Abstract
The mechanism of action of 6-mercaptopurine (6-MP) on an egg albumin-induced inflammatory lesion in the skin has been studied in rabbits treated with 6-MP in a daily dosage of 18 mg/kg. Relative to control animals, significant decreases in the numbers of large lymphocytes and monocytes in the blood were observed in the 6-MP-treated animals by the 9th day of treatment, without significant decrease in the numbers of polymorphonuclear leukocytes and small and medium lymphocytes. Concurrently, a significant decrease was also seen in the percentage of tissue mononuclear cells in the inflammatory skin lesion. There was a highly significant correlation between the numbers of monocytes in the blood and the per cent of mononuclear cells in the lesion. A mean of 52% of the mononuclear cells in the tissue lesion phagocytosed carbon offering further evidence that the major cell involved was the blood monocyte. In vitro incorporation of 3H-Tdr by blood mononuclear cells was significantly reduced in the 6-MP-treated animals as determined by scintillation counting and radioautography. The large lymphocyte was the predominant cell type which was labeled in vitro. Small lymphocytes and monocytes were rarely labeled. The data obtained suggest that the anti-inflammatory effect of 6-MP, reflected in these experiments by a decrease in mononuclear cells in a tissue lesion, results from suppression of a bone marrow response to local inflammation, affecting principally proliferating precursors of blood monocytes and large lymphocytes. The possible importance of this action of 6-MP in the treatment of inflammatory and immunologically mediated disease is discussed.
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Selected References
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- BOREL Y., SCHWARTZ R. INHIBITION OF IMMEDIATE AND DELAYED HYPERSENSITIVITY IN THE RABBIT BY 6-MERCAPTOPURINE. J Immunol. 1964 May;92:754–761. [PubMed] [Google Scholar]
- Craddock C. G. Kinetics of lymphoreticular tissue, with particular emphasis on the lymphatic system. Semin Hematol. 1967 Oct;4(4):387–414. [PubMed] [Google Scholar]
- Craddock C. G., Winkelstein A., Matsuyuki Y., Lawrence J. S. The immune response to foreign red blood cells and the participation of short-lived lymphocytes. J Exp Med. 1967 Jun 1;125(6):1149–1172. doi: 10.1084/jem.125.6.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- ELION G. B., HITCHINGS G. H., VANDERWERFF H. Antagonists of nucleic acid derivatives. VI. Purines. J Biol Chem. 1951 Oct;192(2):505–518. [PubMed] [Google Scholar]
- ELION G. B., SINGER S., HITCHINGS G. H. Microbiological effects of 6-mercaptopurine. Ann N Y Acad Sci. 1954 Dec 6;60(2):200–206. doi: 10.1111/j.1749-6632.1954.tb40009.x. [DOI] [PubMed] [Google Scholar]
- ELION G. B., SINGER S., HITCHINGS G. H. The purine metabolism of a 6-mercaptopurine-resistant Lactobacillus casei. J Biol Chem. 1953 Sep;204(1):35–41. [PubMed] [Google Scholar]
- Elion G. B. Symposium on immunosuppressive drugs. Biochemistry and pharmacology of purine analogues. Fed Proc. 1967 May-Jun;26(3):898–904. [PubMed] [Google Scholar]
- FRANEK F., RIHA I., STERZL J. Characteristics of gamma-globulin, lacking antibody properties, in new-born pigs. Nature. 1961 Mar 25;189:1020–1022. doi: 10.1038/1891020a0. [DOI] [PubMed] [Google Scholar]
