Biomedical subjects
H B Levy
Publications and source records attributed to H B Levy.
Poly ICLC in the treatment of postinfectious demyelinating encephalomyelitis.
Three weeks after a mild and presumably infectious illness, a 21-year-old man developed a CNS disorder characterized by involvement of the cerebellum, cerebrum, and brainstem. It progressed, sometimes stepwise, without remission, over five months to being bedfast with total spastic paraplegia, severe ataxia, and unintelligible dysarthric speech. The CSF showed increased levels of protein, IgG, and myelin basic protein, as well as five oligoclonal bands. Because of failure of the patient's condition to respond to prolonged prednisone therapy, poly ICLC was given intravenously weekly for 20 weeks (median dose, 100 microgram/kg). Improvement, evident after the first dose, progressed to the point of ambulation with some assistance. Even though the relation of the patient's marked recovery to poly ICLC therapy remains unproved, this experience provides reason for considering a possible therapeutic role of the drug in postinfectious demyelinating encephalomyelitis and perhaps in multiple sclerosis.
Protectivity of herpes simplex virus antigens: studies in mice on the adjuvant effect of PICLC and on the dependence of protection on T cell competence.
The efficacy of a herpes simplex virus type 1 (HSV-1) envelope antigen (EAG) preparation against HSV infection was studied in T cell competent and T cell deficient mice. Immuno-competent mice were successfully protected against herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) infection when immunized 2 weeks prior to this infection with a heat-inactivated whole virus preparation or a HSV-1 envelope antigen (HSV-1 EAG) preparation. Since HSV-1 EAG was considerably less effective than the whole virus preparation, a poly.riboinosinic-poly.ribocytidylic acid complex with poly-L-lysine and carboxymethylcellulose (PICLC) was used as adjuvant. Immunization with HSV-1 EAG plus PICLC resulted in a pronounced increase of this protection rate as compared with that obtained after immunization solely with HSV-1 EAG. PICLC alone, however, offered no protection when given 2 weeks before challenge. In T cell deficient nu/nu mice no protection was achieved with HSV-1 EAG while their T cell competent, heterozygous littermates were protected. From these results it may be concluded that T cell competence is a prerequisite for establishing a protective immunity against HSV infection after immunization with HSV-1 EAG.
Immune response modifying activity in mice of polyinosinic: polycytidylic acid stabilized with poly-L-lysine, in carboxymethylcellulose [poly-ICLC].
Poly-ICLC, a polyinosinic: polycytidylic acid stabilized with poly-L-lysine in carboxymethyl-cellulose was tested in mice for its immunoregulatory activity. Poly-ICLC was found to enhance T cell responsiveness but not B cells. It augmented the delayed type hypersensitivity response significantly. The results indicate Poly-ICLC to be a T cell stimulator. Macrophage tumoricidal activity was markedly enhanced both in vitro and in vivo after exposure to Poly-ICLC. Natural killer cell cytotoxicity was significantly augmented in vivo. Both macrophage and natural killer cell activity was maintained for over 3 days after only one treatment. The extended period of tumor cell cytotoxicity, exhibited by macrophages and natural killer cells, may correlate to Poly-ICLC induction of early and high levels of interferon which are maintained in the serum for a longer period of time.
Treatment of recurrent laryngeal papillomatosis with an artificial interferon inducer (poly ICLC).
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Epstein-Barr virus and Herpesvirus saimiri: sensitivity to interferons and interferon inducers.
The in vitro sensitivity of oncogenic herpesviruses, Epstein-Barr virus (EBV), and Herpesvirus saimiri (HVS) to human interferon produced by normal human leukocytes (Le), lymphoblastoid cell lines (LYI), and diploid fibroblasts (Fi) was studied. Four virus strains were used: HVS S295C, the highly oncogenic HVS S396-O, the transforming B95-8 strain of EBV, and the nontransforming P3HR1 strain of EBV. All interferons were active when applied to the cells after absorption of HVS and P3HR1-EBV, although different amounts were required to achieve 50% inhibition of HVS-induced cytopathic effect or EBV-induced early antigen (EA) expression. Transformation of human umbilical cord blood lymphocytes (HCBL) by the B95-8 strain of EBV was prevented only by Le and LYI. In these experiments, the most effective inhibitor of the oncogenic herpesviruses was Le, and the least effective was Fi. The effect of polynucleotides poly(I).poly(C) and the complex of poly(I).poly(C) with poly-L-lysine and carboxymethylcellulose on HVS and EBV was also studied. Their inhibitory action was proportionate to the ability of herpesvirus-infected cells to produce interferon. Thus owl monkey kidney cells, which produce relatively high levels of interferon, required nanogram quantities of polynucleotides to become resistant to HVS. Transformation of HCBL by B95-8-EBV was also prevented by poly(I).poly(C). In Raji cells superinfected with P3HR1-EBV, polynucleotides failed to stimulate interferon, and higher EBV-induced EA expression was observed. The percentage of P3HR1 and Raji cells spontaneously expressing EBV-associated antigens remained unchanged after exposure to either interferon or polynucleotides.
