Degradation of Poly(inosinic acid) · poly(cytidylic acid) [(I)n· (Cn)] by Human Plasma

Clercq, Erik De

doi:10.1111/j.1432-1033.1979.tb12807.x

Cited by 27 publications

(22 citation statements)

References 28 publications

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“…This is supported by a UV hydrolysis study done on a series of mismatched duplexes of (I,U), and (C,U), copolymers with (C), and (I),, respectively, which had been exposed to pancreatic ribonuclease (Carter et al, 1972). Our observed parallelism points to a close, if not casual, relationship between the interferon-inducing potency of the duplexes and their resistance to ribonuclease A. Ribonuclease A has been shown to selectively degrade the (C), strand of (I),-(C), (De Clercq, 1979).…”

Section: Discussionmentioning

confidence: 66%

Interferon induction by poly(inosinic acid).cntdot.poly(cytidylic acid) segmented by spin-labels

Bobst¹,

Langemeier²,

Torrence³

et al. 1981

Biochemistry

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Poly(inosinic acid).poly(cytidylic acid) [(I)n.(C)n] duplexes of which the (C)n strand was modified to various degrees chemically or enzymatically with nitroxide radicals (spin-labels) were evaluated for interferon-inducing activity. Upon annealing of the chemically modified (C)n, (1C,Cx)n (X = 1000 or 16), with (I)n, the interferon-inducing activity was similar to that of (I)n.(C)n in PRK cell cultures. However, to overcome hydrolysis of the spin-label linkage in (1C,Cx)n, and enzymatic approach was taken to synthesize (1S(4)U,Cx)n copolymers with x = 100, 38, 16, and 8. The (1s(4)U,Cx)n copolymers were chemically stable, and upon annealing with (I)n the correlation time of the nitroxide moiety in (I)n. (1s(4)U,Cx)n was determined. A comparison of this correlation time with that measured for (RUGT,U100)n.(A)n, which contains the nitroxide moiety in position 5 of the U moiety, suggests that the 1s(4)U residue is in a nonintrahelical conformation and partitions the duplex into double-helical segments of varying size. The interferon-inducing activity of (I)n. (1s(4)U,Cx)n was evaluated in primary rabbit kidney, human skin fibroblast (strain VGS), and mouse L-929 cell cultures as well as in rabbits. The 1s(4)U residue did not cause a significant change in the interferon induction as compared to (I)n.(C)n in most systems tested unless x less than 16. These findings indicate that double-helical segments of approximately 16 base pairs partitioned by nonintrahelical 1s(4)U residues suffice to trigger the interferon response in all systems studied.

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Section: Discussionmentioning

confidence: 66%

Interferon induction by poly(inosinic acid).cntdot.poly(cytidylic acid) segmented by spin-labels

Bobst¹,

Langemeier²,

Torrence³

et al. 1981

Biochemistry

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“…PolyICLC is resistant to endogenous RNase activity present in primate blood that breaks down polyIC (de Clercq, 1979; Nordlund et al, 1970). Pregnancy was confirmed at approximately 20 days of gestation via ultrasound.…”

Section: Methodsmentioning

confidence: 99%

Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation

Weir

Forghany

Smith

et al. 2015

Brain, Behavior, and Immunity

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Maternal infection during pregnancy increases the risk for neurodevelopmental disorders in offspring. Rodent models have played a critical role in establishing maternal immune activation (MIA) as a causal factor for altered brain and behavioral development in offspring. We recently extended these findings to a species more closely related to humans by demonstrating that rhesus monkeys (Macaca mulatta) prenatally exposed to MIA also develop abnormal behaviors. Here, for the first time, we present initial evidence of underlying brain pathology in this novel nonhuman primate MIA model. Pregnant rhesus monkeys were injected with a modified form of the viral mimic polyI:C (poly ICLC) or saline at the end of the first trimester. Brain tissue was collected from the offspring at 3.5 years and blocks of dorsolateral prefrontal cortex (BA46) were used to analyze neuronal dendritic morphology and spine density using the Golgi-Cox impregnation method. For each case, 10 layer III pyramidal cells were traced in their entirety, including all apical, oblique and basal dendrites, and their spines. We further analyzed somal size and apical dendrite trunk morphology in 30 cells per case over a 30μm section located 100±10μm from the soma. Compared to controls, apical dendrites of MIA-treated offspring were smaller in diameter and exhibited a greater number of oblique dendrites. These data provide the first evidence that prenatal exposure to MIA alters dendritic morphology in a nonhuman primate MIA model, which may have profound implications for revealing the underlying neuropathology of neurodevelopmental disorders related to maternal infection.

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“…The synthetic dsRNA, polyinosinic-polycytidylic acid (Poly-I:C), is known as the strongest type I IFN inducer through TLR3 [24], and can induce LC maturation [25]. However, in vivo Poly-I:C is rapidly inactivated by blood enzymes making it inadequate for clinical applications [26]. To counter this, positively charged polypeptides have been demonstrated to stabilize Poly-I:C (s-Poly-I:C) thereby promoting their use in clinical settings [27]; poly-arginine stabilized Poly-I:C is known as Poly-ICR and poly-lysine and carboxymethylcellulose stabilized Poly-I:C is known as Poly-ICLC.…”

Section: Introductionmentioning

confidence: 99%

Langerhans cells from women with cervical precancerous lesions become functionally responsive against human papillomavirus after activation with stabilized Poly-I:C

Silva

Woodham

Skeate

et al. 2015

Clinical Immunology

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Human papillomavirus (HPV)-mediated suppression of Langerhans cell (LC) function can lead to persistent infection and development of cervical intraepithelial neoplasia (CIN). Women with HPV-induced high-grade CIN2/3 have not mounted an effective immune response against HPV, yet it is unknown if LC-mediated T cell activation from such women is functionally impaired against HPV. We investigated the functional activation of in vitro generated LC and their ability to induce HPV16-specific T cells from CIN2/3 patients after exposure to HPV16 followed by treatment with stabilized Poly-I:C (s-Poly-I:C). LC from patients exposed to HPV16 demonstrated a lack of costimulatory molecule expression, inflammatory cytokine secretion, and chemokine-directed migration. Conversely, s-Poly-I:C caused significant phenotypic and functional activation of HPV16-exposed LC, which resulted in de novo generation of HPV16-specific CD8+ T cells. Our results highlight that LC of women with a history of persistent HPV infection can present HPV antigens and are capable of inducing an adaptive T cell immune response when given the proper stimulus, suggesting s-Poly-I:C compounds may be attractive immunomodulators for LC-mediated clearance of persistent HPV infection.

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Degradation of Poly(inosinic acid) · poly(cytidylic acid) [(I)_n· (C_n)] by Human Plasma

Cited by 27 publications

References 28 publications

Interferon induction by poly(inosinic acid).cntdot.poly(cytidylic acid) segmented by spin-labels

Interferon induction by poly(inosinic acid).cntdot.poly(cytidylic acid) segmented by spin-labels

Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation

Langerhans cells from women with cervical precancerous lesions become functionally responsive against human papillomavirus after activation with stabilized Poly-I:C

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