- Gowans J. L., Uhr J. W. The carriage of immunological memory by small lymphocytes in the rat. J Exp Med. 1966 Nov 1;124(5):1017–1030. doi: 10.1084/jem.124.5.1017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- HITCHINGS G. H., ELION G. B. Chemical suppression of the immune response. Pharmacol Rev. 1963 Jun;15:365–405. [PubMed] [Google Scholar]
- Holm G., Perlmann P. Cytotoxic potential of stimulated human lymphocytes. J Exp Med. 1967 Apr 1;125(4):721–736. doi: 10.1084/jem.125.4.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kolouch F. The lymphocyte in acute inflammation. Am J Pathol. 1939 Jul;15(4):413–428.5. [PMC free article] [PubMed] [Google Scholar]
- LATTA J. S., GENTRY R. P. The hematological alterations resulting from repeated injections of 6-mercaptopurine into AKR mice. Anat Rec. 1958 Sep;132(1):1–23. doi: 10.1002/ar.1091320102. [DOI] [PubMed] [Google Scholar]
- Lubaroff D. M., Waksman B. H. Delayed hypersensitivity: bone marrow as the source of cells in delayed skin reactions. Science. 1967 Jul 21;157(3786):322–323. doi: 10.1126/science.157.3786.322. [DOI] [PubMed] [Google Scholar]
- MILLER J. J., 3rd AN AUTORADIOGRAPHIC STUDY OF PLASMA CELL AND LYMPHOCYTE SURVIVAL IN RAT POPLITEAL LYMPH NODES. J Immunol. 1964 May;92:673–681. [PubMed] [Google Scholar]
- Miller J. J., 3rd, Cole L. J. Resistance of long-lived lymphocytes and plasma cells in rat lymph nodes to treatment with prednisone, cyclophosphamide, 6-mercaptopurine, and actinomycin D. J Exp Med. 1967 Jul 1;126(1):109–125. doi: 10.1084/jem.126.1.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller J. J., Cole L. J. The radiation resistance of long-lived lymphocytes and plasma cells in mouse and rat lymph nodes. J Immunol. 1967 May;98(5):982–990. [PubMed] [Google Scholar]
- NOSSAL G. J., ADA G. L., AUSTIN C. M. ANTIGENS IN IMMUNITY. IV. CELLULAR LOCALIZATION OF 125-I- AND 131-I-LABELLED FLAGELLA IN LYMPH NODES. Aust J Exp Biol Med Sci. 1964 Jun;42:311–330. [PubMed] [Google Scholar]
- PAGE A. R., CONDIE R. M., GOOD R. A. Effect of 6-mercaptopurine on inflammation. Am J Pathol. 1962 May;40:519–530. [PMC free article] [PubMed] [Google Scholar]
- SANTOS G. W., OWENS A. H., Jr A COMPARISON OF THE EFFECTS OF SELECTED CYTOTOXIC AGENTS ON THE PRIMARY AGGLUTININ RESPONSE IN RATS INJECTED WITH SHEEP ERYTHROCYTES. Bull Johns Hopkins Hosp. 1964 Jun;114:384–401. [PubMed] [Google Scholar]
- SCHWARTZ R., EISNER A., DAMESHEK W. The effect of 6-mercaptopurine on primary and secondary immune responses. J Clin Invest. 1959 Aug;38(8):1394–1403. doi: 10.1172/JCI103915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- STERZL J. Inhibition of the inductive phase of antibody formation by 6-mercaptopurine examined by the transfer of isolated cells. Nature. 1960 Jan 23;185:256–257. doi: 10.1038/185256a0. [DOI] [PubMed] [Google Scholar]
- Santos G. W. Symposium on immunosuppressive drugs. Immunosuppressive drugs. I. Fed Proc. 1967 May-Jun;26(3):907–913. [PubMed] [Google Scholar]
- Spector W. G., Walters M. N., Willoughby D. A. The origin of the mononuclear cells in inflammatory exudates induced by fibrinogen. J Pathol Bacteriol. 1965 Jul;90(1):181–192. doi: 10.1002/path.1700900119. [DOI] [PubMed] [Google Scholar]
- Swanson M. A., Schwartz R. S. Immunosuppressive therapy. The relation between clinical response and immunologic competence. N Engl J Med. 1967 Jul 27;277(4):163–170. doi: 10.1056/NEJM196707272770401. [DOI] [PubMed] [Google Scholar]
- Vischer T. L., Stastny P. Time of appearance and distribution of cells capable of secondary immune response following primary immunization. Immunology. 1967 Jun;12(6):675–687. [PMC free article] [PubMed] [Google Scholar]