Huber Ch, Batchelor JR, Fuchs D, Hausen A, Lang A, Niederwieser D, Reibnegger G, Swetly P, Troppmair J, Wachter H. Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma. J Exp Med. 1984;160:310. doi: 10.1084/jem.160.1.310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Jameson P, Dixon MA, Grossberg SE. A sensitive interferon assay for many species of cells: Encephalomyocarditis virus hemagglutinin yield reduction (39768) Proc Soc Exp Biol Med. 1977;155:173. doi: 10.3181/00379727-155-39768. [DOI] [PubMed] [Google Scholar]
  • 16.Janossy G. The leukemic cell. Edinburgh, London, Melbourne, New York: Churchill Livingstone; 1981. Membrane markers in leukemia; p. 129. [Google Scholar]
  • 17.Liberati AM, Brugia M, Edwards BS, Bertoni P, Ballatori E, Puxeddu A, Grignani F. Immunorestorative properties of thymostimulin (TS) in patients with Hodgkin's disease in clinical remission. Cancer Immunol Immunother. 1985;19:136. doi: 10.1007/BF00199722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Liberati AM, Ballatori E, Fizzotti M, Schippa M, Proietti MG, Di Marzio R, Pecci A, Biscetti L, Sbarretti R, Cini L, Grignani F. Immunologic profile in patients with Hodgkin's disease in complete remission. Cancer. 1987;59:1906. doi: 10.1002/1097-0142(19870601)59:11<1906::aid-cncr2820591111>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  • 19.Low TLK, Thurman GB, Chincarini C, McClure JE, Marshall GD, Hu SK, Goldstein AL. Current status of thymosin research: evidence for the existence of a family of thymic factors that control T cell maturation. Ann NY Acad Sci. 1979;332:33. doi: 10.1111/j.1749-6632.1979.tb47095.x. [DOI] [PubMed] [Google Scholar]
  • 20.Margreiter R, Fuchs D, Hausen A, Huber C, Reibnegger G, Spielberger M, Wachter H. Neopterin as a new biochemical marker for diagnosis of allograft rejection. Experience based upon evaluation of 100 consecutive cases. Transplantation. 1983;36:650. doi: 10.1097/00007890-198336060-00013. [DOI] [PubMed] [Google Scholar]
  • 21.Martelli MF, Velardi A, Rambotti P, Cernetti C, Bracaglia AM, Ballatori E, Davis S. The in vitro effect of a calf thymus extract (thymostimulin) on the immunologic parameters of patients with untreated Hodgkin's disease. Cancer. 1982;49:245. doi: 10.1002/1097-0142(19820115)49:2<245::aid-cncr2820490209>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  • 22.Martelli MF, Velardi A, Rambotti P, Cernetti C, Bertotto A, Spinozzi F, Bracaglia AM, Falini B, Davis S. The in vivo effect of a thymic factor (thymostimulin) on immunologic parameters of patients with untreated Hodgkin's disease. Cancer. 1982;50:490. doi: 10.1002/1097-0142(19820801)50:3<490::aid-cncr2820500318>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  • 23.Meuer SC, Hussey RE, Penta AC, Fitzgerald KA, Stalder BM, Schlossman SF, Reinherz EL. Cellular origin of interleukin 2 (IL-2) in man: evidence for stimulus-restricted IL-2 production by T4+ and T8+ T lymphocytes. J Immunol. 1982;129:1076. [PubMed] [Google Scholar]
  • 24.Neauport-Sautes C, Bismuth A, Kourilsky FM, Manuel Y. Relationship between HL-A antigens and β2-microglobulin as studied by immunofluorescence on the lymphocyte membrane. J Exp Med. 1974;139:957. doi: 10.1084/jem.139.4.957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Neta R, Salvin SB. Resistance and susceptibility to infection in inbred murine strains. II Variations in the effect of treatment with thymosin fraction 5 on the release of lymphokines in vivo. Cell Immunol. 1983;75:173. doi: 10.1016/0008-8749(83)90316-7. [DOI] [PubMed] [Google Scholar]
  • 26.Palacios R. Role of serum thymic factor (FTS) in the development of interleukin-2 producer lymphocytes. Clinics Immunol Allergy. 1983;3:83. [Google Scholar]
  • 27.Palacios R, Fernandez C, Sideras P. Development and continuous growth in culture of interleukin 2-producer lymphocytes from athymic nu/nu mice. Eur J Immunol. 1982;12:777. doi: 10.1002/eji.1830120914. [DOI] [PubMed] [Google Scholar]
  • 28.Schulof RS. Thymic peptide hormones: basic properties and clinical applications in cancer. CRC Crit Rev Oncol Hematol. 1985;3:309. doi: 10.1016/s1040-8428(85)80035-4. [DOI] [PubMed] [Google Scholar]
  • 29.Schulof RS, Goldstein AL. Lymphokines. Clifton, New Jersey: Humana Press; 1981. Thymosins and other thymic hormones; p. 397. [Google Scholar]
  • 30.Schulof RS, Goldstein AL. Recent advances in clinical immunology. New York: Churchill Livingstone; 1983. Clinical applications of thymosin and other thymic hormones; p. 243. [Google Scholar]
  • 31.Schulof RS, Lloyd MJ, Cleary PA, Palaszynski SR, Mai DA, Cox JW, Jr, Alabaster O, Goldstein AL. A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-α1 in patients with lung cancer. J Biol Resp Mod. 1985;4:147. [PubMed] [Google Scholar]
  • 32.Shoham J, Eshel I, Mordechai A, Salzberg S. Thymic hormonal activity on human peripheral blood lymphocytes in vitro. II. Enhancement of the production of immune interferon by activated cells. J Immunol. 1980;125:54. [PubMed] [Google Scholar]
  • 33.Soulillou JP, Douillard JY, Vie H, Harousseau JL, Guenel J, Le Mevelle Pourhiet A, Le Mevel B. Defect in lectin-induced interleukin 2 (IL-2) production by peripheral blood lymphocytes of patients with Hodgkin's disease. Eur J Cancer Clin Oncol. 1985;21:935. doi: 10.1016/0277-5379(85)90111-7. [DOI] [PubMed] [Google Scholar]
  • 34.Svedersky LP, Hui A, May L, McKay P, Stebbing N. Induction and augmentation of mitogen-induced immune interferon production in human peripheral blood lymphocytes by N α-desacetylthymosin-α1 . Eur J Immunol. 1982;12:244. doi: 10.1002/eji.1830120314. [DOI] [PubMed] [Google Scholar]
  • 35.Tovo PA, Bernengo MG, Cordero di Montezemolo L, Del Piano A, Saitta M, Nicola P. Thymus extract therapy in immunodepressed patients with malignancies and herpes virus infections. Thymus. 1980;2:41. [Google Scholar]
  • 36.Vitetta ES, Poulik MD, Klein J, Uhr JW. Beta 2-microglobulin is selectively associated with H-2 and TL alloantigens on murine lymphoid cells. J Exp Med. 1976;144:179. doi: 10.1084/jem.144.1.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Wachter H, Hausen A, Grassmayr K. Erhöhte Ausscheidung von Neopterin im Harn von Patienten mit malignen Tumoren und mit Viruserkrankungen. Hoppe-Seyler's Z Physiol Chem. 1979;360:1957. [PubMed] [Google Scholar]
  • 38.Zatz MM, Oliver J, Sztein MB, Skotnicki AB, Goldstein AL. Comparison of the effects of thymosin and other thymic factors on modulation of interleukin-2 production. J Biol Resp Modif. 1985;4:365. [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES