[State surveillance and control of food quality and safety in USA]. / Sistema gosudarstvennogo nadzora za kachestvom i bezopasnost'iu pishchevykh produktov v SShA.

The article is dealt with organization of agencies of U.S. federal government responsible for control of food safety and quality. An organizational chart of the Food and Drug Administration (FDA) of Department of Health and Human services is shown in great details. The U.S. federal legislation on food safety and quality is also described. Legal terms and definitions set by Federal Food, Drug and Safety Act for food safety and quality as well as basis requirements set in U.S.A. for food operation facilities are also discussed.

The secretory immune system as part of the placental barrier in the second trimester of pregnancy in humans.

The objective of this study was to describe the development of the secretory immune system (SIS) in the placenta of 32 human fetuses who had died from different causes during the second trimester of pregnancy. The distribution of SIS protein elements, including the secretory component (SC), J-chain, IgA, IgM, IgG, as well subsets of lymphocytes and macrophages, were studied by immunohistochemical methods. Both the fetal and maternal parts of the placenta were found to contain these elements. In the fetal part, the immunoglobulins, SC and J chain were located in the syncytio- and cytotrophoblast of the chorion and in the epithelium of the amnion. The villous stroma contained a small amount of different subsets of lymphocytes. Macrophages accounted for up to 45% of the stromal cells of the villi and contained IgG and J-chain. In the maternal part of the placenta, the SIS proteins were in the decidual cells. Relatively few lymphocytes and macrophages were observed in the decidual stroma. Our data suggest that the placenta has two different SIS, one in the fetal part and the other in the maternal part. They differ in their structure and orientation: the maternal SIS protects the mother against paternal antigens from the fetus, while the fetal SIS protects the fetus against macromolecules and infectious agents penetrating from the mother. The placenta represents the largest extracorporal immune system that is functionally active during the whole second trimester of gestation. We suggest that the concept of placental barrier should be expanded to include both fetal and maternal parts of the SIS, fetal membranes and the decidual tissue.

[Comparative characteristics of state control of food quality and safety in various countries of the world. I. State control of quality and safety of food products in Germany and Denmark]. / Sravnitel'naia kharakteristika sistem gosudarstvennogo kontrolia kachestva i bezopasnosti pishchevykh produktov v raznykh stranakh mira. Soobshchenie 1-e. Gosudarstvennyi kontrol' kachestva i bezopasnosti pishchevykh produktov v Germanii i Danii.

The official control of food safety and quality is the most important tool for governmental protection of public health and consumers rights in foodstuffs business sector. Although historically each country developed it's own system reflecting national culture, economy etc., tremendous efforts were made in recent decades to pursue international harmonization of national food laws and regulation. The major goal of harmonization is to ensure that food laws and regulations of various countries are based on sound science and that consumers of various countries benefit from advances of new technologies. Germany and Denmark are members of European Union. Therefore basic principles of official foodstuffs control of both countries have been harmonized with respective EU directives. In contrast to Russia, the systems in both countries are not based on pre-market product certification and are focused instead on approval of manufacturing, storage and sale facilities as well as products related business practices of foodstuff suppliers.

Expression of apoptosis and apoptosis-related proteins in microvessels of human ovarian epithelial tumors.

We performed an immunohistochemical analysis of apoptosis and the expression of apoptosis-related proteins (ARP) such as Fas and Fas ligand (FasL), bcl-2 and p53 in human ovarian epithelial tumors. Fas and FasL were abundant in endothelial cells of microvessels, and were observed, at times, in the myocytes of small arteries and veins, in parietal or in obstructive thrombi and fibroblasts. Apoptosis was also noticed in the endothelial cells of capillaries and sinuses. The expression of bcl-2 or p53 was rare. We found that the progression of tumor development was accompanied by considerable changes in the microvessels of ovarian tumors. These changes are probably related to the effect of ARP that are expressed by tumor epithelial cells, lymphocytes and macrophages. We suggest that the ARP are released as a result of necrosis of these cells and are taken up by cells of microvessels and by the cellular remnants of blood clots. The effect of tumors on the microvasculature can be regarded as an angiopathy that results in necrosis and hemorrhage within the tumoral tissue and enhances the progression of the malignancy.

