Showing papers by "Thomas C. Merigan published in 1970"
TL;DR: The ability to produce high levels of cutaneous interferon, perhaps related to white-cell function, may be important in determining the outcome of varicella infection in patients recovering from serious complications of smallpox vaccination.
Abstract: Thirteen of 14 persons without cancer produced at least 1000 U per 4 ml of vesicle-fluid interferon (VF-IF) during varicella infection (that is, herpes zoster or chicken pox). Three of seven patients with cancer in whom varicella infections developed were leukopenic and produced less than 100 U per 4 ml. These three patients had further viral spread, and two of them died from the infection. One of them was treated with an interferon inducer, polyinosinic acid-polycytidylic acid, without increasing interferon levels or clinical improvement. The other four patients were not leukopenic and had interferon levels greater than 1000 U per 4 ml when studied late during the infection, and all recovered. Between 30 and 170 U per 4 ml of interferon were demonstrated from crust extracts of three patients recovering from serious complications of smallpox vaccination. The ability to produce high levels of cutaneous interferon, perhaps related to white-cell function, may be important in determining the outcome ...
77 citations
TL;DR: The mechanism of induction and action of interferon, its mo lecular properties, and its biological role in viral and non viral infections, and in neoplastic diseases are studied.
Abstract: Although viral interference was described some 30 years ago (1, 2), the role of a specific protein, called "interferon," in the resistance to viral in fection was noted by Isaacs & Lindenmann (3) in 1957. Interferon appears to be a stable, nontoxic, potent, broadly active substance which is produced early in viral infection and functions at the intracellular level to inhibit viral multiplication. Because of these properties much attention has been paid to the practical use of interferon in clinical medicine. This promise is as yet unfulfilled. Recent developments have markedly increased our under standing of the mechanism of induction and action of interferon, its mo lecular properties, and its biological role in viral and non viral infections, and in neoplastic diseases. A new area of emerging importance has appeared, that is, interferon as part of the immune response. These aspects will be emphasized in the present review. Previous reviews in this series covered the interferon literature up to 1963 (4) and 1966 (5), respectively. More recent findings on interferon have been summarized by Finter (6), Wagner & Smith (7), Ho & Postic (8), Merigan (9), Paucker & Boxaca (10), Burke & Skehel (11), Lockart (12), Wheelock, Larke & Caroline (13), Hilleman (14), and Finkelstein & Merigan (15).
73 citations
TL;DR: Three anionic polymers*, pyran copolymer, polyacrylic acid and the double stranded synthetic ribonucleic acid poly I·poly C, each conferred resistance to Listeria monocytogenes infection in mice.
Abstract: A NUMBER of synthetic polyanions stimulate interferon production1–7 and these materials are active against infection with viruses and also with parasites of a more complex nature8–12. Mice inoculated intraperitoneally with pyran, a random copolymer of divinyl ether and maleic acid anhydride, are resistant to an ordinarily lethal challenge of mengo virus7. Such antiviral resistance persists for as long as 60 days in spite of the absence of measurable levels of interferon in the sera of the mice after 4 to 6 days7,13. These polyanions modify a number of host defence mechanisms including delayed hypersensitivity14, antibody response15 and the number of circulating white blood cells16. In view of the suggestion that a common mechanism of host resistance to intracellular pathogens may exist17, we were interested to determine if the long term resistance against viral challenge observed following administration of such polymers may also be extended to intracellular bacterial infection. In these studies, three anionic polymers*, pyran copolymer, polyacrylic acid and the double stranded synthetic ribonucleic acid poly I·poly C, each conferred resistance to Listeria monocytogenes infection in mice.
61 citations
TL;DR: The increased resistance to breakdown by ribonuclease and serum paralleled an increased capacity to confer cellular resistance to virus infection, suggesting that protection against premature enzymatic degradation might underly the increased antiviral activity of the thiophosphate analogs in vitro and in vivo.
55 citations
TL;DR: In this article, the authors summarize previous work on interferon-inducing polyanions and their mechanisms, and extend these studies to polyphosphates and homopolyribonucleotides.
Abstract: Various s y n t h e t i c polyanions have been r epor t ed to stiuulate t h e production of i n t e r f e r o n e i t h e r i n v i v o or i n v i t r o : polycarboxylates i nc lud ing pyran ( m l e i c anhydr ide /d iv iny l e t h e r ) copolymer, l Y 3 polya c r y l i c and polymethacrylic a c i d s , 3 * 4 po lysu l f a t e s i nc lud ing polyvinyl s u l f a t e 5 and polysaccharide s u l f a t e s ex t r ac t ed from seaweedsS4 and polyphosphates inc lud ing r ibonuc leo t ide homopolymer p a i r s (e.g. polyriboi n o s i n i c ac id /po lycy t idy l i c ac id and polyadenyl ic a c i d / p o l y u r i d y l i c a c i d ) I a1 t erna t i n g po ly r ibonuc l e o t i d es (e . g . r ibo inos inic-cy t i d y l i c and r iboadeny l i c -u r idy l i c copolymers) , * and homopolyribonucleotides (polyr iboguanyl ic , po ly r ibo inos in i c and polyr iboxanthyl ic a c i d s ) .g I n t h i s paper we w i l l summarize t h e previous r epor t ed interferon-inducing p rope r t i e s of t h e polyr ibonucleot ides and extend these s t u d i e s t o o the r polyphosphates inc lud ing polydeoxyribonucleotides. phosphorylated polys accha r ides and thiophosphate s u b s t i t u t e d polyr ibonucleot ides . These f ind ings al lm a b e t t e r understanding of t h e mechanism of i n t e r f e r o n s t i n u l a t i o n and of t h e e s s e n t i a l s t r u c t u r a l c h a r a c t e r i s t i c s of t h e inducer r equ i r ed f o r t h i s a c t i v i t y .
52 citations
TL;DR: Treatment with exogenous interferon in amounts which closely mimicked the levels of circulatingInterferon produced endogenously by an effective dose of poly rI gave protection against intranasal VSV which was identical with that dose of (poly rC), which strongly suggests thatinterferon production accounts for the whole protective effect of (Poly rI).
Abstract: Intravenous injection of polyinosinic acid/polycytidylic acid [(poly rI)·(poly rC)] offered significant protection against intranasal challenge of young mice with vesicular stomatitis virus (VSV). Optimal protection was obtained when a single dose was administered 2 hr before virus challenge, but repeated doses were effective when started as late as 3 days after virus challenge. The therapeutic ratio or ratio of maximum tolerated dose to minimum effective dose for a single intravenous injection of (poly rI)·(poly rC) 2 hr before virus inoculation was ≥8 mg/kg:0.004 mg/kg or ≥200.
Dose-response curves for interferon production and antiviral protection by (poly rI)·(poly rC) were closely parallel. Equivalent doses of poly rI or poly rC alone did not exert any interferon-inducing capacity or protective effect on intranasal VSV challenge. Several factors, which are known to potentiate or antagonize interferon production, increased or decreased the interferon-inducing capacity and antiviral protection of either (poly rI)·(poly rC) or maleic acid/divinyl ether copolymer (MA/DVE) in parallel. Interferon production and antiviral protection by MA/DVE were enhanced by arginine but abolished by prior treatment with MA/DVE; DEAE-dextran (intraperitoneally), kinetin riboside and isopentenyladenosine, and prior injection of endotoxin reduced both interferon production and antiviral protection by (poly rI)·(poly rC).
Treatment with exogenous interferon in amounts which closely mimicked the levels of circulating interferon produced endogenously by an effective dose of (poly rI)·(poly rC) gave protection against intranasal VSV which was identical with that dose of (poly rI)·(poly rC). This strongly suggests that interferon production accounts for the whole protective effect of (poly rI)·(poly rC) in the intranasal VSV assay.
42 citations
TL;DR: Preincubation at 37° C was found to increase the activity of several synthetic polynucleotides in producing cellular resistance to virus infection in vitro by several orders of magnitude, and to a lesser extent, induction of interferon in vitro and in vivo.
Abstract: LIMITED preincubation (5 min to 2 h) at 37° C was found to increase the activity of several synthetic polynucleotides in producing cellular resistance to virus infection in vitro by several orders of magnitude, and to a lesser extent, induction of interferon in vitro and in vivo. The thermal activating effect was observed for both alternating copolymers and homopolymer pairs of either RNA or DNA types, but was most marked with the alternating polyribonucleotides such as poly A·poly U and poly I·poly C. Our findings might help to explain the variable biological activity of polynucleotides according to the way they are processed before testing.
36 citations
TL;DR: It is demonstrated in 1963 that nonviral nucleic acids, provided they were foreign to the cells (heterologous or chemically modified homologous RNA), could also initiate the production of interferon.
Abstract: Until 1963, only viruses were known to stimulate interferon production in cells. The nucleic acid of the virus was generally regarded as the essential stimulus for interferon production. 1 Rotem et al and Isaacs et al 2,3 demonstrated in 1963 that nonviral nucleic acids, provided they were foreign to the cells (heterologous or chemically modified homologous RNA), could also initiate the production of interferon. Although their "foreign nucleic acid" hypothesis was received with some scepticism and retracted later, 4 it offered a reasonable explanation for the nucleic acid-induced resistance to viral infection, which had been described 5 as early as 1953. Moreover, it raised a possible explanation for the antiviral action of agents such as bacteria or apparently nonviral agents as the mold products statolon (culture filtrate of Penicillium stoloniferum ) and helenine (mycelium extract of Penicillium funiculosum ) which had been found active in a number of experimental viral infections. 6-13
34 citations
TL;DR: Two animal models f o r human v i rus infect ion are presented, together with s tudies examining mechanisms underlying the pro tec t ion observed, whereas the second w i l l review s tudsies performed in man are reviewed.
Abstract: The purpose of t h i s paper is t o present some of our observations on in te r fe ron inducers i n r e l a t i o n t o t h e i r possible use i n cont ro l of v i r u s infec t ions in man and domestic animals. paper v i l l present two animal models f o r human v i rus infect ion, together with s tudies examining t h e mechanisms underlying the pro tec t ion observed, whereas the second w i l l review s tudies performed in man. The f i r s t port ion of the
23 citations
TL;DR: Interferon represents an interesting approach to the control of viral disease in man and his domestic animals, for it is a part of the animal's own recovery processes during naturally occurring infection and active against most viruses that cause acute infection.
Abstract: Interferon represents an interesting approach to the control of viral disease in man and his domestic animals, as this review shows, for it is a part of the animal's own recovery processes during naturally occurring infection and active against most viruses that cause acute infection.
21 citations
TL;DR: Intraperitoneal injection of mice with mineral oil, incomplete (IFA) or complete Freund's adjuvant (CFA) increased the interferon response to endotoxin or (poly rI)*(poly rC) administered intravenously 2 days later and became more resistant to intranasal vesicular stomatitis virus challenge than mice injected with endotoxin alone.
Abstract: Intraperitoneal injection of mice with mineral oil, incomplete (IFA) or complete Freund's adjuvant (CFA) increased the interferon response to endotoxin or (poly rI)*(poly rC) administered intravenously 2 days later. After endotoxin administration, circulating interferon titers were increased at several different times of sampling and with a variety of endotoxin dosages. When injection of endotoxin was delayed until 6 to 8 days after the administration of IFA or CFA, interferon production was markedly decreased. Mice treated with CFA and injected with endotoxin 2 days later became more resistant to intranasal vesicular stomatitis virus challenge than mice injected with endotoxin alone. Hyporeactivity to the interferon-inducing capacity of a second injection of endotoxin 2 days after the first injection could not be overcome by administering CFA simultaneously with the first dose. CFA treatment not only raised the serum interferon titers produced by endotoxin, but also increased the number of interferon-forming cells in the spleen after administration of endotoxin in vivo. In addition, CFA enhanced the intravascular clearance of (poly rI)*(poly rC). The possibility that Freund's adjuvant increased the interferon response to endotoxin and (poly rI)*(poly rC) by stimulating the uptake and processing of the interferon inducer by lymphoreticular cells is discussed.
TL;DR: Human fibroblasts treated with the synthetic interferon-stimulating polymer polyinosinate:polycytidylate became resistant (or “tolerant”) to a subsequent stimulation ofinterferon by either I:C or Newcastle disease virus (NDV).
Abstract: SummaryHuman fibroblasts treated with the synthetic interferon-stimulating polymer polyinosinate:polycytidylate (I:C) became resistant (or “tolerant”) to a subsequent stimulation of interferon by either I:C or Newcastle disease virus (NDV). Tolerance to I:C reached a maximum around the time of termination of the first interferon response. After this time the cells gradually recovered some sensitivity to a second stimulation of interferon by I:C. In contrast, tolerance to NDV persisted and increased after termination of the primary interferon response by I:C. Treatment of human fibroblasts with interferon inhibited the subsequent production of interferon by NDV but not by I:C. When human fibroblasts were pretreated with a moderate dose of actinomycin D, tolerance to I:C was not observed. Furthermore, tolerance to I:C was significantly diminished when cells were only briefly exposed to I:C, although high levels of interferon were produced by this treatment. A model is proposed by which cells develop resista...
TL;DR: A quality-control program using a timesharing, on-line computer was employed to compare the results of testing the antibiotic sensitivity of new microbial isolates with previous results, and the program has uncovered 43 errors in identification and 551 changes in sensitivity category.
Abstract: A quality-control program using a timesharing, on-line computer was employed to compare the results of testing the antibiotic sensitivity of new microbial isolates with previous results. In 10 months of use the program has uncovered 43 errors in identification and 551 changes in sensitivity category. The computer has completely eliminated errors in conversion from zone size to sensitivity category that otherwise occur once in every 12 reports. In all, the program detects and corrects 16 errors in each 100 isolates screened before results are issued to physicians. In addition, the sensitivity-testing data can be stored in a form suitable for hospital epidemiologic studies and for guidance in treatment before specific antibiotic-sensitivity results are available.
TL;DR: Information from animal models resembling human diseases suggests that certain nucleotide inducers may have clinical usefulness in therapy or prophylaxis.
Abstract: Interferon production can be stimulated by a great variety of microbial and nonmicrobial agents other than viruses. The nonmicrobial inducers can be divided into polyanions, mitogens, and a miscellaneous category including the various endotoxins and antibiotics. The polyanions appear to require a stable, high molecular weight backbone and a high density of free anionic groups whether they are polynucleotides, plastics, or polysaccharides. Mitogen-induced interferon appears to be but one of a constellation of substances produced following lymphocyte transformation. The process of transformation can be stimulated either by specific immune recognition or non-specifically by phytohemagglutinin. Synthetic polynucleotide inducers are active; the thermostable, double-stranded RNA's are much more active than the double-stranded DNA's or 1-, 3-, or 4-stranded RNA's. Some success has been obtained with potentiation of nucleotide inducers through the use of polycationic substances, complexing with a polysaccharide, concurrent administration of a metabolic antagonist, or substitution of phosphate by thiophosphate in the polynucleotide backbone. The stages in the interaction of interferon stimulating RNA and cells can be divided into three steps: first, binding to cell surface, next, a temperature dependent "recognition" step, and finally, degradation and utilization of monomers in cellular RNA synthesis; the critical recognition site has not yet been determined. The vast majority of cell-associated polynucleotide remains at the surface of the cell. Information from animal models resembling human diseases suggests that certain of these nucleotide inducers may have clinical usefulness in therapy or prophylaxis.
TL;DR: It appears that a inhibitor substance blocked the continued formation of nonviral interferon, without significantly affecting the induction of viral interferons, in dually stimulated monolayers.
Abstract: SummaryHomogeneous monolayers of human fibroblasts were infected with Newcastle disease virus (NDV) and 1 hr later treated with the synthetic RNA polycytidylate: polyinosinate (poly C:I) The induction of interferon by poly C:I and NDV could be distinguished on the basis of differences in (1) the kinetics of interferon production, and (2) the sensitivity to inhibitors of RNA and protein synthesis The results indicated that both poly C:I and NDV were fully able to induce the production of interferon in these dually stimulated monolayers The release of interferon induced by poly C:I appeared to be terminated shortly before the appearance of viral interferon in the extracellular medium Our findings suggest that termination of the nonviral interferon response did not involve direct inactivation of interferon It appears that a inhibitor substance blocked the continued formation of nonviral interferon, without significantly affecting the induction of viral interferon
TL;DR: This symposium issue was organized with the specific aim of bringing to the physician contemporary knowledge in this area as it is likely he will be required to evaluate clinical investigation with this material in the near future.
Abstract: In the 13 years since its discovery, there has been enormous interest in interferon, both from the standpoint of evaluating its role in the cell-virus interaction and the potential clinical use of the mechanism. The contributions for this issue were solicited with the aim of evaluating our progress toward those ends. In recent years there have been many review articles 1 and several volumes 2-6 published in this area. This symposium issue was organized with the specific aim of bringing to the physician contemporary knowledge in this area as it is likely he will be required to evaluate clinical investigation with this material in the near future. Interferon studies have involved a diversity of investigators including biochemists committed to molecular level studies on its mechanism of action, biologists interested in its relative role in the in vivo host response, and clinicians and clinical pharmacologists interested in its therapeutic usefulness. Friedman's and
TL;DR: Although Sendai infection does not interfere with host-cell protein or RNA synthesis, interferon added 6 hr or later after infection did not affect any Sendai replicative functions.
Abstract: Summary
The incorporation of [3H]uridine into the four species of RNA specified by Sendai virus in monolayers of chick embryo fibroblasts was inhibited to an equal degree by addition of purified chick interferon to cultures before infection with virus. The inhibition of RNA synthesis was dose-dependent. Similarly, [3H]uridine incorporation into RNA of virus nucleocapsid and polyribosomes was completely inhibited by pretreatment with interferon. When interferon was added 2 hr after infection, there were only small effects on the synthesis of total virus-specific RNA and significantly greater reduction was observed in [3H]uridine incorporation into the RNA of nucleocapsid and polyribosomes. Although Sendai infection does not interfere with host-cell protein or RNA synthesis, interferon added 6 hr or later after infection did not affect any Sendai replicative functions.
TL;DR: Treatment of mice with the interferon inducer polyinosinic:polycytidylic acid failed to inhibit multiplication of Mycobacterium leprae in the mouse foot pad.
Abstract: SummaryTreatment of mice with the interferon inducer polyinosinic:polycytidylic acid failed to inhibit multiplication of Mycobacterium leprae in the mouse foot pad. This same treatment has recently been shown to inhibit multiplication in vivo of several intra-and extracellular pathogenic microorganisms.