Skip to main content
NCBI home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1995 Jun;100(3):529–535. doi: 10.1111/j.1365-2249.1995.tb03733.x

Ketotifen therapy in chronic graft-versus-host disease (cGVHD): effect on mast cells and fibroblasts.

A Nagler 1, V Segal 1, S Slavin 1, F Levi-Schaffer 1
PMCID: PMC1534472  PMID: 7539727

Abstract

Current treatment options for cGVHD are limited. Mast cells (MC) and fibroblasts have been shown to play a role in the murine model of cGVHD. Ketotifen is an anti-H-1 antihistamine with MC-stabilizing properties. We therefore treated eight patients with cGVHD with ketotifen (6 micrograms/day for 3 months). Three additional age- and sex-matched cGVHD patients served as controls. MC count and activation state in cGVHD skin biopsies and the in vitro effect of peripheral blood mononuclear cell (PBMC) supernatants on (i) histamine release by MC; (ii) 3T3-fibroblast proliferation; and (iii) prostaglandin E2 (PGE2) production, were evaluated. Ketotifen therapy resulted in clinical improvement in 4/8 patients, stabilization of the disease in 2/8, while in 2/8 patients the cGVHD progressed and they died of bacterial sepsis. Side effects were minimal. In the skin biopsies the number of MC was found to be 0.58 +/- 0.17 (n = 8) (field x 400) and the MC looked degranulated (toluidine blue staining). Following ketotifen therapy MC number was increased to 1.2 +/- 0.28 (n = 8) (P < 0.05). PBMC supernatants of cGVHD patients stimulated histamine release from cultured rat MC (n = 8) (2.7 +/- 0.5 micrograms/ml; normal values are 2.1 +/- 0.4 micrograms/ml, n = 5). Ketotifen therapy reduced the histamine release level to the normal range (2.0 +/- 0.5 micrograms/ml, P < 0.05) (n = 8). Ketotifen therapy had no significant effect on: (i) 3T3 fibroblast proliferation which was suppressed by cGVHD PBMC supernatants; (ii) the elevated PGE2 production which we observed when fibroblasts were incubated with the PBMC supernatants. These results indicate that ketotifen may play a therapeutic role in cGVHD.

