The Effect of Altering the Size of Poly C on the Toxicity and Antigenicity of Poly I:C

The purposes of this study were to determine whether the febrile and hypotensive reactions to the administration of polyriboinosinic-polyribocytidylic acid [poly (I)-poly (C)] complexed with poly-L-lysine and carboxymethylcellulose (poly ICLC) (9S) encountered in humans could be duplicated in rabbits, and when such duplication was demonstrated, to ascertain whether these untoward reactions could be avoided by (i) administration of hydrocortisone (HC), (ii) alteration of the route of delivery, or (iii) administration of poly ICLC (4S) an interferon inducer of lower molecular weight. Responses to intravenous poly ICLC (9S) in rabbits reproduced adverse reactions in humans, namely fever and hypotension, and were accompanied by high titers of serum interferon. Continuing investigations showed that (i) intravenous pretreatment of rabbits with HC ameliorated hypotensive responses but markedly diminished interferon induction. When HC was given after poly ICLC (9S), both interferon and hypotension induction were likewise depressed. (ii) Intramuscular or subcutaneous poly ICLC (9S) produced neither high titers of serum interferon nor toxic effects. (iii) Poly ICLC (4S) induced high titers of serum interferon and fever, but no hypotension. Poly ICLC (4S) warrants further study.When megaunits of human leukocyte interferon are given to patients, interferon is potentially a potent therapeutic agent (5, 11). Unfortunately, to date, quantities of exogenous human interferon available for clinical trials are limited (7). Therefore, interferon inducers are being sought. One such promising agent is polyriboinosinic-polyribocytidylic acid [poly IC] complexed with poly-L-lysine (Miles Laboratories, Inc., Elkhart, Ind.) and carboxymethylcellulose (Hercules Powder Co., Wilmington, Del.) [poly ICLC (9S)]. This modified complex [poly ICLC (9S)], unlike the parent poly IC, is quite resistant to nucleases in primate serum and induces high titers of serum interferon in mice, monkeys, and chimpanzees. In these species, only mild deleterious effects have been noted due to the administration of poly ICLC (9S) (4,10,12,14).In a phase 1 clinical trial in humans with serious viral illnesses, poly ICLC (9S) injected intravenously (i.v.) induced high titers of serum interferon which were ordinarily somewhat higher than those produced by exogenous human leukocyte interferon. Unfortunately, fever and significant falls in blood pressure also occurred in some patients (3). To attempt to reproduce and, hopefully, ameliorate the hypotensive effects in an animal model, poly ICLC (9S) was given to rabbits, a species known to be very sensitive to poly IC. Here, we report results of initial studies with poly ICLC (9S) in rabbits, along with our initial attempts to alter favorably the toxicity which we fmd. MATERIALS AND METHODSGeneral plan of studies. Young male New Zealand white rabbits (2.5 to 3.5 kg) were obtained from Oakhill Co. (Otsego, Mich.). They were housed in individual cages (25°C) and fed standard rabbit chow (Novi Supply, Novi, Mich.) with wa...

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“…injections produced high interferon titers (10,14). It is also noteworthy that in pimates peak interferon titers appeared about 8 (9).…”

Section: Discussionmentioning

confidence: 87%

“…When hydrocortisone preceeded poly ICLC (9S) (group III), blood pressures and temperatures remained normal, but mean interferon titers on days 1 (410 U/ml) and 2 (200 U/ml) were significantly muted (Fig. 2) 8 244 4 8 24 48 244 8 24 4 8 24 ) 4 8 24 4 8 24 4 8 24 4 8 24 4 8 (9) was given by im. (0-0) or 8.C.…”

Section: Methodsmentioning

confidence: 99%

Modified polyriboinosinic-polyribocytidylic acid complex: induction of serum interferon, fever, and hypotension in rabbits

Gatmaitan¹,

Legaspi²,

Levy³

et al. 1980

Antimicrob Agents Chemother

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“…Neither the molecular weight of poly-L-lysine (27,000, 13,000, or 3,400) nor that of carboxymethylcellulose (700,000, 250,000, or 85,000) in the modified complexes substantially affected the toxic responses that were observed (11,16). Poly-L-lysine and carboxymethylcellulose appeared to stabilize the internucleotide linkages of the poly(I)-poly(C) polymer to phosphodiesterases of monkey (and human) serum which, of course, are not present in rabbits.…”

