The immune system response during development and progression of carcinogen-induced rat mammary tumors: prevention of tumor growth and restoration of immune system responsiveness by thymopentin.
A detailed analysis of the immune system response has been performed during the development and progression of dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors. For this aim, a number of immune parameters (thymocyte and splenocyte proliferative response to T-dependent mitogens, antibody production, lymphocyte subset phenotyping, interleukin 2 receptor expression in resting and activated lymphocytes, thymus morphology and morphometry), were correlated with tumor appearance and growth at different (-7, 0, +15, +30, +60, +90, and +120 days) time intervals after intragastric administration of DMBA, in the absence or the presence of a concomitant treatment with the thymic pentapeptide thymopentin (TP5). A profound and time-dependent immunosuppression characterized the treatment with the carcinogen. Both cell-mediated and humoral immune responses showed a 50% inhibition 2 weeks after DMBA administration, with a peak after 30 days, followed by a plateau until 120 days of observation. The mechanism responsible for reduced ability of thymocytes and splenocytes to respond to both Con-A and PHA was explained by the significant inhibition of one of the key steps of T cell activation, namely the expression of IL-2 receptor in lymphocytes from DMBA-treated animals. The flow cytometric analysis of lymphocyte subpopulations revealed an important reduction in the overall populations of thymocytes and splenocytes. At the thymus gland level, a dramatic reduction of double positive CD4+CD8+ and a decrease of CD4+CD8- and CD4-CD8+ were observed, together with a marked atrophy of the thymic cortex, and impairment of the thymic microenvironment. One hundred and twenty days after DMBA administration, approximately 60 to 70% of the animals developed tumors with a mean tumor surface area of 2.88 +/- 0.86 cm2, and a number of 2.44 +/- 1.0. Treatment with TP5 (100 ng/animal, three times a week, starting a week before DMBA), produced specific effects on different immune compartments and tumoral growth, characterized by a significant reversal of immune depression with a stimulatory effect measured on lymphoproliferative assays, lymphocyte subset distribution, and IL-2 receptor expression. Moreover, thymic atrophy was almost completely prevented in TP5 treated animals. Of major interest, a significant delay in the appearance and growth of tumors was observed in TP5 treated rats. When DMBA-treated animals were followed for the entire observation period (0-120 days) and the immune responsiveness correlated according to tumor progression, stability, or regression, a positive correlation was calculated between the degree of immune system depression and the individual rate of tumor growth; in TP5-treated rats the majority of the tumors were static or regressing tumors.(ABSTRACT TRUNCATED AT 400 WORDS)
Gallo
F
F
Department of Pharmacology, Medical School, University of Catania, Italy.
Morale
M C
MC
Sambataro
D
D
Farinella
Z
Z
Scapagnini
U
U
Marchetti
B
B
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000096:biosynthesis; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015375:Receptors, Interleukin-2 / Q000032:analysis; D016305:Thymopentin / Q000627:therapeutic use*; D013950:Thymus Gland / Q000473:pathology / Q000502:physiology
D007074:Immunoglobulin G; D015375:Receptors, Interleukin-2; D015127:9,10-Dimethyl-1,2-benzanthracene; D016305:Thymopentin