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. 1991 Sep;214(3):264–275. doi: 10.1097/00000658-199109000-00009

Immunomodulatory therapy with thymopentin and indomethacin. Successful restoration of interleukin-2 synthesis in patients undergoing major surgery.

E Faist 1, A Markewitz 1, D Fuchs 1, S Lang 1, S Zarius 1, F W Schildberg 1, H Wachter 1, B Reichart 1
PMCID: PMC1358645  PMID: 1929608

Abstract

Prostaglandin E2 (PGE2)-mediated monocyte (M phi) suppressor activity and inadequate T-helper cell function represent the mechanistic keystones of trauma-induced impairment of cell-mediated immunity (CMI). In a prospective randomized trial, the immunorestorative potential of a combined therapy with the thymomimetic substance Thymopentin (TP-5; Timunox, Cilag GMBH, Sulzbach, FRG) and the cyclooxygenase inhibitor indomethacin (Indo) in 60 patients (mean age, 63 +/- 2 years) undergoing open heart surgery was studied. Perioperative immunologic screening was carried out on days -2, 3, 1, 5, and 7 and included the in vivo delayed type hypersensitivity (DTH) skin response, phenotyping for peripheral blood mononuclear cell (PBMC)-specific and nonspecific induction of lymphoproliferative responses, in vitro interleukin-2 (IL-2) synthesis, as well as the serum concentration of D-erythro-Neopterin (NPT) and of gamma interferon (gamma-IFN). The study protocol comprised three groups (n = 20): PA (Indo 150 mg administered intravenously on days 0 to 5), PB (TP-5 administered subcutaneously on days 0, 2, 4, and Indo), and PC (control). In contrast to PC, significant immunorestoration could be demonstrated in PB, as DTH scores on day 7, as well as proliferative responses in cell cultures were not depressed after operation (p less than 0.05). Cell-surface receptor expression for the CD3+, CD4+, and IL-2 receptor-positive (IL-2R+) lymphocyte subpopulations following surgery was reduced to 75% of baseline values in PC, while in PB, receptor protection for CD4+ and IL-2R+ subpopulations (more than 15% above baseline) was observed. Interleukin-2 synthesis (average baseline value, 0.7 + 0.08 U/mL) in cell cultures of PC was massively suppressed, with lymphokine concentrations in the supernatants never more than 0.27 +/- 0.05 U/mL. In PA cultures, IL-2 synthesis was impaired as well but not as precipitously as in PC. In contrast, in PB cultures, the average IL-2 production on consecutive postoperative days was never below baseline values. This study clearly demonstrates that the combined Indo/TP-5 therapy is superior to single Indo administration and can adequately preserve and/or restore intact M phi T-cell interaction and thus appears to be a feasible approach to maintain normal host defense activity in traumatized individuals.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Browder W., Williams D., Pretus H., Olivero G., Enrichens F., Mao P., Franchello A. Beneficial effect of enhanced macrophage function in the trauma patient. Ann Surg. 1990 May;211(5):605–613. [PMC free article] [PubMed] [Google Scholar]
  2. Chouaib S., Chatenoud L., Klatzmann D., Fradelizi D. The mechanisms of inhibition of human IL 2 production. II. PGE2 induction of suppressor T lymphocytes. J Immunol. 1984 Apr;132(4):1851–1857. [PubMed] [Google Scholar]
  3. Faist E., Ertel W., Cohnert T., Huber P., Inthorn D., Heberer G. Immunoprotective effects of cyclooxygenase inhibition in patients with major surgical trauma. J Trauma. 1990 Jan;30(1):8–18. doi: 10.1097/00005373-199001000-00002. [DOI] [PubMed] [Google Scholar]
  4. Faist E., Ertel W., Salmen B., Weiler A., Ressel C., Bolla K., Heberer G. The immune-enhancing effect of perioperative thymopentin administration in elderly patients undergoing major surgery. Arch Surg. 1988 Dec;123(12):1449–1453. doi: 10.1001/archsurg.1988.01400360019001. [DOI] [PubMed] [Google Scholar]
  5. Faist E., Mewes A., Baker C. C., Strasser T., Alkan S. S., Rieber P., Heberer G. Prostaglandin E2 (PGE2)-dependent suppression of interleukin alpha (IL-2) production in patients with major trauma. J Trauma. 1987 Aug;27(8):837–848. doi: 10.1097/00005373-198708000-00001. [DOI] [PubMed] [Google Scholar]
