Biomedical subjects

M R Anver

Publications and source records attributed to M R Anver.

At least 37 records · Page 2Linked to original sources

PubMed1998

Inflammatory large bowel disease in immunodeficient rats naturally and experimentally infected with Helicobacter bilis.

Proliferative and ulcerative typhlitis, colitis, and proctitis were found incidentally in a breeding colony of male athymic nude (Cr:NIH-rnu) rats. Within the crypts of the large intestine, modified Steiner's silver stain revealed spiral organisms that were identified by culture, polymerase chain reaction, and sequencing to be Helicobacter bilis. The large bowel disease was reproduced in H. bilis-free male athymic nude rats that were injected intraperitoneally with a culture of H. bilis from the affected colony. The organism was isolated from the feces and cecum of the experimentally infected rats. H. bilis should be considered a potential pathogen in immunocompromised rats. The infection in immunocompromised rats may serve as an animal model for inflammatory large bowel disease.

Animals↗

PubMed1997

Immunologic and hematopoietic effects of CD40 stimulation after syngeneic bone marrow transplantation in mice.

CD40 is a molecule present on multiple cell types including B lymphocyte lineage cells. CD40 has been shown to play an important role in B cell differentiation and activation in vitro, although little is known concerning the effects of CD40 stimulation in vivo. We therefore examined the effects of CD40 stimulation in mice using a syngeneic bone marrow transplantation (BMT) model in an effort to augment B cell recovery after high dose therapy with hematopoietic reconstitution. After the BMT, mice were treated with or without 2-6 microg of a soluble recombinant murine CD40 ligand (srmCD40L) given intraperitoneally twice a week. A significant increase in B cell progenitors (B220+/ surface IgM-) was observed in the bone marrow of mice receiving the srmCD40L. The treated recipients also demonstrated improved B-cell function with increases in total serum immunoglobulin and increased splenic mitogen responsiveness to LPS being noted. Additionally, srmCD40L treatment promoted secondary lymphoid organ repopulation, accelerating germinal center formation in the lymph nodes. Total B cell numbers in the periphery were not significantly affected even with continuous srmCD40L administration. Lymphocytes obtained from mice treated with the ligand also had increases in T cell mitogen and anti-CD3 mAb responsiveness and acquired the capability to produce IL-4. Surprisingly, treatment with srmCD40L also produced hematopoietic effects in mice, resulting in an increase of BM and splenic hematopoietic progenitor cells in the mice after BMT. Treatment with srmCD40L significantly increased granulocyte and platelet recovery in the peripheral blood. Incubation of BMC with srmCD40L in vitro also resulted in increased progenitor proliferation, demonstrating that the hematopoietic effects of the ligand may be direct. Thus, stimulation of CD40 by its ligand may be beneficial in accelerating both immune and hematopoietic recovery in the setting of bone marrow transplantation.

Animals↗

PubMed1997

Lack of p53 and ras mutations in Helicobacter hepaticus-induced liver tumors in A/JCr mice.

Helicobacter hepaticus is a recently discovered bacterium that invades mouse liver causing chronic active hepatitis followed by development of preneoplastic hepatocellular foci, hepatocellular adenomas and carcinomas. This establishes a unique animal model for study of the mechanisms of cancer development due to a chronic bacterial infection. A possible mechanism of bacteria-associated tumorigenesis is mutation of oncogenes or tumor suppressor genes. Since mutations in ras oncogenes have been widely detected in a variety of chemically induced and spontaneous mouse liver tumors and specific mutations in the p53 tumor suppressor gene have been associated with human bladder cancers attributed to chronic schistosomal infection, we studied exons 1 and 2 of the N-, K- and H-ras genes and exons 5-8 of the p53 gene for the presence of point mutations in 25 liver tumors from 10 naturally infected A/JCr mice, ranging in age from 16 to 24 months. The 20 adenomas and five carcinomas varied in size from 0.1 to 2.3 cm and arose in livers characterized by a wide assortment of pathological profiles, including hepatitis, inflammation, hyperplasia, hypertrophy, leukocyte infiltration, necrosis and focal phenotypic alteration. DNA samples extracted from formalin-fixed paraffin-embedded tissues were screened by PCR/SSCP analysis and showed no mutations in the analyzed genes. Complete absence of mutations in ras genes in 25 mouse liver tumors is unusual. Other genes may be targeted or H. hepaticus infection causes liver cancer through other pathways than direct damage to DNA.

Adenoma↗

PubMed1997

Distinct time courses of increase in cytochromes P450 1A2, 2A5 and glutathione S-transferases during the progressive hepatitis associated with Helicobacter hepaticus.

Mice naturally infected by Helicobacter hepaticus develop a chronic active hepatitis leading to hepatocellular carcinoma. This mouse model of liver cancer was used to examine the impact of bacterial infection on the hepatic expression and activity of enzymes involved in carcinogen bioactivation (phase I enzymes) and detoxification (phase II enzymes). No major differences in total cytochrome P450 (CYP) content were found between control and infected mice during the course of the study. The most striking modulations of individual isoenzymes were the increases in immunohistochemical staining observed for CYP1A and CYP2A5 in relation to increasing age and liver lesions. The increase in CYP2A5 in mice aged over 12 months was confirmed by the observed increases in coumarin 7-hydroxylation (CYP2A5 substrate) in vitro and CYP2A5 mRNA levels by Northern blot analysis. Immunoblotting confirmed the specific induction of CYP1A2 in infected mice 12 and 18 months of age. Perfusion of liver with nitroblue tetrazolium, an indicator for superoxide formation, demonstrated that in livers of infected mice, hepatocytes often co-expressed CYP2A5 and formazan deposition. Concerning phase II enzymes, an enhancement of glutathione S-transferase (GST) activities, related to the disease process, was observed in infected mice. An age-specific increase of GSTpi and A4.4 (early stage of disease) and GST YaYa (>9 months) expression was also demonstrated by immunohistochemical staining. In contrast, catalase and glutathione-peroxidase activities, as well as reduced glutathione content were decreased in the early stages of disease (3-9 months) in infected mice compared to age-matched control mice. Overall, these results suggest that alterations in CYP and GST expression may contribute to the aetiology of tumour incidence due to H. hepaticus infection via production of reactive oxygen species.

Age Factors↗

PubMed1996

Adoptive immunotherapy involving recombinant human M-CSF and R24 anti-melanoma antibody induces human T-cell infiltration into human melanoma xenografts.

Directed motion toward and infiltration of tumor masses by effector cells is essential for successful adoptive immunotherapy. A human/SCID mouse chimeric system was used to examine whether an antitumor antibody and recombinant human monocyte colony-stimulating factor (rhM-CSF) could promote human T-cell infiltration of a human tumor in vivo. Fourteen days after subcutaneous injection of the human melanoma cell line M-14 into SCID recipients, several adoptive immunotherapy regimens were initiated using activated human T cells, an anti-melanoma monoclonal antibody (MoAb) (R24), and rhM-CSF. Effects on tumor growth and human T-cell infiltration into the tumor were assessed. Compared with other treatment groups, only mice treated with the combination of activated human T cells, anti-tumor MoAb, and rhM-CSF demonstrated a significant cellular infiltrate in the melanoma. Immunohistology demonstrated human T cells present in the tumor up to 7 days after injection. Groups treated with rhRANTES or rmGM-CSF in place of rhM-CSF exhibited markedly less human T-cell infiltration. Additionally, only mice treated with human T cells, R24, and rhM-CSF demonstrated a significant antitumor response in vivo. This model suggests that activated human T cells can be specifically targeted to in vivo tumor sites by combined treatment with an antitumor antibody and rhM-CSF.

Animals↗

PubMed1996

Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus.

Large bowel disease detected clinically by rectal prolapse was studied in 64 immunodeficient mice (37 athymic NCr-nu/nu, 12 BALB/c AnNCr-nu/nu, 9 C57BL/6NCr-nu/nu, and 6 C.B17/Icr-scid/NCr) naturally infected with Helicobacter hepaticus. Rectal prolapse was found in approximately 5% of immunodeficient mice maintained in a research facility over a period of 3.5 years. All mice had various degrees of chronic proliferative typhlitis, colitis, and proctitis, usually without concomitant hepatitis. Some mice had severe proliferative proctitis with cystic hyperplasia. Histologic study of the large bowel of 48 athymic NCr-nu/nu mice without H. hepaticus infection and housed in another clean facility revealed only 12% of the mice with minimal-to-mild large bowel inflammation. Helicobacter hepaticus infection is associated with large bowel disease in immunodeficient mice but is not seen in H. hepaticus-infected immunocompetent mice. This new pathogenic bacterial infection should be considered as another potential cause or co-factor for rectal prolapse and large bowel disease in mice.

Animals↗

PubMed1995

Chemopreventive activity of tamoxifen, N-(4-hydroxyphenyl)retinamide, and the vitamin D analogue Ro24-5531 for androgen-promoted carcinomas of the rat seminal vesicle and prostate.

We evaluated the ability of dietary N-(4-hydroxyphenyl)retinamide; 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalcifero l (Ro24-5531); and tamoxifen to inhibit the development of androgen-promoted carcinomas of the accessory sex organs of male Lobund-Wistar rats. Invasive carcinomas of the seminal vesicle (SV) and anterior prostate (AP) were induced in Lobund-Wistar rats with three different combinations of initiator [N-nitroso-N-methylurea (NMU)] and promoter [testosterone propionate (TP)]: (a) high-dose NMU (30 mg/kg) + high-dose TP (20 mg via implant every 2 months); (b) high-dose NMU + low-dose TP (10 mg implanted every 2 months); or (c) low-dose NMU (15 mg/kg) + low-dose TP. During the period of TP administration, rats were fed a diet supplemented with either N-(4-hydroxyphenyl)retinamide (1 or 2 mmol/kg diet), Ro24-5531 (1.25 or 2.5 nmol/kg diet), tamoxifen (0.5 or 5 mg/kg diet), or vehicle alone. After sacrifice at 8.5 or 11 months, the prostate-seminal vesicle complex from each rat was processed in toto and histologically staged as to the extent of tumor involvement. In animals given low-dose TP, all three agents were significantly effective at reducing the incidence of invasive carcinomas of the SV and, to a lesser degree, the AP. Of the three agents, tamoxifen given in high dose (5 mg/kg) had the strongest activity, reducing the occurrence of invasive SV carcinomas from 72-83% in controls to 6% (P = 0.0001) and the occurrence of invasive AP carcinomas from 50-72% to 18-22% (P < 0.05).

Androgens↗

PubMed1995

Promotion of N-nitrosodiethylamine-initiated hepatocellular tumors and hepatoblastomas by 2,3,7,8-tetrachlorodibenzo-p-dioxin or Aroclor 1254 in C57BL/6, DBA/2, and B6D2F1 mice.

To investigate the hypothesis that tumor promotion by chlorinated aromatic hydrocarbons involves Ah receptor occupation and subsequent induction of cytochromes P-450 1a-1, effects of Aroclor 1254 or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were examined in N-nitrosodiethylamine-initiated mice with different Ah receptor phenotype. Levels of cytochromes P-450 1a and 2b were measured by enzyme assay and Western immunoblots. Males of the C57BL/6, DBA/2, or (C57BL/6 x DBA/2)F1 (hereafter referred to as "B6D2F1") strain were initiated with a single i.p. dose of N-nitrosodiethylamine (90 mg/kg body weight), followed by either multiple doses of TCDD (0.05 micrograms/kg) weekly or Aroclor 1254 chronically in the diet (100 ppm) for 20 weeks, and then no treatment for 24 weeks. Lung tumor incidence or multiplicity was not altered by either of the promoters. Liver tumor incidence was similar among the three strains after N-nitrosodiethylamine alone (14, 21, and 21%, respectively). In DBA/2 mice, TCDD neither induced Cyp 1a nor promoted liver tumors. Aroclor caused an 8-fold induction of hepatic Cyp 2b, which was its maximum at the 12-week time point but did not promote tumors. Inductions of hepatic Cyp 1a by TCDD and 1a and 2b by Aroclor were similar in C57BL/6 and B6D2F1 mice, but tumor promotion responses were quite different. Dietary Aroclor significantly promoted liver tumors in C57BL/6 mice (59 versus 14%) but not in B6D2F1 mice (24 versus 21%). Repeated TCDD promoted only in B6D2F1 mice (52 versus 21%) and not in C57BL/6 mice (19 versus 14%). Thus, whereas these data confirm that a functional Ah receptor is required for liver tumor promotion, the degree of activation as measured by induction of Cyp 1a is not directly related to the degree of tumor-promoting capability. Other genetic factors must play a role in mediating the final tumor outcome.

Animals↗

PubMed1995

Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain.

The common gamma chain (gamma c) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors is defective in humans with XSCID. Mice lacking gamma c expression had hypoplastic thymuses; the thymocytes responded to gamma c-independent mitogens, but not gamma c-dependent stimuli. Splenic T cells were diminished at 3 weeks of age, but CD4+ T cells markedly increased by 4 weeks. B cells were greatly diminished in contrast with the situation in XSCID. NK cells, gamma delta intestinal intraepithelial lymphocytes, dendritic epidermal T cells, peripheral lymph nodes, and gut-associated lymphoid tissue were absent. These findings underscore the importance of gamma c in lymphoid development. Moreover, differences in humans and mice lacking gamma c expression indicate species-specific differences in the roles of gamma c-dependent cytokines or in the existence of redundant pathways. These mice provide an important model for studying the pathophysiology provide an important model for studying the pathophysiology of and gene therapy for human XSCID.

Animals↗

PubMed1995

Promotion of N-nitrosodimethylamine-initiated mouse lung tumors following single or multiple low dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is highly toxic to several rodent species and may have adverse health effects in exposed human populations. Further, TCDD has been shown to be a potent liver tumor promoter in the rat after repeated administration. These studies were conducted to determine the tumor promoting capability of TCDD in the Swiss mouse following single or multiple exposures. Following tumor initiation with N-nitrosodimethylamine (NDMA; 25 mg/kg), animals were given either a single dose (1.6, 16 or 48 micrograms/kg) or repeated injections (0.05 microgram/kg/week for 20 weeks) of TCDD and sacrificed at 52 weeks of age. Neither NDMA nor TCDD caused an increase in incidence of liver tumors. NDMA induced lung tumors in 100% of animals, with 12 +/- 0.1 tumors/mouse. The multiplicity of lung tumors was significantly increased by low dose TCDD treatment, with 20 +/- 2.6 tumors/mouse following a single 1.6 micrograms/kg dose (P = 0.016) and 18 +/- 1.7 (P = 0.031) following repeated 0.05 microgram/kg doses (x 20). Higher doses of TCDD did not increase multiplicity of lung tumors and, in fact, may have been toxic to the lungs of NDMA-treated mice, as evidenced by the infiltration of pigmented macrophages. These data demonstrate the potent tumor promoting capability of TCDD in mouse lung.

Animals↗

PubMed1995

Use of antibiotics to prevent hepatitis and typhlitis in male scid mice spontaneously infected with Helicobacter hepaticus.

The use of antibiotic combinations to prevent acute and progressive chronic hepatitis and proliferative typhlitis associated with Helicobacter hepaticus infection in male scid/NCr mice was evaluated. The drug combinations used were amoxicillin-metronidazole-bismuth, tetracycline-metronidazole-bismuth, amoxicillin-neomycin, neomycin alone, and amoxicillin alone. Treatments were administered per os for 14 days beginning at 4 weeks of age. All mice remained clinically normal throughout the study. Specimens from mice were evaluated histologically at 21, 60, 90, and 120 days after initiation of the antibiotic treatments. Results of histologic examination and use of special stains indicated that the antibiotic regimens containing amoxicillin prevented progressive chronic hepatitis and typhlitis. Helical bacteria were not observed histologically in the liver or cecum of amoxicillin-treated mice. Helical bacteria were observed in the liver and cecum of untreated mice and in the cecum of mice treated with antibiotic regimens not containing amoxicillin. Untreated mice and those treated with amoxicillin were evaluated by culture for presence of H. hepaticus at 60 and 90 days and by polymerase chain reaction at 90 days after initiation of the antibiotic treatment. All untreated mice were test-positive by fecal/cecal culture, and three of five were positive by polymerase chain reaction. All mice treated with amoxicillin were negative for H. hepaticus by results of culture and polymerase chain reaction. The oral administration of amoxicillin to young scid mice via the drinking water prevents hepatitis and typhlitis caused by H. hepaticus.

Amoxicillin↗

PubMed1994

Chronic active hepatitis and associated liver tumors in mice caused by a persistent bacterial infection with a novel Helicobacter species.

BACKGROUND: In the autumn of 1992, a novel form of chronic, active hepatitis of unknown etiology was discovered in mice at the National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, Md. A high incidence of hepatocellular tumors occurred in affected animals. The disease entity was originally identified in A/JCr mice that were untreated controls in a long-term toxicologic study. PURPOSE: Our original purpose was to determine the origin and etiology of the chronic hepatitis and to quantify its association with hepatocellular tumors in mice of low liver tumor incidence strains. After a helical microorganism was discovered in hepatic parenchyma of diseased mice, we undertook characterization of the organism and investigation of its relationship to the disease process. METHODS: Hepatic histopathology of many strains of mice and rats, as well as guinea pigs and Syrian hamsters, in our research and animal production facilities was reviewed. Steiner's modification of the Warthin-Starry stain and transmission electron microscopy were used to identify bacteria in the liver. We transmitted the hepatitis with liver suspensions from affected mice and by inoculation with bacterial cultures. Bacteria were cultivated on blood agar plates maintained under anaerobic or microaerophilic conditions and characterized morphologically, biochemically, and by 16S rRNA sequence. RESULTS: We report here the isolation of a new species of Helicobacter (provisionally designated Helicobacter hepaticus sp. nov.) that selectively and persistently colonizes the hepatic bile canaliculi of mice (and possibly the intrahepatic biliary system and large bowel), causing a morphologically distinctive pattern of chronic, active hepatitis and associated with a high incidence of hepatocellular neoplasms in infected animals. CONCLUSIONS: The novel Helicobacter is a likely candidate for the etiology of hepatocellular tumors in our mice. The Helicobacter-associated chronic active hepatitis represents a new model to study mechanisms of carcinogenesis by this genus of bacteria. IMPLICATIONS: Adenocarcinoma of the stomach, the second most prevalent of all human malignancies world-wide, is associated with infection at an early age with Helicobacter pylori. Infection leads to several distinctive forms of gastritis, including chronic atrophic gastritis, which is a precursor of adenocarcinoma. H. hepaticus infection in mice constitutes the only other parallel association between a persistent bacterial infection and tumor development known to exist naturally. Study of the H. hepaticus syndrome of chronic active hepatitis and liver tumors in mice may yield insights into the role of H. pylori in human stomach cancer and gastric lymphoma.

Adenoma, Liver Cell↗

PubMed1994

Induction of T cell differentiation and lymphomagenesis in the thymus of mice with severe combined immune deficiency (SCID).

Severe combined immune deficiency (SCID) mice have a defect in their recombinase system and cannot productively rearrange their immune receptor genes. Thus, SCID thymocytes are arrested at the immature "triple negative" phase, not expressing CD3, CD4, or CD8 surface markers. Whole body irradiation of SCID mice induced maturation of their thymocytes to the CD4+/CD8+ double positive, CD3+low stage of differentiation, and resulted in the generation of a thymic cortical region on histologic examination. No mature single positive T cells were detected in the thymus or the periphery. VDJ rearrangements of TCR-beta with restricted clonality were observed in the double positive cells from a given individual. The CD3 complex was expressed on some of these cells, but the cells failed to mobilize intracellular calcium after cross-linking with CD3 Abs. The double positive cells appeared several weeks after irradiation, persisted for many months in the thymus, and by 6 mo generally developed into metastatic lymphoma. Retroviral activation was undetectable in both the preneoplastic and transformed thymocytes. Thus, it appears that the earliest steps in T cell development can be induced in SCID mice by inducing DNA breaks with radiation. This system represents a model of early thymic development, preneoplasia, and neoplasia.

Animals↗

PubMed1994

Effects of inhibition of O6-alkylguanine-DNA alkyltransferase in rats on carcinogenesis by methylnitrosourea and ethylnitrosourea.

Many alkylating agents are potent carcinogens and there is considerable evidence that the formation of O6-alkylguanine in DNA can lead to mutations and the initiation of neoplastic growth. The repair of O6-methyl- or O6-ethylguanine in DNA is known to be brought about by the action of a protein termed O6-alkylguanine-DNA alkyltransferase. In order to investigate the role of this activity in the carcinogenic action of methylnitrosourea and ethylnitrosourea, O6-benzylguanine, a potent inhibitor of the alkyltransferase, was used. Groups of 20 female F344 rats were treated with the nitrosourea (0.2 mmol) by gavage in 10 weekly doses and a parallel group was also treated with 4 mg of O6-benzylguanine, 2 h prior to each dose of the nitrosourea. This dose of O6-benzylguanine was sufficient to reduce the alkyltransferase activity to zero in the liver for at least 8 h but activity had returned to about 60% of normal within 24 h. Animals were maintained until they became moribund, when they were killed, or until death related to tumors. The median week of death in the animals receiving methylnitrosourea was reduced from 60 wk to 52 wk by co-treatment with O6-benzylguanine. There was a smaller reduction from 55 to 50 wk in the rats receiving ethylnitrosourea. The treatment with O6-benzylguanine caused no significant change in the incidence of the principal tumors induced by the alkylnitrosoureas and there were no liver tumors produced by the combined treatments. These results show that the level of inactivation of alkyltransferase produced by this dose of O6-benzylguanine was not sufficient to greatly alter the potent carcinogenic effect of these doses of alkylnitrosoureas in this system.

Animals↗

PubMed1994

Chronic active hepatitis in mice caused by Helicobacter hepaticus.

Helicobacter infections cause chronic gastroenteritis in humans and several animal species. We recently discovered a new Helicobacter (H. hepaticus) that is the etiological agent of a unique chronic active hepatitis in mice. Natural infection appeared to be acquired early in life in enzootically infected colonies. Liver lesions arose as focal necrosis and focal nonsuppurative inflammation by 1 to 4 months of age in susceptible mouse strains. By 6 to 8 months, extensive liver involvement included hepatocytomegaly, bile ductular (oval cell) hyperplasia, and cholangitis. There was an age-related increase in proliferating cell nuclear antigen hepatocyte nuclear labeling index. The bacteria were usually found within bile canaliculi as determined by ultrastructural evaluation of liver lesions, the Steiner modification of the Warthin-Starry stain and immunohistochemistry with a rabbit antibody to Helicobacter pylori. Naturally infected mice showed an age-related increase in serum IgG antibodies to Helicobacter hepaticus proteins. The disease was experimentally reproduced by intraperitoneal injection of liver suspensions from affected livers or bacteria cultivated in vitro. The earliest lesions of the experimental disease appeared 4 weeks after injection. The course of spontaneous and experimental infection was slow and insidious and resulted in high titers of antibodies to bacterial proteins. This chronic bacterial infection represents a new model of chronic liver disease.

Animals↗

PubMed1993

Collaboration between growth factors and diverse chemical carcinogens in hepatocarcinogenesis of transforming growth factor alpha transgenic mice.

Transforming growth factor alpha (TGF-alpha) has been shown to induce liver tumors within 1 year in transgenic male mice in which this potent mitogen is overexpressed. To determine more precisely how TGF-alpha participates in multistep tumorigenesis of the liver, genotoxic (diethylnitrosamine or dimethylnitrosamine) and nongenotoxic (phenobarbital) chemical carcinogens were administered independently to TGF-alpha transgenic mice [line MT42 on a Crl:CD-1(ICR)BR background]. TGF-alpha overexpression dramatically accelerated carcinogen-induced hepatocarcinogenesis in MT42 males but not females. Interestingly, all three chemical agents were found to enhance strongly both hepatic tumor formation and progression in TGF-alpha transgenic male mice. In this study 100%, 90%, and 78% of transgenic males exposed to diethylnitrosamine, dimethylnitrosamine or phenobarbital, respectively, developed tumors between 24 and 32 weeks of age. Moreover, approximately 70% of tumor-bearing transgenic mice from each treatment group had hepatocellular carcinomas; no malignant lesions were found in any carcinogen-treated or untreated nontransgenic mice or in untreated MT42 mice at this age. These results demonstrate that chemical agents as diverse as nitrosamines and phenobarbital act as cocarcinogens with TGF-alpha in the livers of these transgenic mice, indicating that TGF-alpha possesses the unique ability to complement both initiation and promotion in hepatocarcinogenesis. Furthermore, because carcinogen-induced malignant conversion was restricted to transgenic mice, constitutive TGF-alpha overexpression may promote liver tumor progression as well.

Animals↗

PubMed1992

Immunologic and hematologic effects of neuroendocrine hormones. Studies on DW/J dwarf mice.

DW/J dwarf mice lack acidophilic anterior pituitary cells and are deficient in growth hormone and other neuroendocrine mediators. These mice were examined to determine the effects of these deficiencies on hematopoietic and immune system development. Previous studies have suggested that these mice had immunologic defects primarily involving T cell development. However, we have found that these mice exhibit decreased peripheral blood cell counts affecting all lineages (erythrocytic, leukocytic, and platelets). Examination of lymphoid tissues of dwarf mice indicated that their spleens were hypoplastic. Treatment of these mice with recombinant human growth hormone resulted in a significant improvement of peripheral blood counts and spleen cell number. Analysis of the bone marrow indicated a profound deficiency of B cell progenitors in the dwarf mice. However, in untreated dwarf mice, mature B cells and T cells were observed in the spleens. Although treatment with recombinant human growth hormone could correct the hematopoietic deficiencies in these mice, it did not restore the B cell progenitor populations, suggesting that an absence of growth hormone is not solely responsible for this deficiency. Thus, these mice display significant myeloid and lymphoid deficiencies that have been previously undetected.

Animals↗

PubMed1992

Human-mouse lymphoid chimeras: host-vs.-graft and graft-vs.-host reactions.

Human peripheral blood lymphocytes (huPBL) were injected into mice with severe combined immune deficiency (SCID). It was ascertained that murine natural killer (NK) cells were capable of affecting engraftment of human lymphocytes in SCID mice. The presence of host NK cells resulted in the clearance of the human lymphocytes. Human T lymphocytes were the primary cell to engraft in the SCID recipients, with human T cells being detected in the spleen, lymph nodes, bone marrow and peritoneal cavity of the mice up to several months after transfer. No human T cells were detected in the murine thymus and the level of engraftment in the periphery could be highly variable. Additionally, there appeared to be significant reactions between the human lymphocytes and the murine host resulting in a xenogeneic graft-vs.-host reaction (XGVHR). The predominant manifestation involved splenomegaly resulting from an expansion of murine hematopoietic cells in the spleens of these xenogeneic chimeras. The severity of the XGVHR could be correlated with the extent of human T cell engraftment and the recovered human T cells were found to be in a proliferative state. Thus, there appear to be significant host-vs.-graft and graft-vs.-host interactions occurring in human/mouse lymphocyte chimeras.

Animals↗