Full text

PDF
529

Images in this article

533Fig. 2
on p.533

Selected References

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

  1. Barrett A. J. Graft versus host disease--clinical features and biology. Bone Marrow Transplant. 1989 Dec;4 (Suppl 4):18–21. [PubMed] [Google Scholar]
  2. Choi K. L., Giorno R., Claman H. N. Cutaneous mast cell depletion and recovery in murine graft-vs-host disease. J Immunol. 1987 Jun 15;138(12):4093–4101. [PubMed] [Google Scholar]
  3. Choi K. L., Maier T., Holda J. H., Claman H. N. Suppression of cytotoxic T-cell generation by natural suppressor cells from mice with GVHD is partially reversed by indomethacin. Cell Immunol. 1988 Apr 1;112(2):271–278. doi: 10.1016/0008-8749(88)90297-3. [DOI] [PubMed] [Google Scholar]
  4. Chosidow O., Bagot M., Vernant J. P., Roujeau J. C., Cordonnier C., Kuentz M., Wechsler J., André C., Touraine R., Revuz J. Sclerodermatous chronic graft-versus-host disease. Analysis of seven cases. J Am Acad Dermatol. 1992 Jan;26(1):49–55. doi: 10.1016/0190-9622(92)70005-z. [DOI] [PubMed] [Google Scholar]
  5. Claman H. N. Mast cell depletion in murine chronic graft-versus-host disease. J Invest Dermatol. 1985 Apr;84(4):246–248. doi: 10.1111/1523-1747.ep12265302. [DOI] [PubMed] [Google Scholar]
  6. Claman H. N. On scleroderma. Mast cells, endothelial cells, and fibroblasts. JAMA. 1989 Sep 1;262(9):1206–1209. doi: 10.1001/jama.262.9.1206. [DOI] [PubMed] [Google Scholar]
  7. Craps L. P. Immunologic and therapeutic aspects of ketotifen. J Allergy Clin Immunol. 1985 Aug;76(2 Pt 2):389–393. doi: 10.1016/0091-6749(85)90659-1. [DOI] [PubMed] [Google Scholar]
  8. Craps L. P., Ney U. M. Ketotifen: current views on its mechanism of action and their therapeutic implications. Respiration. 1984;45(4):411–421. doi: 10.1159/000194648. [DOI] [PubMed] [Google Scholar]
  9. Doutrelepont J. M., Moser M., Leo O., Abramowicz D., Vanderhaegen M. L., Urbain J., Goldman M. Hyper IgE in stimulatory graft-versus-host disease: role of interleukin-4. Clin Exp Immunol. 1991 Jan;83(1):133–136. doi: 10.1111/j.1365-2249.1991.tb05602.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ferrara J. L., Deeg H. J. Graft-versus-host disease. N Engl J Med. 1991 Mar 7;324(10):667–674. doi: 10.1056/NEJM199103073241005. [DOI] [PubMed] [Google Scholar]
  11. Fitzpatrick D. W., Fisher H. Histamine synthesis, imidazole dipeptides, and wound healing. Surgery. 1982 Apr;91(4):430–434. [PubMed] [Google Scholar]
  12. Gruber B. L., Kaufman L. D. A double-blind randomized controlled trial of ketotifen versus placebo in early diffuse scleroderma. Arthritis Rheum. 1991 Mar;34(3):362–366. doi: 10.1002/art.1780340315. [DOI] [PubMed] [Google Scholar]
  13. Gruber B. L., Kaufman L. D. Ketotifen-induced remission in progressive early diffuse scleroderma: evidence for the role of mast cells in disease pathogenesis. Am J Med. 1990 Sep;89(3):392–395. doi: 10.1016/0002-9343(90)90360-p. [DOI] [PubMed] [Google Scholar]
  14. Heney D., Lewis I. J., Bailey C. C. Thalidomide for chronic graft-versus-host disease in children. Lancet. 1988 Dec 3;2(8623):1317–1317. doi: 10.1016/s0140-6736(88)92931-5. [DOI] [PubMed] [Google Scholar]
  15. Hsieh K. H. The effect of ketotifen on the in vitro immune function of asthmatic children. Asian Pac J Allergy Immunol. 1983 Dec;1(2):85–88. [PubMed] [Google Scholar]
  16. Jaffee B. D., Claman H. N. Chronic graft-versus-host disease (GVHD) as a model for scleroderma. I. Description of model systems. Cell Immunol. 1983 Apr 1;77(1):1–12. doi: 10.1016/0008-8749(83)90001-1. [DOI] [PubMed] [Google Scholar]
  17. Jampel R. M., Farmer E. R., Vogelsang G. B., Wingard J., Santos G. W., Morison W. L. PUVA therapy for chronic cutaneous graft-vs-host disease. Arch Dermatol. 1991 Nov;127(11):1673–1678. [PubMed] [Google Scholar]
  18. Levi-Schaffer F., Austen K. F., Caulfield J. P., Hein A., Bloes W. F., Stevens R. L. Fibroblasts maintain the phenotype and viability of the rat heparin-containing mast cell in vitro. J Immunol. 1985 Nov;135(5):3454–3462. [PubMed] [Google Scholar]
  19. Levi-Schaffer F., Klapholz L., Kupietzky A., Weinrauch L., Shalit M., Okon E. Increased numbers of mast cells in pemphigus vulgaris skin lesions. A histochemical study. Acta Derm Venereol. 1991;71(3):269–271. [PubMed] [Google Scholar]
  20. Levi-Schaffer F., Mekori Y. A., Segal V., Claman H. N. Histamine release from mouse and rat mast cells cultured with supernatants from chronic murine graft-vs-host splenocytes. Cell Immunol. 1990 Apr 15;127(1):146–158. doi: 10.1016/0008-8749(90)90121-7. [DOI] [PubMed] [Google Scholar]