Interferon induction in primates by stabilized polyriboinosinic acid-polyribocytidylic acid: effect of component size.
Two series of interferon-inducing complexes containing polyriboinosinic and polyribocytidylic acids, poly-L-lysine, and carboxymethyl cellulose were prepared. One series contained carboxymethyl cellulose, 27,000-molecular-weight poly-L-lysine, and either 4S, 6S, or 9S polyriboinosinic and polyribocytidylic acids. The other series contained carboxymethyl cellulose, 9S polyriboinosinic and polyribocytidylic acids, and poly-L-lysine, whose molecular weights ranged from 2,000 to 27,000. The homogeneity of these double-stranded polynucleotide complexes was confirmed by single-step thermal denaturation profiles and by single peaks in sucrose gradient velocity sedimentation. The complexes have a greater resistance to hydrolysis by ribonuclease than does polyriboinosinic-polyribocytidylic acid. The resistance to ribonuclease increased with the increasing size of polynucleotide homopolymers and poly-L-lysine. In monkeys and, to a lesser extent, in mice, serum interferon levels induced by the different complexes were related to the degree of resistance of the complexes to hydrolysis by ribonuclease. In mice, 4S, 6S, and 9S complexes of polyriboinosinic-polyribocytidylic acid, poly-L-lysine, and carboxymethyl cellulose had a higher level of toxicity than did polyriboinosinic-polyribocytidylic acid as measured by 50% lethal dose. The toxicity was parallel to the ribonuclease resistance of the complexes. It was concluded that an increase in the size of the polynucleotides and the polyamino acids in these complexes leads to higher resistance to hydrolysis by ribonuclease and to greater interferon responses in mice and rhesus monkeys.
Induction of interferon in vivo and in vitro by polynucleotides and derivatives, and preparation of derivatives.
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Meningococcal septic arthritis in an infant.
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Cardiac catheterization in children.
Although cardiac catheterization in children is not without significant risk, it is mandatory before corrective cardiac surgery is undertaken. Not only can the procedure delineate the cardiac anatomy but it also yields information about the direction and amount of shunts, pulmonary vascular resistance and myocardial function. It is used to follow the severity of lesions such as aortic or pulmonic stenosis. Complications include cardiac perforation, renal impairment, neurologic problems and many others.
Immune modulating effects of poly ICLC.
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Modified polyriboinosinic-polyribocytidylic acid complex: induction of serum interferon, fever, and hypotension in rabbits.
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.
Modified polyriboinosinic-polyribocytidylic acid complex: modulation of toxicity for rabbits by alterations in components.
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 n 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.
Paroxysmal supraventricular tachycardia in the infant.
Paroxysmal supraventricular tachycardia has been noted more frequently in fetuses and newborns since the introduction of monitoring devices. These tachyarrhythmias appear to be well tolerated in the fetus, but in newborns and older infants they may lead to congestive heart failure if allowed to persist for prolonged periods. Wolff-Parkinson-White syndrome is commonly associated with paroxysmal supraventricular tachycardia. The drug of choice in infants is digoxin.
Haemophilus influenzae type b pericarditis.
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Protective and toxic effects of a nuclease-resistant derivative of polyriboinosinic-polyribocytidylic acid on Venezuelan equine encephalomyelitis virus in rhesus monkeys.
Polyriboinosinic-polyribocytidylic acid, stabilized with poly-L-lysine and carboxymethylcellulose (poly ICLC), favorably alters the pathogenesis of Venezuelan equine encephalomyelitis virus infection in rhesus monkeys by decreasing the number of infected monkey that become detectably viremic and by delaying the onset of viremia in the remaining monkeys. Poly ICLC is known to induce high circulating levels of interferon in primates, and the interferon system is assumed to be the mechanism by which poly ICLC exerts its antiviral effect. Poly ICLC treatment was associated with a few deaths, but only under certain conditions of infection and handling. The death of some infected, treated monkeys in the absence of death in monkeys that were either infected and untreated or treated and uninfected suggests a synergistic toxicity resulting from the combination of infection, handling, and poly ICLC treatment, although other explanations are possible.