Immunoprotection of gonads and genital tracts in human embryos and fetuses: immunohistochemical study.

PROBLEM: The immune protection of genital organs in embryogenesis has not been sufficiently studied. The purpose of this study was to investigate the development of the secretory immune system (SIS) in the gonads and genital tracts of human embryos and fetuses. MATERIALS AND METHODS: Developing gonads at different stages and genital tracts from 18 embryos and 39 fetuses in the first to third trimester of gestation were analyzed for presence of different component of SIS: secretory component (SC), joining (J) chain. IgA, IgM, IgG, macrophages, and subsets of lymphocytes. The material was divided into two groups: cases not subjected to foreign antigenic effects (group I, n = 31) and those under antigenic attack (chorioamnionitis, group II, n = 26). RESULTS: In embryos and fetuses of group I, SC, J chain, and IgG were seen in the epithelium of mesonephric and paramesonephric ducts, proliferating coelomic epithelium, epithelium of the uterine tubes and uterus, epithelium of the vas deferens, epididymis, and rete testis. IgA and IgM appeared in 6-week-old embryos. J chain, IgA, IgM, and IgG, but not SC, were found in the primary oocytes and oogonia, spermatogonia. and interstitial cells. An abundance of macrophages was seen in 4-week-old embryos. T and B lymphocytes first appeared in 6-7-week-old embryos. In embryos and fetuses of group II, reactivity of immunoglobulins (Igs) decreased until they disappeared altogether. CONCLUSIONS: Components of SIS were seen in genital organs in 4-5-week-old embryos and were present during the whole intrauterine period. We suggest the presence of two forms of immune protection of fetal genital organs. One form contains SC, J chain, and Igs and is present in the genital tract epithelium. The second form contains only J chain and Igs and is present in germ cells of gonads. The loss of Igs in cases with chorioamnionitis reflects the functional participation of the SIS of genital organs in response to antigen attack.

Apoptosis and apoptosis-related proteins (Fas, Fas ligand, bcl-2, p53) in macrophages of human ovarian epithelial tumors.

Apoptosis and the apoptosis-related proteins (ARP) (Fas, Fas ligand (FasL), bcl-2 and p53) were analyzed in macrophages of different human ovarian epithelial tumors. Few macrophages were found in ovaries of women without oncologic disorders. In ovarian benign cysts, macrophagic density reached 4.9+/-1.2 per 50,000 microm2, most were present in lymphoid-macrophagic infiltrates of the sub-epithelial stroma (3.7+/-0.5% of the area of a slide), and 23.4% were Fas and FasL positive. In borderline tumors, the expanse of lymphoid infiltrates increased to 15.6% of the area of a slide, and the number of macrophages increased 2.4-fold compared to benign cysts. Of the macrophages, 83-88% expressed Fas and FasL, few had bcl-2 and CD25 receptors, and isolated ones were apoptotic. In carcinomas with high lymphoid-macrophagic infiltration, the infiltrate occupied 17.5% of the slide and macrophages amounted to 12.1+/-1.5/50,000 microm2. Many macrophages were in regions of grouping apoptosis of tumor epithelial cells and significantly fewer expressed Fas, FasL and bcl-2. Macrophages destroyed by apoptosis accounted for 4.6%. In carcinomas with low lymphoid-macrophageal infiltration, the area of the last was 5.1% of the slide. There were 8.6+/-0.8 macrophages/50,000 microm2, mainly at the margins of zones of necrosis and of tumor cells' grouping apoptosis. Extensive macrophagic infiltration into tumor parenchyma is one way by which the host immune system destroys tumors. Fas and FasL appear in macrophages of benign cysts, but in borderline tumors and in carcinomas with low infiltration their concentration increases sharply, to 79.8% and 96.6%, respectively. In 4.5% of these cells, apoptosis of macrophages was seen. The findings suggest that macrophages participate in the transfer of ARP to tumor epithelial cells, thereby inducing their apoptosis, but undergoing the simultaneous apoptosis.

Melatonin and colon carcinogenesis. III. Effect of melatonin on proliferative activity and apoptosis in colon mucosa and colon tumors induced by 1,2-dimethylhydrazine in rats.

Forty-eight two-month-old outbred female LIO rats were injected weekly with a single dose of 1,2-dimethylhydrazine (DMH; 21 mg/kg of body weight) administered s.c. for 15 consecutive weeks. From the day of the 1st injection of the carcinogen the part of rats were given five days a week during the night time (from 18.00 h to 08.00 h) melatonin dissolved in tap water, 20 mg/l. 10 rats were treated similarly with solvents and served as control. The experiment was terminated 6 months after the first injection of the carcinogen. Colon tumors (mainly adenocarcinomas) developed in a hundred percent of rats exposed both to DMH or to DMH plus melatonin. However, descending colon carcinomas were observed in 65 % of rats exposed to DMH plus melatonin against 100% in those exposed to DMH alone (p < 0.01). The multiplicity of colon tumors was also reduced in rats under the influence of melatonin. This effect is correlated with the significant inhibitory effect of the pineal hormone on mitotic index and with stimulating effect of melatonin on the relative number of apoptotic cells (TUNEL-method) in colon tumors. Long-term treatment with melatonin was followed also by the decrease in the area of lymphoid infiltrates in the colon mucosa of tumor-bearing rats.

Response of the spleen of Balb/c and p53-transgenic mice to low doses of carcinogen and to polyclonal antibodies generated against the soluble 53 kDa protein.

BACKGROUND: We have previously reported that p53-transgenic mice are highly sensitive to low doses of a carcinogen and to vaccination with soluble 53 kDa antibodies, compared to normal mice. The splenic manifestation of this strain dependent hypersensitivity was investigated immunohistochemically and morphometrically. METHODS: The spleen was obtained from Balb/c and human p53 promoter-CAT transgenic mice. Mice had either been treated with the carcinogen dimethylhydrazine (DMH), vaccinated before DMH treatment with polyclonal IgG generated against the soluble 53 kDa protein, or left untreated. RESULTS: Significant differences in the splenic structures were found between the strains compared, including the area occupied by the white and red pulps, the periarterial lymphoid sheath (PALS) and the marginal zone, and in the number of lymphoblasts and lymphocytes. Exposure to DMH stimulated the immune response, but in transgenic mice the number of B and T lymphocytes and especially helper T lymphocytes was significantly lower than in Balb/c mice. Vaccination followed by DMH injections did not improve the insufficiency of the immune response in transgenic mice. In transgenic mice, the number of B lymphocytes in follicles was almost half and the total number of cells in PALS and the number of T lymphocytes were only 71% and 60% respectively in BALB/c mice. In the marginal zone, macrophages proliferated as lymphocytes decreased. CONCLUSIONS: Insufficiency of the immune system after exposure to a carcinogen is more pronounced in transgenic mice, and is mainly related to the B-cell system. It may stem from defects in B lymphocytes or from inherent differences in their maturation and regulation. The increase in the number of macrophages, dendritic cells and neutrophils illustrates the compensatory processes that can remedy this developing immune insufficiency.

Apoptosis and apoptosis-related proteins (Fas, Fas ligand, Blc-2, p53) in lymphoid elements of human ovarian tumors.

Different types of lymphocytes have different roles in tumor suppression. Thus, their expression of apoptosis-related proteins (ARP - Fas and Fas ligand, bcl-2, p53) in lymphocytes and their apoptosis were analyzed immunohistochemically in ovarian tumors of different grades. Ovaries without oncologic disorders had few lymphocytes, mainly T cells, and no ARP. Benign cysts presented features of weak immune reaction: small lymphoid infiltration and few lymphocytes. The ARP were present in 13.7% to 23.5% of the lymphocytes, and apoptosis was rare. In borderline tumors, expansion of lymphoid infiltrates and increased density of lymphocytes resulted in a tenfold rise in total lymphocytes, reflecting intensification of the immune response. Most lymphocytes were T cells (92%) predominated by CD8+ cells that were in direct contact with tumor epithelial cells. ARP species were found in 47% to 65% of the lymphocytes, and apoptosis in 2.2%. In carcinomas with ligh lymphoid infiltration, lymphocytes were 2.5 times more abundant, and the apoptotic index as well as the number of CD20+ and CD25+ lymphocytes rose sharply, whereas bcl-2 positive lymphocytes decreased to 8% of their number in borderline tumors. In carcinomas with low lymphoid infiltration, the total lymphocyte count decreased eightfold compared to carcinomas with high lymphoid infiltration, reflecting the deep subcompensation of the lymphoid system. Few p53-positive lymphocytes were found in the carcinomas. In conclusion, we found a positive correlation between apoptosis and the numbers of CD4+ or CD8+ lymphocytes in epithelial ovarian tumors. This correlation could reflect the antitumor activity of T cells. However, the high expression of ARP studied by immune cells at the vicinity of the tumor ARP reveals the lymphoid vulnerability to apoptosis, resulting in devastation of the lymphoid tissue, and consequently in tumor progression.

Apoptosis and apoptosis-related proteins in the epithelium of human ovarian tumors: immunohistochemical and morphometric studies.

BACKGROUND: The origin of malignant ovarian tumors is the subject of considerable controversy, which may be resolved by elucidation of molecular mechanisms of tumorigenesis. Therefore we have undertaken the study of apoptosis in these tumors. METHODS: Apoptosis and the expression of its related proteins, Fas, Fas ligand (FasL), bcl-2 and p53, in epithelial cells of human ovarian tumors of different histological grades, were determined immunohistochemically and morphometrically. RESULTS: Apoptosis-related proteins were absent from ovarian epithelia of patients afflicted with non-cancerous diseases. In ovarian tumors, the distribution of individual proteins varied, and depended on the grade and type of tumor. Fas and FasL were highly expressed in all tumors, while epithelial cells expressing bcl-2 were abundant in benign tumors, but their numbers significantly dwindled with the progression of malignancy. Cells expressing p53 were found in borderline tumors, and their numbers increased with malignancy, inverse of bcl-2 expression. Apoptotic tumor cells were scarce in borderline tumors and abundant in carcinomas. Grouping apoptosis was found in approximately 60% of the carcinomas. CONCLUSIONS: The initial development of ovarian tumors is accompanied by high epithelial expression of Fas, FasL and bcl-2 proteins, while apoptosis and p53 proteins are detected only at later stages of tumorigenesis.

Transplacental effects of IgG generated against soluble 53 kDa protein on the splenic lymph system of rat progeny exposed to carcinogen: rate of apoptosis, proliferation of lymphocytes and expression of Fas and Fas ligand proteins.