Section: Discussionmentioning

confidence: 98%

“…When poly(I)-poly(C) (4S) was administered, no animal experienced falls in blood pressure, and none died (11,16). Neither the molecular weight of poly-L-lysine (27,000, 13,000, or 3,400) nor that of carboxymethylcellulose (700,000, 250,000, or 85,000) in the modified complexes substantially affected the toxic responses that were observed (11,16).…”

Section: Discussionmentioning

confidence: 99%

Modified polyriboinosinic-polyribocytidylic acid complex: modulation of toxicity for rabbits by alterations in components

Gatmaitan¹,

Levy²,

Lerner³

1980

Antimicrob Agents Chemother

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In an earlier study the physiological effects encountered in humans of a modified complex of polyriboinosinic acid-polyribocytidylic acid [poly(I)-poly(C)] with carboxymethylcellulose and poly-L-lysine [poly(ICLC) (9S)], namely, the induction of high titers of serum interferon along with fever and hypotension, were reproduced in rabbits. In the present studies, also in rabbits, we evaluated effects of complexes with homopolymer polyribonucleotide sedimentation coefficients decreasing from 9S to 6S and 4S. Modified complexes of carboxymethylcellulose and poly-L-lysine with decreasing molecular weights were also tested. In several studies diphenhydramine and indomethacin were administered concomitantly. These experiments showed that at a daily intravenous dose of 0.2 mg/kg the various preparations of poly(I)-poly(C) (9S) and poly(I)-poly(C) (6S) induced falls in blood pressure, but stabilized complexes of poly(I)-poly(C) (4S) did not. Alterations in the molecular weights of carboxymethylcellulose and poly-L-lysine in the modified complex and the concomitant administration of diphenhydramine did not influence the occurrence or severity of untoward reactions. In rabbits, poly(ICLC) (4S) along with indomethacin induced high titers of serum interferon without fever or hypotension.In a phase I clinical trial in humans with serious viral illnesses, polyriboinosinic acid-polyribocytidylic acid [poly(I)-poly(C)] complexed with poly-L-lysine and carboxymethylcellulose [poly(ICLC) (9S)] was administered intravenously. Titers of serum interferon somewhat higher than those produced by exogenous human leukocyte interferon were induced, but fever and significant falls in blood pressure also occurred (4). Both the salutary and toxic effects of intravenous infusions of poly(ICLC) (9S) were reproduced in rabbits in an earlier study (7). As reported there, concomitant administration of hydrocortisone succinate ameliorated the hypotensive response, but also reduced interferon titers markedly. A lower-molecular-weight preparation of poly(ICLC) (4S) induced high titers of serum interferon (approximately 2,000 U/ml) and fever, but no hypotension (7).The

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“…Mice receiving fragmented RNA produced by any of the above techniques were frequently ~4 vi R ~3 I94 Short communications ill in appearance (ruffled fur, hunched posture) and several mice out of each group (between 3 and 7 out of each group of I5) died in the 8 h period before sacrifice. No increased toxicity of fragmented poly(I), poly(C) has been reported; on the contrary, some authors claim to have found a slight decrease in toxicity with decreasing size of the polymer (Levy et aL I97O, Hilleman et al 1971 ;Niblack & McCreary, 1971 ;Lampson et al 1972;Morahan et al 1972). The increased toxicity of fragmented Penicillium chrysogenum RNA did-not appear related to the interferon-inducing capacity of the fragments, and its cause is unknown.…”

mentioning

confidence: 99%

Effect of Fragmentation on Interferon Induction by Double-stranded Virus RNA

Edy

Székely

Himmelweit

et al. 1974

Journal of General Virology

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The Effect of Altering the Size of Poly C on the Toxicity and Antigenicity of Poly I:C

Cited by 8 publications

References 2 publications

Modified polyriboinosinic-polyribocytidylic acid complex: induction of serum interferon, fever, and hypotension in rabbits

Modified polyriboinosinic-polyribocytidylic acid complex: induction of serum interferon, fever, and hypotension in rabbits

Modified polyriboinosinic-polyribocytidylic acid complex: modulation of toxicity for rabbits by alterations in components

Effect of Fragmentation on Interferon Induction by Double-stranded Virus RNA

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