Summary
The effect of a single subcutaneous injection of various doses of the lipophilic muramyl tripeptide MTP-PE on cell proliferation was investigated in autoradiographs of histological sections of various organs of the guinea pig. The animals either received first MTP-PE in saline and then one3H-thymidine pulse 1 h prior to sacrifice, or they were prelabeled with3H-thymidine and then received MTP-PE. The number of proliferating cells increased up to between two and fivefold (marginally after 0.3 mg/kg and maximally after 30 mg/kg MTP-PE), but differed in the various organs. In addition, the time of the maximal increase varied between 5 h and 72 h after MTP-PE treatment and also depended on the organ. The majority of proliferating cells were of the monocyte lineage seen in conjunction with the vascular system. They were apparently promonocytes still capable of proliferation. Evidence for this conclusion is derived from (i) the distribution of 1 h-pulse-labeled cells in the various organ compartments in relation to the stimulated proliferation of the bone-marrow cells, and (ii) the distribution of the prelabeled, mainly bone-marrow derived cells, to the various organs. The augmented proliferation of the monocyte lineage is preceded by a dose-dependent, short-lasting increase in the proliferation of some epithelia and also by an increase in body temperature and a transient change in plasma proteins. These effects are part of a limited inflammatory reaction and may contribute to the immunostimulation.
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References
Allison AC, Wachsmuth ED (1986) MDP and derivatives II. In: Chedid L, Hadden JW, Spreafico F, Dukor P, Willoughby D (eds) Advances in immunopharmacology 3. Pergamon Press, London, pp 479–485
Braun DG, Dukor P, Lukas B, Schumann G, Tarsay L, Court M, Schaffner JC, Skripsky T, Fischer M, Graepel P (1987) MTP-PE, a synthetic lipophilic muramyltripeptide, biological and toxicological properties. In: Berlin A, Dean J, Draper H, Smith EMB, Spreafico F (eds) Immunotoxicology. Martinus Nijhoff Publ, Dordrecht, pp 219–233
Brownbill AF, Braun DG, Dukor P, Schumann G (1985) Induction of tumouricidal leucocytes by the intranasal application of MTP-PE, a lipophilic muramyl dipeptide. Cancer Immunol Immunother 20:11–17
Broudy VC, Kaushansky K, Adamson JW (1988) Muramyl dipeptide (MDP) induced hematopoetic growth factor production in vivo by a mechanism independent of tumor necrosis factor (TNF). Clin Res 36:406 A
Dietrich FM, Hochkeppel HK, Lukas B (1986) Enhancement of host resistance against virus infections by MTP-PE, a synthetic muramyl peptide. I. Increased survival in mice and guinea pigs after a single drug administration prior to infection, and the effect of MTP-PE on interferon levels in sera and lungs. Int J Immunopharmacol 8:931–942
Fidler IJ (1986) Optimization and limitations of systemic treatment of murine melanoma metastases with liposomes containing muramyl tripeptide phosphatidylethanolamine. Cancer Immunol Immunother 21:169–173
Fidler IJ, Brown NO, Hart IR (1985) Species variability for toxicity of free and liposome-encapsulated muramyl peptides administered intravenously. J Biol Resp Modif 4:298–309
Fidler IJ, Sone S, Fogler WE, Smith D, Braun DG, Tarcsay L, Gisler RH, Schroit AJ (1982) Efficacy of liposomes containing a lipophilic muramyl dipeptide derivative for activating the tumoricidal properties of alveolar macrophages in vivo. J Biol Resp Modif 1:43–55
Fidler IJ, Jessup JM, Fogler WE, Staerkel R, Mazumder A (1986) Activation of tumoricidal properties in peripheral blood monocytes of patients with colorectal carcinoma. Cancer Res 46:994–998
Gisler RH, Schumann G, Sackmann W, Pericin C, Tarcsay L, Dietrich FM (1982) A novel muramyl peptide, MTP-PE: Profile and biological activities. In: Yamamura Y, Kotani S (eds) Immunomodulation by microbial products and related synthetic compounds. Excerpta Medica, Amsterdam, pp 167–170
Hanagan JR, Trunet P, LeSher D, Andrejcio K, Frost H (1989) Phase I development of CGP 19835A lipid (MTP-PE encapsulated in liposomes). In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the therapy of infectious diseases and cancer. A R Liss Inc, New York, pp 305–315
Jonckheere AR (1954) Distribution free k-sample test against ordered alternatives. Biometrika 41:133–145
Key ME, Talmadge JE, Fogler WE, Bucana C, Fidler FJ (1983) Isolation of tumoricidal macrophages from lung melanoma metastases of mice treated systemically with liposomes containing a lipophilic derivative of muramyl dipeptide. J Natl Cancer Inst 69:1189–1198
Kleinermann ES, Erickson KL, Schroit AJ, Fogler WE, Fidler IJ (1983) Activation of tumoricidal properties in human blood monocytes by liposomes containing lipophilic muramyl tripeptide. Cancer Res 43:2010–2014
Masek K (1986) Immunopharmacology of muramyl peptides. Fed Proc Fed Am Soc Exp Biol 45:2549–2551
MacEwen EG, Kurzman ID, Smith BW, Rosenthal RC (1989) Therapy of metastasis in canine osteosarcoma. In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the therapy of infectious diseases and cancer. A R Liss Inc, New York, pp 117–124
Mutzuura S, Sone S, Tsubura K, Tachibana K, Kishino Y (1986) Activation of antitumor properties in alveolar macrophages from protein-calorie malnourished rats. Cancer Immunol Immunother 21:63–68
Osada Y, Otani T, Sato M, Une T, Matsumoto K, Ogawa H (1982) Polymorphonuclear leukocyte activation by a synthetic muramyl dipeptide analog. Infect Immun 38:848–854
Pabst JJ, Johnston jr, RB (1980) Increased production of superoxide anion by macrophages exposed in vitro to muramyl dipeptide or lipopolysaccharide. J Exp Med 151:101–114
Schroit A, Galligioni E, Fidler IJ (1983) Factors influencing the in situ activation of macrophages by liposomes containing muramyl dipeptide. Biol Cell 47:87–94
Schumann G (1987) Biological activities of a lipophilic muramyl peptide (MTP-PE). In: Azuma I, Jolles G (eds) Immunostimulants: now and tomorrow. Japan Sci Soc Press, Tokyo and Springer, Berlin, pp 71–77
Seifert J, Sebestova L, Masek K (1988) The stimulatory effect of muramyl dipeptide (MDP) on the proliferation processes in parenchymal organs of rats. Int J Immunopharmacol 10:67–72
Sone S, Utsugi T, Tandon P, Ogawara M (1986) A dried preparation of liposomes containing muramyl tripeptide phosphatidyl-ethanolmaine as a potent activator of human blood monocytes to the antitumor state. Cancer Immunol Immunother 22:191–196
Stukart MJ, Rijnsent A, Roos E (1987) Induction of tumoricidal activity in isolated rat liver macrophages by liposomes containing recombinant rat gamma-interferon supplemented with lipopolysaccharide or muramyldipeptide. Cancer Res 47:3880–3885
Wachsmuth ED (1988) Stimulation of cell proliferation in rabbits by MTP-PE, a lipophilic muramyl peptide. Virchows Arch [B] 54:195–206
Wachsmuth ED, Becker M, Grieve AP, Maurer-Schultze B (1984) Fully automated and fast image analysis of autoradiographs with a TAS-Leitz. Determination of size. Feulgen fluorescence and grain counts of individual nuclei and their evaluation by a simplified cluster analysis. Histochemistry 81:227–236
Wachsmuth ED, Dukor P (1982) Immunopathology of muramyl-peptides. In: Yamamura Y, Kotani S (eds) Immunomodulation by microbial products and related synthetic compounds. Excerpta Medica, Amsterdam, pp 60–71
Waters RV, Terrell TG, Jones GH (1986) Uveitis induction in the rabbit by muramyl dipeptides. Infect Immun 51:816–825
Wuest B, Wachsmuth ED (1982) Stimulatory effect of N-acetyl muramyl dipeptide in vivo: Proliferation of bone marrow progenitor cells in mice. Infect Immun 37:452–462
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Wachsmuth, E.D., Huber, J. Stimulant effect of the immunomodulator MTP-PE on proliferation of monocytic cells in the guinea pig. Virchows Archiv B Cell Pathol 58, 45–57 (1989). https://doi.org/10.1007/BF02890058
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DOI: https://doi.org/10.1007/BF02890058