BACKGROUND: We have previously shown that vaccination with IgG generated against the soluble 53 kDa (s53) protein modified the splenic response to carcinogens. Here we studied whether such immunization could affect the splenic lymphatic system of the offspring. METHODS: Offspring of normal female rats or of rats immunized with anti-s53 IgG were exposed to a carcinogen (dimethyl-benz(a)antracene). After 4 months, their spleens were resected and evaluated immunohistochemically for lymphocyte proliferation, apoptosis and apoptosis-related proteins (Fas and Fas ligand), in tumor-free and tumor-bearing animals. RESULTS: Spleens of progeny of unvaccinated rats had a significant decrease in the areas of follicles, germinal centers and the mantle layer after exposure to carcinogens, while maternal vaccination resulted in a significant expansion of the progeny's splenic follicles and germinal centers, the zones of B cell proliferation. The area of periarterial lymph sheaths (PALS) expanded in these offspring, reflecting activation of the T-zone. Maternal vaccination also resulted in a significant rise of Fas ligand-positive lymphocytes in the follicles and PALS of their tumor-free offspring. Tumorigenesis stimulated the Fas activity of B and T cells in the spleens, and this was much enhanced by maternal vaccination. CONCLUSIONS: Maternal vaccination before pregnancy results in altered morphological and functional attributes of the splenic immune system of the offspring. This increased immunoreactivity could reduce the risk of tumors in progeny of vaccinated mothers.

Effects of low doses of carcinogen and different antibodies on the splenic lymphoid system of p53 transgenic mice: morphometric and immunohistochemical studies.

The role of the splenic immune system in the development of high sensitivity of p53 transgenic mice to low doses of carcinogen and vaccination was investigated immunohistochemically and morphometrically. Spleens were obtained from human p53 promoter-chloramphenicol acetyl transferase transgenic mice, grouped as follows: 1, untreated controls; 2, exposed to dimethylhydrazine (DMH); 3, and 4, vaccinated with polyclonal antibodies to soluble-53 kDa protein (s53); 5, vaccinated with monoclonal PAb DO1; 6, vaccinated with monoclonal PAb 421; 7, vaccinated with polyclonal alphaH-p53 antibody. Mice in groups 4-7 were treated with DMH after the course of vaccination. Six months later all the mice were tumor-free, but effects of the low dose carcinogen were distinct in the splenic immune system. They were mainly manifested in blast transformation: the total number of lymphocytes and lymphoblasts decreased to 56.5% of the controls. The total of lymphoid cells in the follicles (B zone) and periarterial lymph sheath (T zone) declined, reflecting moderate insufficiency of the spleen's lymphoid system. Vaccination of transgenic mice with antibodies to soluble-p53 elicited mainly a B system response, with lesser T system involvement. Only few signs of B system insufficiency were found in these mice. Vaccination of mice with different antibodies, with subsequent carcinogen treatment, caused changes in the spleen that were similar to those described for DMH alone, but varied with different anti-p53 antibodies. Vaccination with polyclonal antibodies to soluble-p53, or with monoclonal antibodies PAb DO1 or PAb 421, stimulated the splenic activity of T system, and therefore can decrease the tumorigenic effect of carcinogens.

Estrogen and progesterone receptors in normal and varicose saphenous veins.

The presence of estrogen and progesterone receptors was investigated in the walls of normal and varicose veins. Cryostat sections from the saphenous veins of 29 normal individuals, and varicose and normal vein segments of 32 patients with varicose veins, were stained with anti-estrogen or anti-progesterone receptor antibodies. Nuclear stain intensity was scored by three independent observers. Receptors to both hormones were detected in the nuclear regions of the intima and media in females and males. In the adventitia, estrogen and the progesterone receptors were found only in nuclei of the vasa vasorum. Estrogen receptor levels were lower in non-varicose segments of varicose veins compared with normal veins. In varicose segments, estrogen receptors were more abundant than in the non-varicose parts of the same vein, especially in females. Similarly, progesterone receptor levels in the non-varicose portions were higher in females. These gender differences may be related to hormonal action. However, these differences may also be age related. These findings may be related to the involvement of sex-hormones in varicosis, by mechanisms as yet unknown.

Morphological and morphometric studies of the splenic antitumor immune response, elicited by liposome-covered soluble p53 kDa antigen, in chemically-induced rat colon cancer.

