Biomedical subjects

T G Terrell

Publications and source records attributed to T G Terrell.

At least 19 recordsLinked to original sources

PubMed1994

Induction of apoptosis in the murine liver with recombinant human activin A.

Recombinant human activin A, a member of the transforming growth factor-beta superfamily, induced significant cell loss in rodent livers and in primary hepatocyte cultures. Histologically and biochemically the hepatocyte death was mediated by apoptosis, a form of programmed cell death. Male mice were treated with 200 or 500 micrograms recombinant human activin A/kg body wt/day for up to 3 days by means of a subcutaneously implanted minipump. Livers were taken for light and electron microscopy, DNA isolation and in situ nick end-labeling. Primary cultures of rat hepatocytes were treated with 10 ng/ml recombinant human activin A for 24 hr before being harvested for electron microscopy and DNA isolation. Infusion of activin A evoked dose-dependent loss of liver mass due to the atrophy and death of hepatocytes around the central vein. Morphologically, the dying cells demonstrated all the characteristic nuclear and cytoplasmic features of apoptosis. Low molecular weight DNA isolated activin A-treated intact livers and primary cultures exhibited the typical oligosomal ladder. Nick end-labeling of DNA in situ confirmed that virtually all topographical apoptotic hepatocytes had fragmented DNA. The currently accepted criteria for apoptosis (i.e., specific morphological alterations and internucleosomal clipping of DNA) were evident in activin A-treated hepatocytes both in vitro and in vivo, leading to the conclusion that cell loss occurs mainly through apoptosis. These observations suggest that activin A may be important in hepatic homeostasis.

Activins↗

PubMed1993

Activin induces cell death in hepatocytes in vivo and in vitro.

While studying endocrine responses to activin in female rats, we discovered that activin caused a marked reduction in liver mass. The regressed livers exhibited no gross signs of necrosis or infarction, but histopathological evaluation revealed extensive cell death in the centrilobular regions. The dying cells appeared to fragment into structures resembling apoptotic bodies. Liver mass and histological appearance were restored after cessation of activin infusion, indicating that on an organ level, this effect was reversible. To determine whether the effects observed in vivo were caused by direct actions on the liver, we then tested activin on isolated hepatocytes in serum-free medium. Under these conditions, activin caused many hepatocytes to undergo fragmentation, which was accompanied by a loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-reducing activity, an index of viability. We compared the effects of activin with those of transforming growth factor-beta because activin is structurally related to transforming growth factor-beta and because transforming growth factor-beta has been shown previously to induce cell death in hepatocytes. Both proteins caused cell death of comparable magnitude, as defined by the extent of loss of MTT-reducing activity, but transforming growth factor-beta was active at one tenth of the effective activin concentrations. A neutralizing monoclonal antibody to transforming growth factor-beta blocked the response to transforming growth factor-beta but had no effect on the response to activin. Conversely, follistatin, an activin-binding protein, blocked the response to activin but not to transforming growth factor-beta. Inhibin, which antagonizes the effects of activin in many systems, had little effect on the response to activin. Activin and transforming growth factor-beta differed in their onset of action; exposure to transforming growth factor-beta for only 1 hr induced a maximal response, whereas maximal response to activin required its continuous presence for 24 hr. These results show a novel effect of activin on cell death in hepatocytes in vivo and in vitro, suggesting that activin may have a previously unrecognized role in regulating hepatic function.

Activins↗

PubMed1993

Pathology of recombinant human transforming growth factor-beta 1 in rats and rabbits.

The systemic administration of high doses of rHuTGF-beta 1 to rats produced a spectrum of lesions in multiple target tissues, including liver, bone, kidney, heart, thymus, pancreas, stomach, cecum, at the injection vein, and in skeletal muscle at the site of anesthetic injection. The majority of these lesions can be attributed to known biological activities of TGF-beta 1. High-dose dermal application resulted in local effects at the wound sites without systemic toxicity.