  6. Faist E., Mewes A., Strasser T., Walz A., Alkan S., Baker C., Ertel W., Heberer G. Alteration of monocyte function following major injury. Arch Surg. 1988 Mar;123(3):287–292. doi: 10.1001/archsurg.1988.01400270021002. [DOI] [PubMed] [Google Scholar]
  7. Fuchs D., Hausen A., Reibnegger G., Werner E. R., Dierich M. P., Wachter H. Neopterin as a marker for activated cell-mediated immunity: application in HIV infection. Immunol Today. 1988 May;9(5):150–155. doi: 10.1016/0167-5699(88)91203-0. [DOI] [PubMed] [Google Scholar]
  8. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  9. Goldstein G., Audhya T. K. Thymopoietin to thymopentin: experimental studies. Surv Immunol Res. 1985;4 (Suppl 1):1–10. doi: 10.1007/BF02919050. [DOI] [PubMed] [Google Scholar]
  10. Goodwin J. S., Ceuppens J. L. Effect of nonsteroidal antiinflammatory drugs on immune function. Semin Arthritis Rheum. 1983 Aug;13(1 Suppl 1):134–143. doi: 10.1016/0049-0172(83)90033-1. [DOI] [PubMed] [Google Scholar]
  11. Hisatomi K., Isomura T., Kawara T., Yamashita M., Hirano A., Yoshida H., Eriguchi N., Kosuga K., Ohishi K. Changes in lymphocyte subsets, mitogen responsiveness, and interleukin-2 production after cardiac operations. J Thorac Cardiovasc Surg. 1989 Oct;98(4):580–591. [PubMed] [Google Scholar]
  12. Maghsudi M., Miller C. L. The immunomodulating effect of TP5 and indomethacin in burn-induced hypoimmunity. J Surg Res. 1984 Aug;37(2):133–138. doi: 10.1016/0022-4804(84)90173-2. [DOI] [PubMed] [Google Scholar]
  13. Murray H. W., Hillman J. K., Rubin B. Y., Kelly C. D., Jacobs J. L., Tyler L. W., Donelly D. M., Carriero S. M., Godbold J. H., Roberts R. B. Patients at risk for AIDS-related opportunistic infections. Clinical manifestations and impaired gamma interferon production. N Engl J Med. 1985 Dec 12;313(24):1504–1510. doi: 10.1056/NEJM198512123132403. [DOI] [PubMed] [Google Scholar]
  14. Polk H. C., Jr, George C. D., Wellhausen S. R., Cost K., Davidson P. R., Regan M. P., Borzotta A. P. A systematic study of host defense processes in badly injured patients. Ann Surg. 1986 Sep;204(3):282–299. [PMC free article] [PubMed] [Google Scholar]
  15. Roth J. A., Golub S. H., Cukingnan R. A., Brazier J., Morton D. L. Cell-mediated immunity is depressed following cardiopulmonary bypass. Ann Thorac Surg. 1981 Apr;31(4):350–356. doi: 10.1016/s0003-4975(10)60965-4. [DOI] [PubMed] [Google Scholar]
  16. Wakasugi H., Bertoglio J., Tursz T., Fradelizi D. IL 2 receptor induction on human T lymphocytes: role for IL 2 and monocytes. J Immunol. 1985 Jul;135(1):321–327. [PubMed] [Google Scholar]
  17. Werner E. R., Bichler A., Daxenbichler G., Fuchs D., Fuith L. C., Hausen A., Hetzel H., Reibnegger G., Wachter H. Determination of neopterin in serum and urine. Clin Chem. 1987 Jan;33(1):62–66. [PubMed] [Google Scholar]
  18. Woloszczuk W. A sensitive immunoradiometric assay for gamma interferon, suitable for its measurement in serum. Clin Chem. 1985 Jun;31(6):1090–1090. [PubMed] [Google Scholar]
  19. Wood J. J., Rodrick M. L., O'Mahony J. B., Palder S. B., Saporoschetz I., D'Eon P., Mannick J. A. Inadequate interleukin 2 production. A fundamental immunological deficiency in patients with major burns. Ann Surg. 1984 Sep;200(3):311–320. doi: 10.1097/00000658-198409000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. van Oeveren W., Kazatchkine M. D., Descamps-Latscha B., Maillet F., Fischer E., Carpentier A., Wildevuur C. R. Deleterious effects of cardiopulmonary bypass. A prospective study of bubble versus membrane oxygenation. J Thorac Cardiovasc Surg. 1985 Jun;89(6):888–899. [PubMed] [Google Scholar]
  21. van Velzen-Blad H., Dijkstra Y. J., Heijnen C. J., Schurink G. A., Zegers B. J., Ballieux R. E. Cardiopulmonary bypass and host defense functions in human beings: II. Lymphocyte function. Ann Thorac Surg. 1985 Mar;39(3):212–217. doi: 10.1016/s0003-4975(10)62581-7. [DOI] [PubMed] [Google Scholar]

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