We evaluated the splenic morphometric changes in rats treated with carcinogen to study development of anti-cancer immune response. When liposome-covered soluble 53 kDa antigen (s53) was injected into these rats, significant tumor-suppression was seen and the percentage of tumor-free animals rose from 15.4% in non-vaccinated rats to 53.8%. In the spleens of carcinogen treated rats that did not develop tumors, activity of B lymphocytes increased significantly. This was manifested by the expansion of the germinal centers to 50.9% of the follicular area reflecting depletion of B cells, and the decrease of the mantle layer to 48.9% of the follicles. A similar picture was seen with T lymphocytes: the area of the marginal zone decreased to 55.2% of the T zone of the white pulp, and that of the periarterial lymph sheaths (PALS) to 33.6%. In tumor-bearing rats features of the immune decompensation were seen: the germinal centers increased to 96.5% of the follicular area, and the mantle layer and PALS decreased significantly. Vaccination prevented these effects, especially in tumor-bearing rats: the PALS occupies 30.4% of the white pulp and the marginal zone 56.1%, and the mantle layer occupied 58.1% of the follicular zone. Similar changes were found in vaccinated rats without tumors reflecting the compensatory character of the immune reaction in vaccinated rats. In conclusion, we found that treatment with carcinogen followed by vaccination with the s53-liposomes complex stimulated the activity of the splenic B, and to a lesser degree the T systems.

Fairness and health care decision making: testing the group value model of procedural justice.

Considerable research has supported the notion that procedural justice is important to individuals independent of outcome considerations. Tyler and his associates (Lind and Tyler, 1988; Lind and Earley 1992; Tyler, 1989) proposed that this is so because procedural justice serves a group value function. In the present research, we explore aspects of this group value formulation in a real life health care context. Specifically, we assessed the relationship between individuals' appraisals of procedural justice following health care treatment decisions as well ass (i) expectations for different consequences to self; (ii) estimates of how they were viewed by the health care authorities; (iii) attributions about the reasons for their treatment; and (iv) ratings of emotional reactions. Results confirmed many components of the relational, group value model of procedural justice (Lind and Tyler, 1988; Lind and Earley, 1992; Tyler, 1989). Specifically, respondents who felt that they had been treated fairly expected that their status and their relationship with the health care decision maker and others in their health care group would improve; perceived that the health care decision maker would rate them positively on a variety of personality dimensions; felt that the health care decision maker's interactions with them revealed quite a lot about the decision-maker's personality characteristics; and indicated increased levels of pride and pleasure as well as lower levels of anger as a result of their treatment. Results were discussed from several frameworks including Markus and Kitayama's (1991) concept of independent and the interdependent self.

Effects of dietary fiber on the rat intestinal mucosa exposed to low doses of a carcinogen.

BACKGROUND: Changes in morphological and immunohistochemical parameters were studied in the rat intestinal mucosa exposed to low doses of a carcinogen and administered with dietary fibers. METHODS: Tumors were induced by five subcutaneous injections of 1,2-dimethylhydrazine, 10 mg/kg rat, once a week. Rats were fed a semi-synthetic fiber-free diet (control) or a high-fiber diets (15%) derived from cellulose, tomato peels or white grape. The rats were sacrificed 24 weeks after the first carcinogen's injection. The ileum, colon and tumors were removed for the study. Areas of the mucosal stroma and of lymph infiltrations, and mitotic index were studied along with morphological parameters. Immunohistochemical parameters included determination of Ki-67 proliferating protein and apoptotic index. RESULTS: Areas of the stroma in colon tumors increased in rats fed tomato peels. Changes in areas of lymphoid infiltrates were related to the type of diet and tumor presence. Lymphoid infiltrations were found to be highly developed in the colon area close to tumors, especially in rats fed the white-grape diet. Mitotic index and Ki-67 protein increased significantly in the colon area close to a tumor and in tumors themselves without any relation to the fiber varieties consumed. Changes in the rate of apoptosis were not related to the preventive effect of diets: apoptotic index was high in tumors obtained from rats fed the high-cellulose diet with high tumor-preventive effects and also from rats fed the high-tomato-peel diet with low tumor-preventive effects. CONCLUSIONS: No morphological changes were found in the ileum of rats exposed to a carcinogen and fed different dietary fibers. In the colon, a carcinogen even in low concentrations inhibited the lymphoid system in the mucosa located far from the tumor or close to the tumor. An increase in the proliferation rate in the colon close to the tumor may reflect the development of precanceromatous processes or may be related to the effect of growth factors expressed by tumor cells. Finding adenoma-like dysplasia near tumors may be possible in early stages of the development of new tumors. In addition, activation of the lymphoid system of the colon following consumption to specific dietary fiber may be a mechanism by which fiber protect against cancer.

The immune response of rat spleen to dietary fibers and to low doses of carcinogen: morphometric and immunohistochemical studies.

The effects of high-fiber diets on anticancer immune response are often masked by the effects of high-dose carcinogens. Using low levels of carcinogen the splenic immune response can be evaluated. Colon tumors were induced in rats with low doses of 1, 2-dimethylhydrazine, in the following experimental groups: rats fed with low fiber diet without exposure to carcinogen; rats exposed to the carcinogen and fed with low-fiber diet; rats exposed to carcinogen, and maintained on high-fiber diets, and did not develop tumors; and rats that developed tumors after exposure to carcinogen and maintenance on either low-fiber or high-fiber diets. After 24 weeks their spleens were studied immunohistochemically and morphometrically. In tumor-free rats, low doses of carcinogen caused significant response of the lymphoid system. This was manifested in the intensive blast transformation and in an increase in the number of dendritic cells and macrophages in different structures of the spleen. Dietary fibers activated these processes: the number of Ki-67 positive cells, macrophages and plasma cells increased significantly in the red pulp. A positive correlation was found between the effects of the carcinogen and proliferation of lymphocytes in the white pulp, and to lesser degree between high-fiber diets and lymphocytic abundance in the red pulp. The number of splenic apoptotic lymphocytes decreased in rats exposed to carcinogen. In tumor-bearing rats, immune insufficiency of the splenic responses was seen in the significant decrease of the areas of the mantle layer and the periarterial sheaths, as result of the decreased number of lymphocytes. Dietary fibers reduced the degree of this insufficiency. Even low doses of carcinogen cause a significant splenic immune response. This reaction has a compensatory character with macrophages, B and T cells participating. Addition of any high-fiber diet after the exposure to carcinogen activated the lymphocyte proliferation in the spleen.

Immune response of rat spleen cells to a carcinogen and to vaccination with anti-p53 polyclonal antibodies.

BACKGROUND: The tumor-suppressive effects of rabbit anti-p53 antibodies on chemically induced rat colon cancer were demonstrated previously (Cancer J, 10:116-120, 1997). METHODS: In this communication, the spleen's role in the immune response of rats to cancer and vaccination was evaluated histologically and immunohistochemically. The following groups of rats were studied: a) control non treated rats; b) tumor-free non vaccinated rats treated with a carcinogen; c) tumor-bearing non vaccinated rats; d) tumor-free vaccinated rats exposed to a carcinogen; e) tumor-bearing vaccinated rats. RESULTS: Exposure to a carcinogen (group 2) caused the appearance of the proliferative and apoptotic changes associated with immune response. They included abundant blast transformation of CD20-positive B lymphocytes, expansion of germinal centers and of periarterial sheaths (CD3-positive T cells), an increase in the number of plasma cells, mitotic and apoptotic cells in the follicles, and in CD25 IL2-depending T cells. The presence of colon tumors (group 3) caused insufficiency of the splenic lymphoid system: blast transformation was weaker, the white pulp area decreased and its devastation was reflected in fewer lymphoid cells. There were less plasma cells in the red pulp, while the number of dendritic cells, CD25+ T cells, macrophages and neutrophils increased sharply, suggesting a compensatory reaction to the severe antigenic effects. Similar, but stronger changes, occurred in tumor-free vaccinated rats (group 4). In tumor-bearing vaccinated rats (group 5), the rate of proliferation change was higher than in group 3, probably as a result of a weaker splenic insufficiency. A strong correlation was found between the number of mitotic, apoptotic or dendritic cells, tumorigenesis and vaccination. CONCLUSIONS: A sharp increase in the number of dendritic cells in vaccinated tumor-bearing rats suggests that these cells participate in the host's reaction to tumorigenesis. We conclude that vaccination with anti-p53 polyclonal antibodies activates lymph components of the spleen.

Tumor-preventive effects of the soluble p53 antigen on chemically-induced skin cancer in mice.

BACKGROUND: The tumor-suppressive effects of the rat soluble p53 antigen on chemically induced skin cancer in mice and the role of the spleen in the immune response to a carcinogen and vaccination were studied. METHODS: Skin cancer was induced by 9,10-dimethyl-1,2-benzanthracene (DMBA). Vaccination was initiated by injection of liposomes with the soluble p53 antigen (10-12 micrograms/mouse) while boosters were with the p53 mixed with Freund's incomplete adjuvant (two injections). Four months later, the spleen and tumors were removed and examined morphometrically (determination of areas of different spleen's zones) and immunohistochemically (determination of number of B lymphocytes and macrophages, apoptotic index). The following groups of mice were studied: A) control non treated mice; Bl) tumor-free mice treated with a carcinogen; B2) tumor-bearing mice; Cl) tumor-free vaccinated mice exposed to a carcinogen; C2) tumor-bearing vaccinated mice. RESULTS: Mice exposed to a carcinogen, which were tumor-free, displayed high proliferative activity of the spleenic lymphoid constitutes such as B lymphocytes and macrophages. This was reflected in the remarkable transformation of B lymphocytes in lymphoblasts (blast transformation) and an increase in the area of germinal centers, compared to untreated controls. In tumor-bearing non vaccinated mice, significantly more spleenic apoptotic cells were found than in their tumor-free counterparts. Shrinkage of the mantle layer and a decrease in cellular density of follicles were seen in all carcinogen-treated mice, reflecting the reduced total production of lymphoid cells, and thus the insufficiency of the immune reaction of animals to a carcinogen. A sharp decrease in the apoptotic index in the spleen of tumor-free mice may reflect an inhibition of apoptotic activity of the spleen by a carcinogen. Vaccination with the soluble p53 protein decreased the incidence of tumors and their size, significantly increased the apoptotic index within tumors, and reversed the splenic parameters of immune insufficiency. CONCLUSIONS: The immune system is active during tumorigenesis. Vaccination with the soluble p53 antigen had positive tumor-suppressive effects. The findings may facilitate the development of vaccines for the prevention of recurrent cancers in humans.

Estrogen, progesterone and testosterone receptors in human fetal cartilaginous tissue: immunohistochemical studies.

Computerized image analysis was used to study the distribution in cartilage of receptors to estrogen, progesterone, and testosterone during human fetal development. We have examined three histologically distinct cell groups (hypertrophic, proliferating, and reserve zones) in long bones, vertebrae, and trachea from 19 fetuses. Comparisons were made across gender and gestational age. Contrasting with controls, we examined the density of receptors, the size of the nuclear area in which the receptors were detected, the number of hormone receptor-bearing cells, and the total receptor quantity per sample. We found that estrogen, progesterone, and testosterone receptors were detected in the nuclei of all cell types, in both female and male embryonic cartilaginous tissue. Gender differences were small and inconsistent. Changes associated with gestational age depicted a pattern of hormone receptor manifestation, shifting from the immature cell types to more differentiated cells. This was evident from the receptor densities and from the cellular area in which receptors were sighted. These dynamics are accompanied by a general increase in receptor content per sample, brought about by the concomitant increase in receptor containing area size and cell number. The increase in receptor levels seems to reflect the maturation and growth of the fetal skeleton.