Animals↗

PubMed1993

Comparative pathology of recombinant murine interferon-gamma in mice and recombinant human interferon-gamma in cynomolgus monkeys.

Interferon-gamma is a highly species-specific cytokine and has the most restricted host range of activity of the interferons. Recombinant human IFN-gamma was one of the first species-specific recombinant proteins to be thoroughly assessed in conventional safety models used for xenobiotics. Acute single-dose intravenous toxicity studies with rHuIFN-gamma were performed in rats, marmosets, and squirrel monkeys with no indications of toxicity. A complete series of subchronic toxicity studies and segment I and II reproductive studies in the rat revealed no evidence of toxicity at any of the doses tested. These results suggested that studies conducted in pharmacologically nonresponsive species may not be predictive of clinical toxicity. Human IFN-gamma is active on nonhuman primate cells, though not at the same level as on human cells. Multidose studies in cynomolgus monkeys with rHuIFN-gamma for 28 or 90 days were predictive of many of the dose-limiting clinical toxicities. Qualitative similarity was observed between toxicity studies employing rHuIFN-gamma in the cynomolgus monkey and rMuIFN-gamma in the mouse. The adverse effects seen in toxicity studies with cytokines and growth factors are often exaggerated pharmacological effects of the molecules, and therefore can only be studied in a responsive species. In situations in which a high degree of species specificity is encountered, studies employing a recombinant protein in a homologous species may provide a useful test system for preclinical safety assessment.

Abnormalities, Drug-Induced↗

PubMed1992

Effects of intravenous IL-8 administration in nonhuman primates.

IL-8, a cytokine known for its potent and specific neutrophil activation and chemoattractant properties, has been recently detected in the circulation during septic shock, endotoxemia, and after IL-1 alpha administration. Because of its observed in vitro actions, it has been hypothesized that IL-8 may contribute to the dynamics of circulating granulocytes and to the pathologic sequelae seen in sepsis. Here, human rIL-8 is administered to healthy nonhuman primates as a single i.v. injection or as a continuous 8-h i.v. infusion. We demonstrate that both methods of i.v. administration result in a rapid but transient, severe granulocytopenia, followed by a granulocytosis that persists as long as IL-8 levels are detectable in the circulation. There were no hemodynamic changes after IL-8 administration, and animals remained clinically stable during the 24-h observation period. No detectable circulating TNF-alpha, IL-1 beta, or IL-6 response was induced by either IL-8 administration regimen. Histopathologic examination revealed mild to moderate neutrophilic margination in lung, liver, and spleen, of greater severity in baboons receiving the 8-h infusion. There was no associated neutrophilic infiltration or tissue injury. Thus, IL-8 modulates circulating granulocyte dynamics and likely directs their actions, but when administered i.v. to healthy animals, either as a bolus dose or as a continuous infusion for up to 8 h, does not induce the hemodynamic and metabolic aberrations or the acute organ damage seen during sepsis.

Animals↗

PubMed1992

Utilization of homologous proteins to evaluate the safety of recombinant human proteins--case study: recombinant human interferon-gamma (rhIFN-gamma).

Interferon-gamma is an immunomodulatory cytokine that has an extremely restricted host range of activities. RhIFN-gamma was one of the first species-specific recombinant proteins to be assessed in conventional safety models typically utilized for xenobiotics. Acute, subchronic and Segment I and II reproductive studies in rats revealed no evidence of toxicity at any of the doses tested; these results were not predictive of clinical toxicity, which is not unexpected since rodents are known to be pharmacologically nonresponsive to rhIFN-gamma. In contrast, 4- and 13-week multidose toxicity studies in cynomolgus monkeys with rhIFN- were predictive of many of the dose-limiting clinical toxicities. RhIFN- is active on non-human primate cells, though not at the same level as on human cells. In addition, qualitative similarities were observed between toxicity studies employing rhIFN-gamma in the cynomolgus monkey and recombinant murine interferon-gamma (rmuIFN-gamma) in the mouse. These results suggest that in situations where a high degree of species specificity is encountered, studies employing a recombinant protein in a homologous species may provide a useful test system for preclinical safety assessment. This information should be evaluated in conjunction with data from studies conducted with the human protein in pharmacologically responsive animal models when possible.

Animals↗

PubMed1992

An evaluation of the functions of the 22-kilodalton (kDa), the 20-kDa, and the N-terminal polypeptide forms of human growth hormone using transgenic mice.

Multiple peptide hormones can be derived from the single human GH gene. In addition to the full-length 191-amino acid 22-kilodalton (kDa) form, a 20-kDa variant can be produced by alternative splicing, and a 5-kDa variant can be produced by posttranslational cleavage. To more fully appreciate the physiological roles of these proteins, we have made a comparison of transgenic mice that constitutively overexpress one or another of these variants. We have found that both the 22-kDa and the 20-kDa forms of human GH stimulate linear growth and liver hypertrophy. The increase in linear growth in 22-kDa transgenic mice does not, however, correlate with an increase in circulating IGF-I; rather, the increase in IGF-I that does finally occur correlates with marked liver pathology. Both groups of mice also develop glomerulosclerosis and suffer from hyperinsulinemia. Although there are histologically obvious lesions in the livers of both the 22-kDa and the 20-kDa transgenic mice, only the former exhibit hyperalbuminemia and hypercholesterolemia. Both forms of GH lead to anemia, which is normocytic in the 20-kDa transgenic mice and macrocytic in the 22-kDa transgenic mice. Despite the presence of high levels of the 5-kDa N-terminal form of human GH, the transgenic mice that express this protein are indistinguishable from their nontransgenic littermates.

Animals↗

PubMed1992

Reduction of alpha-naphthylisothiocyanate-induced hepatotoxicity by recombinant human hepatocyte growth factor.

Hepatocyte growth factor (HGF) is a potent stimulator of DNA synthesis in cultured hepatocytes. To determine whether HGF has any activity in vivo, we have tested HGF in rats in which intrahepatic cholestasis was induced by acute administration of alpha-naphthylisothiocyanate (ANIT). The hepatotoxic effects of a single injection of ANIT were manifested 48 h later as large increases in serum bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. These biochemical changes were accompanied by widespread periportal edema, hypertrophy of bile duct epithelium, and randomly scattered areas of liquifaction necrosis in the hepatic parenchyma. The increases in bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were markedly attenuated when HGF was administered 30 min before ANIT and again at 6, 12, 24, 30, and 36 h after ANIT. In addition, this HGF dosing regimen completely prevented the occurrence of parenchymal lesions, although it had no effect on periportal histopathology. The effect of ANIT was dose dependent; a maximal response was observed at 320 micrograms/kg per injection, with an intermediate response at 105 micrograms/kg. Delaying the administration of HGF until 12 h after ANIT was as effective as when administration was begun 30 min before ANIT. Taken together these results show that HGF can prevent some aspects of ANIT hepatotoxicity.

1-Naphthylisothiocyanate↗

PubMed1989

Prevention of doxorubicin-induced hematotoxicity in mice by interleukin 1.

Interleukin 1 alpha and interleukin 1 beta induce peripheral neutrophilia with stimulation of granulopoiesis in bone marrow. The continuous administration of interleukin 1 (100 ng/day) to mice for 7 days by s.c.-implanted Alzet osmotic minipumps induced marked stimulation of granulopoiesis in marrow and spleen in normal mice, and protected against the marked depletion of myeloid and erythroid cells in bone marrow of mice treated with single injections of either 20 or 30 mg/kg doxorubicin (DXN). Interleukin 1 beta infusion also protected against DXN-induced atrophy of thymus and secondary lymphoid organs. Single i.p. injection of either interleukin 1 alpha or interleukin 1 beta at doses up to 1000 ng 24 h prior to treatment with DXN did not protect against the hematopoietic and lymphoid toxicities of DXN.

Animals↗

PubMed1987

Biology and pharmacology of recombinant human interleukin-1 beta-induced rat ear inflammation.

A single, 10 ng intradermal injection of human recombinant interleukin-1 beta (rIL-1 beta) into rat ears produced acute inflammation. Tissue wet weight (edema) and total myeloperoxidase activity (PMN accumulation), peaked at 3 hours and returned to base line at 3 days. Given orally, 1 hour prior to rIL-1 beta injection, cyproheptadine, dexamethasone, conventional NSAID's, or mixed cyclooxygenase/lipoxygenase inhibitors were potent antagonists of edema and moderate antagonists of PMN accumulation. In addition, the putative DMARD's, auranofin, dapsone, and levamisole were effective inhibitors of rIL-1 beta induced inflammation.

Animals↗

PubMed1986

Uveitis induction in the rabbit by muramyl dipeptides.

Intraocular inflammation (uveitis) was produced in rabbits by intravenous or subcutaneous treatment with N-acetylmuramyl-L-alanyl-D-isoglutamine and several of its synthetic analogs at doses of greater than or equal to 0.2 mg/kg in saline. A dose-dependent increase in permeability of the ocular blood-aqueous barrier as measured by leakage of protein or fluoresceinated dextran from the serum into the eye was observed from 2 to 14 h after glycopeptide treatment. Peak response occurred at approximately 3 h postdose. The lowest dose found to produce maximal vascular leakage for the most active glycopeptide analogs was 1 mg/kg. The adjuvant-inactive L-L stereoisomer of N-acetylmuramyl-L-alanyl-D-isoglutamine was inactive, even at doses as high as 10 mg/kg. Analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine which were homologous in the lactyl side chain were found to cause less uveitis. Chronic biweekly intravenous treatment of rabbits for 1 month with either N-acetyl-L-alpha-aminobutyryl-D-isoglutamine or its lipophilic 6-O-stearoyl derivative at 1 mg/kg, but not with murabutide, resulted in leukocytic inflammatory lesions unique to the uveal tract of the eye. The uveitis was potentially reversible and occurred with decreased severity as long as 2 months after cessation of chronic treatment. Vascular leakage but not cellular infiltrate in the choroid could be modulated by pharmacologic means. Pyrogenicity but not adjuvanticity correlated with ability of glycopeptides to induce vascular leakage. Several adjuvant-active muramyl dipeptide analogs with minimal ability to cause acute vascular leakage or chronic inflammation in the rabbit eye have been identified.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1982

Ontogeny of the immune system.

Cellular and humoral aspects of the immune response develop sequentially in the fetus. Although there is evidence of immunologic activity to some antigens, many of the nonimmune effector systems are neither developed nor fully functional in the fetus. The lack of fully functional systems make the fetus a highly susceptible candidate for invading bacteria and viruses. Often, infection prior to immune competence may lead to abortion, malformation, and in some instances, viral persistence and immune tolerance. On the other hand, immune responses tend to elevate immunoglobulin values and cause specific antibody that may be used for diagnostic purposes. Little work has been done to appreciate fully the immunologic and nonimmune effector systems' role in normal development or during congenital infections.

Adenoviridae Infections↗

PubMed1981

Well-differentiated lymphocytic leukemia in a dog: long-term survival without therapy.

Well-differentiated lymphocytic leukemia was found during routine hematologic examination of a 12-year-old female poodle with signs of anxiousness, panting and pica. The total white blood cell count was 106,900/microliters and at least 90% of the leukocytes were small, normal-appearing lymphocytes. The dog was examined several times during a 23-month period before it was killed at the owner's request for conditions unrelated to the leukemia. The hematologic picture of the leukemia was essentially unchanged during this time. A deep nuclear cleft was seen in most lymphocytes examined by electron microscopy. Cell surface markers showed most blood lymphocytes to be B-cells. These cells responded poorly to mitogen stimulation.

Animals↗

PubMed1980

Paramyxo-like virus infection in a rock rattlesnake.

A rock rattlesnake (Crotalus lepidus) with a history of progressive central nervous disease was submitted for necropsy. The histopathologic findings included evidence of interstitial pneumonia, multifocal areas of gliosis in the brain, and ballooning degeneration and demyelination of brainstem and upper spinal cord axons. By electron microscopy, brainstem tissue was found to contain numerous virus particles in the extracellular spaces. A paramyxo-like virus, isolated in viper heart cells from lung tissue, was observed by electron microscopy to be similar in size and shape to the particles seen in nerve tissue.

Animals↗

PubMed1980

Obstructive jaundice associated with chronic active hepatitis in a dog.

A cholestatic syndrome was the primary manifestation of chronic active hepatitis in a dog. Enzyme determinations did not differentiate between extrahepatic and intrahepatic cholestasis as the cause of the conjugated hyperbilirubinemia, thus necessitating percutaneous liver biopsy. The dog was treated with prednisolone but developed gastrointestinal hemorrhage and terminal hepatic encephalopathy. Morphologic variations in liver biopsy specimens obtained simultaneously and in the specimen obtained at necropsy demonstrated that the disease activity varied by locales in the liver.

Animals↗

PubMed1980

Malignant lymphoma in macaques: a clinicopathologic study of 45 cases.

Malignant lymphoma was diagnosed in 42 rhesus macaques (Macaca mulatta) and 3 stumptail macaques (M. arctoides) between February 1969 and December 1977. The distribution of tumor masses in the tissues of individual animals varied widely. Solitary tumor masses were present in 14 animals and multiple masses in the remaining 31 animals. Visceral lymph nodes, gastrointestinal tract, heart, and kidneys were most commonly affected. Peripheral lymph nodes were rarely involved. Most malignant lymphomas were of an undifferentiated cell type, although tumors of histiocytic, lymphocytic, poorly differentiated, and mixed lymphocytic and histiocytic cell types were also observed. Concurrent bacterial and/or viral infections were evident in 30 of the 45 macaques with malignant lymphoma. Amyloidosis was present in 9 animals. This high incidence of malignant lymphoma suggested that their immune responses were abnormal. The development of malignant lymphoma in the macaques may have been secondary to or enhanced by immunodeficiency.

Animals↗

PubMed1978

Cellular immunologic studies of malignant lymphoma in rhesus macaques.

Cells from malignant lymphoma in 10 rhesus macaques were examined for lymphocyte surface markers. Three had features of T cells, 5 had features of B cells, and 2 lacked evidence of either B- or T-cell differentiation. Correlation between the histologic classification of cell type and the B- or T-cell nature of the neoplasms was not evident. Evaluation of serum electrophoresis, mitogen responses tests, and previous histologic studies suggest that the development of the neoplastic lymphocyte proliferation occurred following or during an abnormal immunologic response.

Animals↗

PubMed1977

Immunologic surface markers on nonhuman primate lymphocytes.

Peripheral blood lymphocytes from 37 healthy rhesus macaques (Macaca mulatta) and thymocytes from 10 fetal and neonatal rhesus macaques were studied for membrane characteristics. Spontaneous rosette formation with sheep erythrocytes, a characteristic of human T lymphocytes, was evaluated. The presence of membrane-bound immunoglobulin and surface receptors for fixed complement was measured, using fluorescent antibody techniques and erythrocyte-antibody-complement rosettes, respectively. The mean percentages +/- 1 standard error of the lymphocyte markers in the peripheral blood lymphocytes from the macaques were: spontaneous rosettes, 63 +/- 1.0; erythrocyte-antibody-complement rosettes, 14.9 +/- 1.2; and membrane immunoglobulin-positive cells, 21.9 +/- 2.2. These values are very similar to values reported for human beings.

Animals↗