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Biomedical subjects

T C Merigan

Publications and source records attributed to T C Merigan.

At least 181 records · Page 10Linked to original sources
PubMed1985

Immunomodulatory and antiproliferative effect of recombinant alpha, beta, and gamma interferons on cultured human malignant squamous cell lines, SCL-1 and SW-1271.

Two different human malignant squamous cell lines (SCL-1 and SW-1271) and normal human foreskin fibroblasts were treated with recombinant human alpha, beta, and gamma interferons. HLA-DR expression was induced in a concentration-dependent fashion only on the SCL-1 cells treated with recombinant human gamma interferon (r-IFN-gamma) (10(2)-10(3) U/ml). No HLA-DR expression was observed with alpha or beta interferon on either malignant squamous cell line, nor with gamma interferon on SW-1271 cells. All three interferons reduced the number of malignant cells growing in culture but had no effect on the fibroblasts. There was a concentration-dependent growth-inhibitory response of the malignant cells by the interferons (dose range 1-10(3) U/ml; 7.1 X 10(-12) M to 7.1 X 10(-9) M). The SCL-1 cells were 10(2) more sensitive (based on weight) to the antiproliferative effects of gamma interferon than alpha or beta interferon. A brief (30-min) exposure of the SCL-1 cells to r-IFN-gamma (10(2) and 10(3) U/ml) produced approximately the same inhibition of cell growth as continuous exposure over a 2-week period. The SW-1271 cells were equally sensitive to alpha, beta, and gamma interferons. However, the maximal inhibitory effect on SW-1271 cells was less than that observed for the SCL-1 cells. Combining beta and gamma interferon resulted in cytotoxicity with SCL-1 cells and additive cytostatic effect on the SW-1271 cells. These additional malignant cell lines with their different sensitivities to alpha, beta, and gamma interferons may prove useful in studying the mechanisms of action of various interferons.

Carcinoma, Squamous Cell↗
PubMed1985

Viral polypeptides detected by a complement-dependent neutralizing murine monoclonal antibody to human cytomegalovirus.

Murine monoclonal antibodies were produced which coimmunoprecipitated, under reducing conditions, 130,000- and 55,000-dalton (Da) polypeptides from cells infected with human cytomegalovirus (CMV) strain AD169. A 92,000-Da species, possibly a biosynthetic intermediate, was also detectable. One of the monoclonal antibodies, 15D8, neutralized CMV AD169 only in the presence of guinea pig complement. A second monoclonal antibody, 14E10, coimmunoprecipitated the 130,000- and 55,000-Da polypeptides but did not neutralize viral infectivity. By sequential immunoprecipitation, both monoclonal antibodies have been shown to recognize the same polypeptides. Monoclonal antibody 15D8 detected the 130,000- and 55,000-Da polypeptides in five of six clinical strains and three laboratory strains tested. The 14E10 monoclonal antibody detected the 130,000-Da protein in four of six CMV clinical isolates and in strain AD169 but did not immunoprecipitate any polypeptides from extracts of cells infected with either Towne or Davis laboratory strains. In kinetic studies, the synthesis of the 130,000-Da polypeptide preceded the appearance of the 55,000-Da polypeptide. In infected cells radiolabeled with a pulse of L-[35S]methionine, the isotope was initially detected in the 130,000-Da polypeptide but could be chased into the 55,000-Da polypeptide. These polypeptides exist in the intracellular and extracellular virus as disulfide-linked multimers. Extracellular virus contained a high-molecular-weight (greater than 200,000 Da) multimer composed entirely of 55,000-Da polypeptides. In extracts from infected cells an additional high-molecular-weight multimer was detected consisting of disulfide-linked 130,000-Da polypeptides.

Antibodies, Monoclonal↗
PubMed1985

Evolution of recurrent herpes simplex lesions. An immunohistologic study.

We performed immunoperoxidase stains on skin biopsies taken from nine patients with recurrent peripheral herpes simplex lesions at 12 h to 6 d after onset of signs of symptoms to phenotype the inflammatory infiltrate, to detect cells producing interferons alpha and gamma, and to locate herpes simplex virus antigen-containing cells. Viral glycoprotein antigen was located in the nuclei and cytoplasm of necrotic epidermal cells, often within vesicles, in biopsies taken between the first and third day. Histologically, biopsies of all stages showed intradermal focal perivascular and diffuse mononuclear inflammatory infiltrates. The cells constituting the infiltrates were predominantly T lymphocytes with lesser numbers of histiocytes; Leu 7+ (most natural killer/killer) cells and B cells were rare in the biopsy specimens. Leu 3a+ ("helper") T lymphocytes predominated in both subepidermal and perivascular regions of early lesions (12-24 h). Tissue helper/suppressor ratios ranged from 6.3 to 3.4 compared with 1.9-1.0 in blood. In later lesions (after 2 d), monocytes/macrophages were more prominent in tissue sections and the helper/suppressor ratios (2.3-2.5) more nearly approximated those of blood (1.6-2.7). The negative correlation of tissue ratios with time was significant (P less than or equal to 0.02). A large proportion of the infiltrated T lymphocytes expressed DR antigens. There was also diffuse strong DR expression on epidermal cells in five cases (all of two or more days). In six biopsies, scattered macrophages and small cells, presumably lymphocytes, demonstrated cytoplasmic or membrane staining for a substance which copurifies with interferon gamma. We identified such stained cells within vessels, suggesting that these cells circulate. Gamma interferon might have an important role within the herpetic lesions, possibly inducing macrophage activation and cytotoxic T lymphocytes and increasing DR expression on monocyte and epidermal cells.

Adult↗
PubMed1985

Treatment of nasopharyngeal carcinoma with human leukocyte interferon.

Nasopharyngeal carcinoma (NPC) is a human neoplasm closely associated with Epstein-Barr virus (EBV). Human leukocyte interferon (IFN) has known antiviral and antineoplastic properties. After initial IFN treatment in one NPC patient demonstrated acceptably low toxicity, 12 additional patients were treated on a protocol with IFN, 10 X 10(6) units intramuscularly (IM) daily for 30 days. IFN did not affect serum anti-EBV antibody titers (IgA and IgG antiviral capsid and early antigens). Of six patients tested, none was found to excrete EBV in saliva before, during, or after IFN. Four patients had measurable tumor regression (two partial responses and two minor responses), three had stable disease, and five patients plus the initial preprotocol patient had progressive disease. Toxicity included fever, fatigue, and myalgias in all patients, thrombocytopenia in two patients, and neutropenia in three patients. Three patients were withdrawn from the study, one each for severe fatigue, neutropenia, and hypotension. This study demonstrates that IFN has sufficient activity in advanced NPC to justify further investigation.

Adult↗
PubMed1984

Interferon enhances antibody-dependent cellular cytotoxicity when suboptimal concentrations of antibody are used.

Polymorphonuclear leukocytes (PMN) and killer (K) cells isolated from buffy coats from normal volunteers were tested for antibody-dependent cellular cytotoxicity (ADCC) against chicken erythrocytes (CRBC) with and without the addition of interferon (IFN). Maximum enhancing activity was found when the anti-CRBC antibodies in the ADCC reaction were at suboptimal concentrations. All three species of pure recombinant Escherichia coli-derived interferon were compared for their ability to enhance ADCC in both effector systems. Recombinant IFN-gamma was found to be effective at lower doses than recombinant IFN-alpha A or recombinant IFN-beta, although maximum activity for all three species was similar in the PMN system. IFN-gamma also enhanced K-cell ADCC but to a lesser extent than in the PMN system. There appeared to be individual variation in response of the K-cell ADCC system to IFN-alpha A and IFN-beta at the doses tested.

Animals↗
PubMed1984

Human leukocyte interferon administration to patients with symptomatic and suspected rabies.

Body fluids and brain tissue from rabid human patients have demonstrated only low titers of interferon. Therefore, pharmacokinetic studies of systemically administered and locally injected leukocyte interferon were performed in 2 North American patients with suspected rabies who showed no clinically important side effects of this therapy. Similar therapy was given to 5 patients with symptomatic rabies in Europe and America. Although no prolongation of the clinical course was seen in 3 patients given high-dose intraventricular and systemic therapy, treatment was not initiated until between 8 and 14 days after symptoms were seen. The intraventricular dosage regimen produced cerebrospinal fluid levels that appeared to fall progressively over the 24 hours after injection and demonstrated good but somewhat delayed distribution into the lumbar sac. Titers produced by this therapy were 30- to 10,000-fold higher than those normally observed in this infection, however. In the patients treated at the highest dosage, a diminished and delayed antirabies neutralizing antibody titer was observed, probably a result of the administration of the exogenous interferon.

Adolescent↗
PubMed1984

DNA of 21 clinical cytomegalovirus strains detected by hybridization to cloned DNA fragments of laboratory strain AD-169.

Nine distinct DNA probes prepared from cloned DNA fragments of the cytomegalovirus (CMV) strain AD-169, each representing a relatively small portion of the total genome, were able to detect all 21 epidemiologically distinct clinical isolates of CMV that had been passaged in tissue culture. All probes were of comparable sensitivity in the detection of CMV, and under the hybridization conditions used, no probe gave an unusually high background with uninfected host cells.

Cells, Cultured↗
PubMed1984

Murine monoclonal antibody to a single protein neutralizes the infectivity of human cytomegalovirus.

Murine monoclonal antibodies to human cytomegalovirus (CMV) strain AD169 were selected that neutralized virus infectivity. One monoclonal antibody-producing hybridoma, 1G6, was used to produce ascites fluid from which immunoglobulin was isolated. This antibody efficiently neutralized CMV AD169, other laboratory strains (Towne, Davis), and clinical isolates of CMV in early tissue culture passage (less than 10) in the absence of complement. The antibody immunoprecipitated a single 86,000-dalton protein from both laboratory and clinical strains. This viral protein was demonstrated by indirect immunofluorescence to be localized in the cytoplasm of CMV-infected cells.

Animals↗
PubMed1984

Decreased interferon synthesis and responsiveness to interferon by leukocytes from multiple sclerosis patients given natural alpha interferon.

Despite the use of interferon (IFN) in numerous clinical trials, relatively little is known about how IFN therapy influences leukocyte function. To evaluate some of its effects, leukocytes from multiple sclerosis (MS) patients given daily treatments of natural alpha IFN (IFN-alpha) were evaluated for IFN synthesis and two responses to IFN in vitro: enhancement (priming) of IFN synthesis and suppression of Concanavalin A (Con A)-induced T-cell mitogenesis. The IFN therapy had no effect on the sensitivity of Con A-stimulated leukocytes to the antiproliferative action of IFN-alpha. However, using Newcastle disease virus (NDV), measles virus, or poly I:C to stimulate IFN synthesis, cells from IFN-treated patients produced less IFN in response to all inducers, with titers ranging between 11% and 44% of pretherapy values. Also, unlike cells from these same patients before therapy or from the placebo recipients, cells from the IFN recipients were not primed by either IFN-alpha or -beta even though IFN-beta had not been used for therapy. The loss of these priming reactivities suggests that resistance to IFN had developed in IFN-treated patients.

Adult↗
PubMed1984

Recombinant gamma interferon induces HLA-DR expression on cultured human keratinocytes.

In normal human epidermis, expression of HLA-DR antigen is restricted to Langerhans cells (LC) and acrosyringial epithelium. However, in diseases such as lichen planus and graft-vs.-host, HLA-DR antigen appears to be expressed by keratinocytes, although the exact source of the HLA-DR is unclear. Two possibilities are that (1) the HLA-DR is shed by neighboring immunocompetent cells, or (2) that the keratinocytes are synthesizing the antigen themselves. Recently, gamma interferon has been shown to induce HLA-DR biosynthesis and expression on human malignant melanoma cells lines and on normal vascular endothelium. We report here that pure recombinant human gamma interferon (100 units/ml) induces HLA-DR expression on 60-70% of cultured human adult keratinocytes depleted of LC within 2-4 days of culture as determined by fluorescence-activated cell sorter (FACS) analysis using monoclonal antibodies. No residual LC or lymphocytes could be detected in these cultures. This is the first demonstration of HLA-DR expression by cultured human keratinocytes. This expression may be of functional significance in antigen presentation and cell-mediated cytotoxicity involving the epidermis.

Antibodies, Monoclonal↗
PubMed1984

Alpha-interferon administration in cytomegalovirus retinitis.

Four patients, including three with the acquired immunodeficiency syndrome (AIDS), were treated with high-dose, buffy coat-derived alpha-interferon for progressive cytomegalovirus retinitis. Two of these patients had decreased viruria during therapy and the other two had increased viruria. There was evidence of progression of disease despite therapy in all patients, although the retinitis eventually became quiescent in the patient without AIDS. The severe immunosuppression encountered in AIDS patients complicates the management of cytomegalovirus and other opportunistic infections.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Inhibition of human cytomegalovirus replication by 9-(1,3-dihydroxy-2-propoxymethyl)guanine alone and in combination with human interferons.

The inhibitory action of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on the replication of human cytomegalovirus was studied. Three laboratory strains (AD-169, Towne, and Davis) and three early passage (less than 10) clinical isolates were all inhibited in yield inhibition assays. In cultures infected with AD-169, virus yields could be inhibited if the drug was added as late as 3 days after the replication cycle had begun. The effects of the drug were fully reversible during the first 4 days of the viral replication cycle. Viral infectivity and viral DNA synthesis were reduced more than viral protein synthesis. Synergistic antiviral effects were observed with beta-cysteine, and to a lesser extent, with beta-serine recombinant interferons, but only over a narrow range of dose combinations.

Acyclovir↗
PubMed1984

Comparison of antiviral activities of cloned and native human interferons against herpes simplex virus types 1 and 2 and human cytomegalovirus.

Five recombinant alpha interferons and two recombinant beta interferons have been tested for their ability to inhibit yields of herpes simplex virus types 1 and 2 and human cytomegalovirus in human embryonic lung cells. All of the alpha species and both of the beta forms (cysteine and serine) were active against the herpesviruses tested in this study. Neither the recombinant alpha nor the recombinant beta interferons exceeded the activity of the native species against herpes simplex viruses types 1 and 2. However, the recombinant beta interferons inhibited cytomegalovirus more than either the native beta or the alpha interferon species with the exception of interferon alpha K (alpha 6).

Cloning, Molecular↗
PubMed1984

Large-scale serological screening for cytomegalovirus antibodies in homosexual males by enzyme-linked immunosorbent assay.

We compared an enzyme-linked immunosorbent assay (ELISA) with complement fixation and radioimmunoassay in determining the presence of immunoglobulin antibodies to cytomegalovirus. Of an initial 93 serum samples tested, the correlation between ELISA and radioimmunoassay was 98.9% and that between ELISA and complement fixation was 96.1%. ELISA was used to screen 1,123 homosexual men in San Francisco. Of 479 men attending a homosexual health fair, 35 (7%) lacked cytomegalovirus antibodies by ELISA. Only 15 (2%) of 644 homosexual men attending a municipal sexually transmitted disease clinic were found to be seronegative. All but one of the seronegatives detected by ELISA were also seronegative by radioimmunoassay and complement fixation. We conclude that ELISA can be used to reliably perform large-scale screening for the presence of immunoglobulin G antibodies to cytomegalovirus.

Antibodies, Viral↗
PubMed1984

Survival in chronic hepatitis B. An analysis of 379 patients.

Survival data from 379 patients with chronic hepatitis B were analyzed to determine life expectancy for the patient from the time of first contact. One hundred twenty-one patients had chronic persistent hepatitis, 128 had chronic active hepatitis, and 130 had chronic active hepatitis with cirrhosis. The frequency of symptoms (p less than 0.001), stigmata of chronic liver disease (p less than 0.001), and liver function test abnormalities (p less than 0.001) increased as the histologic features worsened, whereas the percentage of patients with circulating hepatitis B DNA polymerase declined (p less than 0.001). Women were uncommon in our series and had less severe disease than men (p less than 0.02). Fifty-one patients had died by the time of this analysis. The estimated 5-year survival rates were 97% for patients with chronic persistent hepatitis, 86% for those with chronic active hepatitis, and 55% for those with chronic active hepatitis with cirrhosis. The usual cause of death was liver failure and its sequelae. A multivariate analysis found age of 40 years or more, total bilirubin level of 1.5 mg/dL or more, ascites, and spider nevi to be factors that identified patients at a higher risk of death. The prognosis for patients with chronic hepatitis B is similar to that for patients with chronic hepatitis of other causes.

Adult↗