  21. Levi-Schaffer F., Segal V., Mekori Y. A., Claman H. N., Hammel I. Morphological evidence for chronic mast cell activation after prolonged exposure with supernatants from chronic graft-versus-host splenocytes. Immunol Lett. 1991 Jan;27(1):13–18. doi: 10.1016/0165-2478(91)90237-5. [DOI] [PubMed] [Google Scholar]
  22. Neudorf S., Filipovich A., Ramsay N., Kersey J. Prevention and treatment of acute graft-versus-host disease. Semin Hematol. 1984 Apr;21(2):91–100. [PubMed] [Google Scholar]
  23. Nishioka K., Kobayashi Y., Katayama I., Takijiri C. Mast cell numbers in diffuse scleroderma. Arch Dermatol. 1987 Feb;123(2):205–208. [PubMed] [Google Scholar]
  24. Noma T., Yoshizawa I., Baba M., Yata J., Akasaka T., Maeda K. Effect of ketotifen on antigen-induced interleukin 2 (IL-2) responsiveness in lymphocytes from patients with atopic dermatitis and/or bronchial asthma. Int J Immunopharmacol. 1990;12(3):269–277. doi: 10.1016/0192-0561(90)90082-x. [DOI] [PubMed] [Google Scholar]
  25. Petrasch S., van Tits L. J., Motulsky H. J., Brodde O. E., Michel M. C. Effects of ketotifen on human lymphocytes in vitro and in vivo. Arzneimittelforschung. 1993 Aug;43(8):904–908. [PubMed] [Google Scholar]
  26. Seibold J. R., Giorno R. C., Claman H. N. Dermal mast cell degranulation in systemic sclerosis. Arthritis Rheum. 1990 Nov;33(11):1702–1709. doi: 10.1002/art.1780331114. [DOI] [PubMed] [Google Scholar]
  27. Shaff R. E., Beaven M. A. Increased sensitivity of the enzymatic isotopic assay of histamine: measurement of histamine in plasma and serum. Anal Biochem. 1979 Apr 15;94(2):425–430. doi: 10.1016/0003-2697(79)90385-3. [DOI] [PubMed] [Google Scholar]
  28. Sheppard M. N., Harrison N. K. New perspectives on basic mechanisms in lung disease. 1. Lung injury, inflammatory mediators, and fibroblast activation in fibrosing alveolitis. Thorax. 1992 Dec;47(12):1064–1074. doi: 10.1136/thx.47.12.1064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Socie G., Devergie A., Cosset J. M., Pierga J. Y., Esperou H., Girinski T., Gluckman E. Low-dose (one gray) total-lymphoid irradiation for extensive, drug-resistant chronic graft-versus-host disease. Transplantation. 1990 Mar;49(3):657–658. doi: 10.1097/00007890-199003000-00038. [DOI] [PubMed] [Google Scholar]
  30. Sullivan K. M., Shulman H. M., Storb R., Weiden P. L., Witherspoon R. P., McDonald G. B., Schubert M. M., Atkinson K., Thomas E. D. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood. 1981 Feb;57(2):267–276. [PubMed] [Google Scholar]
  31. Sullivan K. M., Witherspoon R. P., Storb R., Weiden P., Flournoy N., Dahlberg S., Deeg H. J., Sanders J. E., Doney K. C., Appelbaum F. R. Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation. Blood. 1988 Aug;72(2):546–554. [PubMed] [Google Scholar]
  32. Vogelsang G. B., Farmer E. R., Hess A. D., Altamonte V., Beschorner W. E., Jabs D. A., Corio R. L., Levin L. S., Colvin O. M., Wingard J. R. Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med. 1992 Apr 16;326(16):1055–1058. doi: 10.1056/NEJM199204163261604. [DOI] [PubMed] [Google Scholar]
  33. Waldmann H., Polliak A., Hale G., Or R., Cividalli G., Weiss L., Weshler Z., Samuel S., Manor D., Brautbar C. Elimination of graft-versus-host disease by in-vitro depletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody (CAMPATH-1). Lancet. 1984 Sep 1;2(8401):483–486. doi: 10.1016/s0140-6736(84)92564-9. [DOI] [PubMed] [Google Scholar]
  34. Walker M., Harley R., LeRoy E. C. Ketotifen prevents skin fibrosis in the tight skin mouse. J Rheumatol. 1990 Jan;17(1):57–59. [PubMed] [Google Scholar]
  35. Wingard J. R., Piantadosi S., Vogelsang G. B., Farmer E. R., Jabs D. A., Levin L. S., Beschorner W. E., Cahill R. A., Miller D. F., Harrison D. Predictors of death from chronic graft-versus-host disease after bone marrow transplantation. Blood. 1989 Sep;74(4):1428–1435. [PubMed] [Google Scholar]
  36. Wingren U., Enerbäck L. Mucosal mast cells of the rat intestine: a re-evaluation of fixation and staining properties, with special reference to protein blocking and solubility of the granular glycosaminoglycan. Histochem J. 1983 Jun;15(6):571–582. doi: 10.1007/BF01954148. [DOI] [PubMed] [Google Scholar]
  37. Zucali J. R., Dinarello C. A., Oblon D. J., Gross M. A., Anderson L., Weiner R. S. Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony-stimulating activity and prostaglandin E2. J Clin Invest. 1986 Jun;77(6):1857–1863. doi: 10.1172/JCI112512. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES