Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1991 Oct;88(4):1331–1337. doi: 10.1172/JCI115438

Immunosuppressive activity of 13-cis-retinoic acid and prevention of experimental autoimmune encephalomyelitis in rats.

L Massacesi 1, E Castigli 1, M Vergelli 1, J Olivotto 1, A L Abbamondi 1, F Sarlo 1, L Amaducci 1
PMCID: PMC295603  PMID: 1918383

Abstract

Some activities of retinoids on cellular and humoral immunity have been described, but the available data are conflicting or obtained at concentrations that are toxic in vivo. In this study, we demonstrate that 13-cis-retinoic acid (13-cRA), a retinoid well tolerated in human therapy, can suppress T cell-mediated immunity in rats. Treatment with pharmacological concentrations of 13-cRA prevented active as well as passive transfer experimental autoimmune encephalomyelitis (EAE) and suppressed lymphocyte responsiveness to T cell mitogens, suggesting that the drug activity included suppression of an effector T cell response. In addition, mitogen- and antigen-induced lymphocyte proliferation was inhibited in vitro in the presence of concentrations of 13-cRA equivalent to or less than those achieved in vivo, further suggesting that the prevention of EAE was due to a suppressive activity on T cell-mediated immunity. The immunosuppressive activity of 13-cRA included suppression of interleukin 2, whose production was inhibited in splenocytes. These data indicate that, in an in vivo mammalian system, 13-cRA exerts a suppressive activity on T cell-mediated immunity intensive enough to suppress an ongoing immune response, and that this effect can be achieved at nontoxic concentrations that may also be attained in human therapy.

Full text

PDF
1331

Selected References

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

  1. Abb J., Abb H., Deinhardt F. Effect of retinoic acid on the spontaneous and interferon-induced activity of human natural killer cells. Int J Cancer. 1982 Sep 15;30(3):307–310. doi: 10.1002/ijc.2910300309. [DOI] [PubMed] [Google Scholar]
  2. Abb J., Abb H., Deinhardt F. Retinoic acid suppression of human leukocyte interferon production. Immunopharmacology. 1982 Aug;4(4):303–310. doi: 10.1016/0162-3109(82)90051-0. [DOI] [PubMed] [Google Scholar]
  3. Barnett J. B. Immunomodulating effects of 13-cis retinoic acid on the IgG and IgM response of BALB/c mice. Int Arch Allergy Appl Immunol. 1983;72(3):227–233. doi: 10.1159/000234872. [DOI] [PubMed] [Google Scholar]
  4. Bedford P. A., Knight S. C. The effect of retinoids on dendritic cell function. Clin Exp Immunol. 1989 Mar;75(3):481–486. [PMC free article] [PubMed] [Google Scholar]
  5. Ben-Nun A., Lando Z. Detection of autoimmune cells proliferating to myelin basic protein and selection of T cell lines that mediate experimental autoimmune encephalomyelitis (EAE) in mice. J Immunol. 1983 Mar;130(3):1205–1209. [PubMed] [Google Scholar]
  6. Blalock J. E., Gifford G. E. Comparison of the suppression of interferon production and inhibition of its action by vitamin A and related compounds. Proc Soc Exp Biol Med. 1976 Nov;153(2):298–300. doi: 10.3181/00379727-153-39532. [DOI] [PubMed] [Google Scholar]
  7. Blomhoff R., Green M. H., Berg T., Norum K. R. Transport and storage of vitamin A. Science. 1990 Oct 19;250(4979):399–404. doi: 10.1126/science.2218545. [DOI] [PubMed] [Google Scholar]
  8. Bollag W., Ott F. Treatment of lichen planus with temarotene. Lancet. 1989 Oct 21;2(8669):974–974. doi: 10.1016/s0140-6736(89)90976-8. [DOI] [PubMed] [Google Scholar]
  9. Bollag W. Vitamin A and retinoids: from nutrition to pharmacotherapy in dermatology and oncology. Lancet. 1983 Apr 16;1(8329):860–863. doi: 10.1016/s0140-6736(83)91394-6. [DOI] [PubMed] [Google Scholar]
  10. Bolton C., Borel J. F., Cuzner M. L., Davison A. N., Turner A. M. Immunosuppression by cyclosporin A of experimental allergic encephalomyelitis. J Neurol Sci. 1982 Nov;56(2-3):147–153. doi: 10.1016/0022-510x(82)90138-1. [DOI] [PubMed] [Google Scholar]
  11. Brinckerhoff C. E., Coffey J. W., Sullivan A. C. Inflammation and collagenase production in rats with adjuvant arthritis reduced with 13-cis-retinoic acid. Science. 1983 Aug 19;221(4612):756–758. doi: 10.1126/science.6308759. [DOI] [PubMed] [Google Scholar]
  12. Chytil F., Ong D. E. Cellular retinol- and retinoic acid-binding proteins in vitamin A action. Fed Proc. 1979 Oct;38(11):2510–2514. [PubMed] [Google Scholar]
  13. Clamon G., Chabot G. G., Valeriote F., Davilla E., Vogel C., Gorowski E., Birch R. Phase I study and pharmacokinetics of weekly high-dose 13-cis-retinoic acid. Cancer Res. 1985 Apr;45(4):1874–1878. [PubMed] [Google Scholar]
  14. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  15. Deibler G. E., Martenson R. E., Kies M. W. Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species. Prep Biochem. 1972;2(2):139–165. doi: 10.1080/00327487208061467. [DOI] [PubMed] [Google Scholar]
  16. Dennert G., Lotan R. Effects of retinoic acid on the immune system: stimulation of T killer cell induction. Eur J Immunol. 1978 Jan;8(1):23–29. doi: 10.1002/eji.1830080106. [DOI] [PubMed] [Google Scholar]
  17. Dresser D. W. Adjuvanticity of vitamin A. Nature. 1968 Feb 10;217(5128):527–529. doi: 10.1038/217527a0. [DOI] [PubMed] [Google Scholar]
  18. Eremin O., Ashby J., Rhodes J. Inhibition of antibody-dependent cellular cytotoxicity and natural cytotoxicity by retinoic acid. Int Arch Allergy Appl Immunol. 1984;75(1):2–7. doi: 10.1159/000233581. [DOI] [PubMed] [Google Scholar]
  19. Evans R. M. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. doi: 10.1126/science.3283939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Giguere V., Ong E. S., Segui P., Evans R. M. Identification of a receptor for the morphogen retinoic acid. Nature. 1987 Dec 17;330(6149):624–629. doi: 10.1038/330624a0. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Glick A. B., Flanders K. C., Danielpour D., Yuspa S. H., Sporn M. B. Retinoic acid induces transforming growth factor-beta 2 in cultured keratinocytes and mouse epidermis. Cell Regul. 1989 Nov;1(1):87–97. doi: 10.1091/mbc.1.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Goodman D. S. Vitamin A and retinoids in health and disease. N Engl J Med. 1984 Apr 19;310(16):1023–1031. doi: 10.1056/NEJM198404193101605. [DOI] [PubMed] [Google Scholar]
  24. Hashimoto Y., Kagechika H., Shudo K. Expression of retinoic acid receptor genes and the ligand-binding selectivity of retinoic acid receptors (RAR's). Biochem Biophys Res Commun. 1990 Feb 14;166(3):1300–1307. doi: 10.1016/0006-291x(90)91007-f. [DOI] [PubMed] [Google Scholar]
  25. Hughes T. K., Russell J. K., Blalock J. E. Induction of interferon by transformed cells: inhibition by retinoic acid. Biochem Biophys Res Commun. 1986 Jul 16;138(1):47–53. doi: 10.1016/0006-291x(86)90244-5. [DOI] [PubMed] [Google Scholar]
  26. Kalin J. R., Wells M. J., Hill D. L. Disposition of 13-cis-retinoic acid and N-(2-hydroxyethyl)retinamide in mice after oral doses. Drug Metab Dispos. 1982 Jul-Aug;10(4):391–398. [PubMed] [Google Scholar]
  27. Kastner P., Krust A., Mendelsohn C., Garnier J. M., Zelent A., Leroy P., Staub A., Chambon P. Murine isoforms of retinoic acid receptor gamma with specific patterns of expression. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2700–2704. doi: 10.1073/pnas.87.7.2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kensler T. W., Mueller G. C. Retinoic acid inhibition of the comitogenic action of mezerein and phorbol esters in bovine lymphocytes. Cancer Res. 1978 Mar;38(3):771–775. [PubMed] [Google Scholar]
  29. Kensler T. W., Verma A. K., Boutwell R. K., Mueller G. C. Effects of retinoic acid and juvenile hormone on the induction of ornithine decarboxylase activity by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 1978 Sep;38(9):2896–2899. [PubMed] [Google Scholar]
  30. Kerr I. G., Lippman M. E., Jenkins J., Myers C. E. Pharmacology of 13-cis-retinoic acid in humans. Cancer Res. 1982 May;42(5):2069–2073. [PubMed] [Google Scholar]
  31. Kessler J. F., Meyskens F. L., Jr, Levine N., Lynch P. J., Jones S. E. Treatment of cutaneous T-cell lymphoma (mycosis fungoides) with 13-cis-retinoic acid. Lancet. 1983 Jun 18;1(8338):1345–1347. doi: 10.1016/s0140-6736(83)92136-0. [DOI] [PubMed] [Google Scholar]
  32. LEVINE S., STREBEL R., WENK E. J., HARMAN P. J. Suppression of experimental allergic encephalomyelitis by stress. Proc Soc Exp Biol Med. 1962 Feb;109:294–298. doi: 10.3181/00379727-109-27183. [DOI] [PubMed] [Google Scholar]
  33. Larsen P. D., DeLallo L. J. Cerebrospinal fluid transthyretin in multiple sclerosis. Neurology. 1987 Jul;37(7):1262–1263. doi: 10.1212/wnl.37.7.1262. [DOI] [PubMed] [Google Scholar]
  34. MacPhee I. A., Antoni F. A., Mason D. W. Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med. 1989 Feb 1;169(2):431–445. doi: 10.1084/jem.169.2.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mangelsdorf D. J., Ong E. S., Dyck J. A., Evans R. M. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. doi: 10.1038/345224a0. [DOI] [PubMed] [Google Scholar]
  36. Massacesi L., Abbamondi A. L., Giorgi C., Sarlo F., Lolli F., Amaducci L. Suppression of experimental allergic encephalomyelitis by retinoic acid. J Neurol Sci. 1987 Aug;80(1):55–64. doi: 10.1016/0022-510x(87)90220-6. [DOI] [PubMed] [Google Scholar]
  37. McCormick A. M., Napoli J. L., Deluca H. F. High-pressure liquid chromatographic resolution of vitamin A compounds. Anal Biochem. 1978 May;86(1):25–33. doi: 10.1016/0003-2697(78)90315-9. [DOI] [PubMed] [Google Scholar]
  38. Nordlind K., Thyberg J. In vitro effects of 13-cis-retinoic acid (Ro 4-3780) and etretinate (Ro 10-9359) on DNA synthesis and fine structure of guinea pig and human lymphoid cells. Int Arch Allergy Appl Immunol. 1983;71(4):363–367. doi: 10.1159/000233421. [DOI] [PubMed] [Google Scholar]
  39. Norton W. T., Poduslo S. E. Myelination in rat brain: method of myelin isolation. J Neurochem. 1973 Oct;21(4):749–757. doi: 10.1111/j.1471-4159.1973.tb07519.x. [DOI] [PubMed] [Google Scholar]
  40. Ortiz-Ortiz L., Weigle W. O. Cellular events in the induction of experimental allergic encephalomyelitis in rats. J Exp Med. 1976 Sep 1;144(3):604–616. doi: 10.1084/jem.144.3.604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Otani S., Matsui-Yuasa I., Mimura Y., Morisawa S. Potentiation by retinoic acid of ornithine decarboxylase induction by phytohemagglutinin or phorbol 12-myristate 13-acetate in guinea pig lymphocytes. J Biochem. 1986 Jun;99(6):1789–1797. doi: 10.1093/oxfordjournals.jbchem.a135657. [DOI] [PubMed] [Google Scholar]
  42. Panitch H. S., McFarlin D. E. Experimental allergic encephalomyelitis: enhancement of cell-mediated transfer by concanavalin A. J Immunol. 1977 Sep;119(3):1134–1137. [PubMed] [Google Scholar]
  43. Peck G. L., Olsen T. G., Yoder F. W., Strauss J. S., Downing D. T., Pandya M., Butkus D., Arnaud-Battandier J. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med. 1979 Feb 15;300(7):329–333. doi: 10.1056/NEJM197902153000701. [DOI] [PubMed] [Google Scholar]
  44. Rees J. L., Daly A. K., Redfern C. P. Differential expression of the alpha and beta retinoic acid receptors in tissues of the rat. Biochem J. 1989 May 1;259(3):917–919. doi: 10.1042/bj2590917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rhodes J., Stokes P. Interferon-induced changes in the monocyte membrane: inhibition by retinol and retinoic acid. Immunology. 1982 Mar;45(3):531–536. [PMC free article] [PubMed] [Google Scholar]
  46. Richert J. R., Driscoll B. F., Kies M. W., Alvord E. C., Jr Experimental allergic encephalomyelitis: activation of myelin basic protein-sensitized spleen cells by specific antigen in culture. Cell Immunol. 1981 Mar 15;59(1):42–53. doi: 10.1016/0008-8749(81)90432-9. [DOI] [PubMed] [Google Scholar]
  47. Sedgwick J., Brostoff S., Mason D. Experimental allergic encephalomyelitis in the absence of a classical delayed-type hypersensitivity reaction. Severe paralytic disease correlates with the presence of interleukin 2 receptor-positive cells infiltrating the central nervous system. J Exp Med. 1987 Apr 1;165(4):1058–1075. doi: 10.1084/jem.165.4.1058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Sidell N., Ramsdell F. Retinoic acid upregulates interleukin-2 receptors on activated human thymocytes. Cell Immunol. 1988 Sep;115(2):299–309. doi: 10.1016/0008-8749(88)90183-9. [DOI] [PubMed] [Google Scholar]
  49. Sidell N., Rieber P., Golub S. H. Immunological aspects of retinoids in humans. I. Analysis of retinoic acid enhancement of thymocyte responses to PHA. Cell Immunol. 1984 Aug;87(1):118–125. doi: 10.1016/0008-8749(84)90136-9. [DOI] [PubMed] [Google Scholar]
  50. Smith M. E., Somera F. P., Saldivar R., Massacesi L., Trotter J. DNA changes in spinal cords of rats with experimental allergic encephalomyelitis. J Neurochem. 1984 Dec;43(6):1635–1641. doi: 10.1111/j.1471-4159.1984.tb06089.x. [DOI] [PubMed] [Google Scholar]
  51. Spitznagel J. K., Allison A. C. Mode of action of adjuvants: retinol and other lysosome-labilizing agents as adjuvants. J Immunol. 1970 Jan;104(1):119–127. [PubMed] [Google Scholar]
  52. Sporn M. B., Roberts A. B., Wakefield L. M., de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987 Sep;105(3):1039–1045. doi: 10.1083/jcb.105.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Traugott U. Detailed analysis of early immunopathologic events during lesion formation in acute experimental autoimmune encephalomyelitis. Cell Immunol. 1989 Mar;119(1):114–129. doi: 10.1016/0008-8749(89)90228-1. [DOI] [PubMed] [Google Scholar]
  54. Trentham D. E., Brinckerhoff C. E. Augmentation of collagen arthritis by synthetic analogues of retinoic acid. J Immunol. 1982 Dec;129(6):2668–2672. [PubMed] [Google Scholar]
  55. UHR J. W., WEISSMANN G., THOMAS L. Acute hypervitaminosis A in guinea pigs. II. Effects on delayed-type hypersensitivity. Proc Soc Exp Biol Med. 1963 Feb;112:287–291. doi: 10.3181/00379727-112-28018. [DOI] [PubMed] [Google Scholar]
  56. Vane F. M., Stoltenborg J. K., Buggé C. J. Determination of 13-cis-retinoic acid and its major metabolite, 4-oxo-13-cis-retinoic acid, in human blood by reversed-phase high-performance liquid chromatography. J Chromatogr. 1982 Feb 12;227(2):471–484. doi: 10.1016/s0378-4347(00)80400-4. [DOI] [PubMed] [Google Scholar]
  57. Vasios G. W., Gold J. D., Petkovich M., Chambon P., Gudas L. J. A retinoic acid-responsive element is present in the 5' flanking region of the laminin B1 gene. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9099–9103. doi: 10.1073/pnas.86.23.9099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wertz P. W., Kensler T. W., Mueller G. C., Verma A. K., Boutwell R. K. 5,6-epoxyretinoic acid opposes the effects of 12-O-tetradecanoylphorbol-13-acetate in bovine lymphocytes. Nature. 1979 Jan 18;277(5693):227–229. doi: 10.1038/277227a0. [DOI] [PubMed] [Google Scholar]
  59. de The H., Marchio A., Tiollais P., Dejean A. Differential expression and ligand regulation of the retinoic acid receptor alpha and beta genes. EMBO J. 1989 Feb;8(2):429–433. doi: 10.1002/j.1460-2075.1989.tb03394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES