Biomedical subjects

R P Warren

Publications and source records attributed to R P Warren.

At least 19 recordsLinked to original sources

PubMed1992

Suppression of murine retroviral disease by 2',3'-didehydro-2',3'-dideoxythymidine (D4T).

The thymidine analog, 2',3'-didehydro-2',3'-dideoxythymidine (D4T), and 3'-azido-3'-deoxythymidine (AZT) were evaluated for activity against Friend virus complex (FV) in Mus dunni cells using a focal immunoenzyme assay. The 50% effective doses were, respectively, 1.2 and 0.1 microM for the two compounds; the 50% cytotoxic doses using trypan blue dye exclusion were 25.4 and > 100 microM. Four FV inhibition experiments with D4T were run in F1 hybrid mice containing the Rfv-3r/s genotype. This mouse strain allows the study of treatment effects on development of specific neutralizing antibodies and on splenomegaly, splenic and plasma virus titers, and splenic viral RNA. In the first experiment, D4T was given by oral gavage (p.o.) three times daily (t.i.d.) for 14 days beginning 4 h post-virus inoculation. All dosages used (187.5, 375, 750 mg/kg/day) significantly inhibited all viral parameters. Other experiments used D4T p.o. twice daily, with dosages of 46.9, 93.8, 187.5 and 375 mg/kg/day or four times daily with a dose of 375 mg/kg/day. No significant disease inhibition was seen using the twice daily treatment schedule, but efficacy was apparent using the four times daily treatment. The final experiment repeated the initial study, extending the t.i.d. treatments to 25 days and using dosages of 46.9, 93.8, 187.5 and 375 mg/kg/day. All but the lowest dose reduced each virus parameter. None of the D4T treatment regimens caused death in toxicity controls, although moderate host weight loss or less weight gain was seen, and variable hematocrit decreases occurred, particularly in mice receiving the highest drug dosage. Inhibition of natural killer (NK) cell activity also was seen in these same animals, but in infected mice, FV-induced decrease in NK cell activity was prevented by D4T treatment. Virus-specific neutralizing antibodies developed in all infected, treated animals. These data indicate D4T has potential as a possible candidate for anti-human immunodeficiency virus evaluations in the clinic.

Animals↗

PubMed1992

Potential role of immunomodulators for treatment of phlebovirus infections of animals.

Rift Valley fever (RVFV) is a major phlebovirus-induced epizootic disease of domestic animals (primarily cattle and sheep) in Africa. No therapies for the disease are known. A related phlebovirus, Punta Toro virus (PTV), has been adapted to induce an RVFV-like disease in C57BL/6 mice. This PTV infection has been used as a model for RVFV because it is reasonably safe and does not require high-level biologic containment. The infection model has been used to study the potential role of immunomodulating substances as therapies. A spectrum of immunomodulators has been studied; those immunomodulators most capable of preventing death and other disease manifestations are ampligen, bropirimine, poly (ICLC), AM-3, P-136, and 7-thia-8-oxoguanosine. An immunologic parameter common to all these substances has been their ability to induce interferon. Timing studies have indicated that these active substances may be administered therapeutically as well as prophylactically to inhibit markedly the progress of the disease. Further work is needed in the development of these materials for use in treating viral infections in domestic animals. As a next step, studies need to be run to compare the immunologic profiles induced by each substance in domestic animals and in mice.

Adjuvants, Immunologic↗

PubMed1992

Possible association of the extended MHC haplotype B44-SC30-DR4 with autism.

We previously reported that the complement C4B null allele appears to be associated with infantile autism. Since the C4B null allele is known to be part of the extended or ancestral haplotype [B44-SC30-DR4], we investigated the incidence of [B44-SC30-DR4] in 21 autistic children and their parents. This extended haplotype was increased by almost six-fold in the autistic subjects as compared with healthy controls. Moreover, the total number of extended haplotypes expressed on chromosomes of autistic subjects was significantly increased as compared with those expressed on chromosomes of healthy subjects. We conclude that a gene related to, or included in, the extended major histocompatibility complex may be associated with autism.

Adolescent↗

PubMed1992

Elucidation of mode of retroviral-inhibitory effects of imexon through use of immune competent and severe combined immune deficiency (SCID) mice.

Mice infected with various tumor retroviruses have been used as models for evaluating therapeutic substances for the treatment of some cancers, and more recently, for human immunodeficiency virus (HIV) infection, the causative agent of acquired immune deficiency syndrome (AIDS). Consequently, there is a need to determine the ability of biological response modifiers (BRMs) to specifically reduce virus-infected cells, as compared to their non-specific anti-proliferative effects. To address this need, a BRM, imexon, was evaluated in this study using three strains of mice having different Friend virus (FV)-specific immunological capabilities. The first strain, (B10.A x A/WySn)F1, was genetically capable of producing FV-specific neutralization and cytotoxic antibodies, the second, Balb/c, was not, and the third, SCID mice, lacked functional T and B cell immunity. Imexon treatment reduced virally-induced splenomegaly in all 3 strains; however, the concentration of splenic viral infectious centers (IC) were not affected. Since imexon was efficacious in reducing splenomegaly in SCID mice, the mode of action was concluded to not require functional T or B cell immunity. The observation that imexon did not affect splenic IC titers also suggested that imexon did not specifically eliminate virally infected cells, but may have functioned by other mechanisms. This study also demonstrated the use of various mouse strains as a strategy for delineating the modes of action of BRMs against murine retroviral infections.

Animals↗

PubMed1992

Murine retroviral disease-enhancing effects of a pyrimidinone immunomodulator.

(B10.A x A/WySn)F1 mice, infected with the Friend virus (FV) complex, were used as a predictive therapeutic model for AIDS. These infected mice exhibit many of the viral and immunologic manifestations of AIDS. Bropirimine (2-amino-5-bromo-6-phenyl-4[3H]pyrimidinone, ABPP) is an immunomodulating compound which has been shown to inhibit other viral infections. Oral (per os treatment) dosages of ABPP ranging from 50 to 400 mg/kg/day for 3 days resulted in increased numbers of infectious centers in the infected mice and increased splenomegaly and percentage of Ig+ (B cells) in spleens of infected and uninfected mice. Decreased percentages of total Thy-1.2+ (total T) cells and L3T4+ (T-helper) cells were seen in both uninfected and infected mice and a slightly decreased percentage of Ly-2+ (T-suppressor/cytotoxic) cells was observed in spleens of the infected mice. No effect on Ly2+ cells in spleens of uninfected mice was found. Intraperitoneal injection, single or multiple, of 20-200 mg/kg ABPP prior to FV injection resulted in increased spleen weights but had no effect on numbers of infectious centers in the spleens or on FV antibody titers in the plasma. Intraperitoneal treatment of uninfected mice with ABPP resulted in slight or no changes in percentages of Thy-1.2+, L3T4+ and Ly-2+ cells. Mice receiving multiple exposures of ABPP had an increase in percentage of splenic B cells and a depressed response to the T cell mitogen PHA. Treatment with ABPP induced the production of interferon (IFN); however, a state of hyporesponsive IFN production was seen following multiple administrations of ABPP. These data suggest that the immunomodulator ABPP may have an enhancing effect on this retroviral disease.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Utilization of pulse oximetry for the study of the inhibitory effects of antiviral agents on influenza virus in mice.

Pulmonary disease in mice induced by influenza virus was monitored by measurement of oxygen saturation (SaO2) in blood with a pulse oximeter. The SaO2 declined in inverse proportion to the viral inoculum. The known antiviral agent ribavirin inhibited the SaO2 decline, prevented death, lowered lung consolidation, and reduced the level of recoverable virus. Pulse oximetry is an effective means of monitoring murine influenzal disease and can be used in the study of potential antiviral drugs.

Animals↗

PubMed1992

Effect of triacontanol on numbers and functions of cells involved in inflammatory responses.

A preparation of a triacontanol-containing compound was studied for its effect on cells involved in the inflammatory response. C57BL/6 mice were injected intraperitoneally with various concentrations of this compound and investigated for total body weight, wet weight of thymus tissue, number of thymus cells and splenocytes, interleukin 1 production of spleen monocytes, and response of splenocytes to the T cell mitogen, phytohemagglutinin. Mice treated with the triacontanol preparation exhibited decreased total body weight, 24% reduction in thymus weights, 39% decrease in the number of thymus cells, and 21% depression in total splenocytes. Splenic monocytes of these animals produced a significantly reduced amount of interleukin 1 and splenocytes had a significantly depressed response to phytohemagglutinin. It is concluded that triacontanol has an inhibitory effect on at least some of the cells responsible for inflammation.

Animals↗

PubMed1991

Effect of human, recombinant interleukin 2 on Punta Toro virus infections in C57BL/6 mice.

The effect of human recombinant interleukin-2 (rIL-2) on Punta Toro virus (PTV) infection was investigated in C57BL/6 mice. Immunologic and viral parameters were assessed after mice were treated i.p. with rIL-2 for 5 days. Treatment of mice with 25000 and 12500 units/mouse of rIL-2 resulted in significant inhibition of the disease as indicated by increases in survival of mice as well as decreases in liver and serum virus titers. Serum glutamic oxalic acid and pyruvic acid transaminase levels were also lowered indicating reduced liver damage. Murine IL-2 production returned to normal or above-normal levels in rIL-2 treated mice. Natural killer cell activity was also moderately stimulated by rIL-2 treatment. Significant amounts of interferon were not detected in the sera of treated mice. Weight gain and survival rates were similar for both toxicity and normal controls indicating that rIL-2 treatments had no toxic effect.

Animals↗

PubMed1991

Effect of imexon treatment on Friend virus complex infection using genetically defined mice as a model for HIV-1 infection.

Imexon (4-imino-1,4-diazobicyclo-3.1.0-hexan-2-one) was moderately effective in the treatment of a retroviral infection in a genetically defined murine model. The animal model consisted of a Friend virus complex (FV) infection in a hybrid mouse strain, (B10.A x A/WySn)F1, which has similarities with acquired immune deficiency syndrome (AIDS). Intraperitoneal imexon initiated 1 or 3 days after FV inoculation and continued through 13 days after inoculation significantly reduced splenomegaly, splenic cell-free virus titers and viral RNA. Viral infectious centers/10(6) splenocytes and FV titers in the plasma were reduced, though not to a statistically significant level. The effect of imexon on survival was not statistically significant which suggested that the antiviral effects were only transiently effective. Phytohemagglutinin-induced blastogenesis and percent of total T cells, T helper cells and T suppressor/cytotoxic cells in the spleens were increased, and the percentage of B cells decreased by imexon treatment of both FV-infected and uninfected mice. The splenic natural killer cell activity and interleukin-1 production were not markedly affected. Virus specific neutralizing antibody developed in both imexon- and placebo-treated FV-infected mice, although titers were lower in the imexon-treated animals.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Changes of soluble interleukin-2, interleukin-2 receptor, T8 antigen, and interleukin-1 in the serum of autistic children.

Immune abnormalities in autistic children led us to study for indirect evidence of immune activation as measured by the serum analysis of soluble interleukin-2 (sIL-2), interleukin-2 receptor (sIL-2R), T8 antigen (sT8), and interleukin-1 (sIL-1). The serum concentration of these soluble antigens was quantitated by enzyme-linked immunosorbent assays. The concentration of sIL-2 and sT8, but not of sIL-2R and sIL-1, antigens was significantly (P less than 0.05) increased in the sera of autistic children over that in the control healthy children or children with mental retardation (non-Down's syndrome). This finding indirectly indicates that the activation of a subpopulation of T cells occurs in some children with autism.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1991

Increased frequency of the null allele at the complement C4b locus in autism.

Associations between C4 deficiency and autoimmune disorders have been found over the past several years. Since autism has several autoimmune features, the frequencies of null (no protein produced) alleles at the C4A and C4B loci were studied in 19 subjects with autism and their family members. The autistic subjects and their mothers had significantly increased phenotypic frequencies of the C4B null allele (58% in both the autistic subjects and mothers, compared with 27% in control subjects). The siblings of the autistic subjects also had an increased frequency of the C4B null allele, but this increase was not significant. The fathers had normal frequencies of this null allele. All family members had normal frequencies of the C4A null allele, all normal C4A and C4B alleles and all BF and C2 alleles.

Alleles↗

PubMed1990

Binding of [3H]serotonin to lymphocytes in patients with neuropsychiatric disorders.

Based on recent studies of neuroimmune networks, the lymphocyte binding of serotonin neurotransmitter was studied in patients with Alzheimer's disease, idiopathic mental retardation, and autism. The specific binding to lymphocytes of [3H]serotonin, at a single concentration of 100 nM, was significantly reduced in Alzheimer's disease patients as compared to aged controls (group mean of 3.667 +/- 2.301 v 7.506 +/- 1.717 picomoles; p = 0.001), and in children with idiopathic mental retardation as compared to healthy children (group mean of 3.694 +/- 1.627 v 5.792 +/- 1.902 picomoles; p = 0.003). However, autistic children did not differ significantly from the healthy children (group mean of 5.287 +/- 1.987 v 5.792 +/- 1.902 picomoles; p = 0.475). Reduced lymphocyte binding of serotonin may be an indication of breakdown of an unknown neuroimmune pathway relevant to the pathophysiology of Alzheimer's disease and idiopathic mental retardation.

Aged↗

PubMed1990

CD4+ helper T cell depression in autism.

CD4+ (helper) T cells are a heterogenous population of lymphocytes including at least two distinct subpopulations. To investigate the possibility that immune abnormalities in some subjects with autism may involve abnormal distributions of CD4+ and/or CD8+ cells, (suppressor) T cells, peripheral blood lymphocytes of 25 autistic subjects were characterized with monoclonal antibodies and flow cytometry. The autistic subjects had a significantly lower percentage and number of CD4+ cells, a lower number of T cells (CD2+ cells) and B cells (CD20+ cells), and a lower percentage and number of total lymphocytes than siblings and normal subjects. The level of blood values for female subjects appeared lower than those for males as compared to normal subjects of the same sex. These results suggest that a decrease in CD4+ cells is associated with autism.

Adolescent↗

PubMed1990

Effect of oxamisole on immune parameters of mice infected with murine hepatitis.

The effects of Oxamisole, 2,3,5,6,7,8-hexahydro-2-phenyl-8,8- dimethoxyimidazo[1,2a]pyridine on immune parameters of mice infected with murine hepatitis were investigated. Young Swiss Webster mice were injected intraperitoneally (i.p.) with the Friend-Braunsteiner strain of murine hepatitis virus and with various doses of Oxamisole at 48 h pre- 24 h pre-, and 4 h post-virus exposure. Antiviral activity was seen in the drug-treated mice which was approximated on the basis of 21-day survival frequency and hepatic discoloration, SGOT and SGPT levels and amount of infectious virus recoverable from the liver. On day 4 post-viral exposure, splenic cells from some of the drug- and placebo-treated cells of infected mice injected with Oxamisole, 25 mg/kg/day, produced significantly more interleukin-1 and interleukin-2 than cells of infected mice treated with saline only. Similarly, mice treated with 25 mg/kg/day of this compound had cells with significantly increased antibody-dependent cell-mediated cytotoxicity as compared with placebo treated animals. However, cells from mice treated with Oxamisole did not demonstrate altered natural killer cell activity. It is concluded that Oxamisole, when administered to mice infected with murine hepatitis virus, has antiviral properties which possibly are mediated through the immunomodulatory effects of this compound on the immune system.

Adjuvants, Immunologic↗

PubMed1990

Detection of maternal antibodies in infantile autism.

Maternal antibodies reactive with antigenic proteins expressed on the cell surface of paternal lymphocytes can be detected in couples with histories of more than one miscarriage or stillbirth. It is possible, but not proven, that these antibodies also react with tissues of the fetus and result in fetal death. Since many mothers of autistic children have a history of pregnancy disorder, antibodies were studied in 11 mothers of autistic children who were 6 years of age or younger. Six of the mothers had antibodies that reacted with lymphocytes of the autistic child. Five of these six mothers had a history of pregnancy disorder. Since antigens expressed on lymphocytes are found on cells of the central nervous system and, perhaps, other tissues of the developing embryo, it is suggested that aberrant maternal immunity may be associated with the development of some cases of infantile autism.

Adolescent↗

PubMed1990

Deficiency of suppressor-inducer (CD4+CD45RA+) T cells in autism.

CD4+ cells are a heterogenous population of lymphocytes including at least two distinct subpopulations: CD45RA+ cells, inducers of suppressor T cells and CDw29+ cells, inducers of helper function for antibody production. To investigate the possibility that immune abnormalities in autism may involve abnormal distribution of these helper subpopulations, monoclonal antibodies were used in flow cytometric analysis to characterize peripheral blood lymphocytes of 36 subjects with autism. The autistic subjects as compared to a group of 35 healthy age-matched subjects had a significantly reduced number of lymphocytes, a decreased number of CD2+ T cells and reduced numbers of CD4+ and CD4+CD45RA+ lymphocytes. The numbers of B (CD20+) cells, suppressor T (CD8+) cells, inducers of helper function (CD4+CDw29+) and natural killer (CD56+) cells were not altered in the autistic subjects. Our results suggest that an alteration in the suppressor-inducer T-cell subset is associated with autism.

Adolescent↗

PubMed1990

Effects of zidovudine on Friend virus complex infection in Rfv-3r/s genotype-containing mice used as a model for HIV infection.

Infection with the Friend virus complex (FV) in (B10.A x A/WySn)F1 mice containing the Rfv-3r/s genotype results in several disease manifestations analogous to those seen in patients with acquired immune deficiency syndrome, predominantly high levels of specific antibody and low levels of infectious virus with eventual retroviral disease-induced death of the host. Other immunologic manifestations of FV infection in this murine host included inhibition of percent total T, T-helper, and T-suppressor/cytotoxic cells of total splenic lymphocytes and phytohemagglutinin-induced response of spleen cells. Interleukin-1 production was not affected but the numbers of splenic B cells were increased by the infection. 3'-Azido-3'-deoxythymidine (zidovudine, AZT) administered (a) intraperitoneally three times daily for 24 days beginning 4 h after virus inoculation in doses of 60 to 480 mg/kg/day, (b) in drinking water for 22 days beginning 4 h after virus inoculation in doses of 22 to 216 mg/kg/day, or (c) in drinking water for 29 days beginning 6 days after virus inoculation in doses of 22 to 216 mg/kg/day markedly inhibited FV-induced disease. In the mice receiving early-initiated AZT therapy, FV-induced splenomegaly and hematocrit values were inhibited and infectious centers in the spleen and FV titers in the plasma were reduced to below detectable levels at the higher AZT dosage levels. The percent of total T cells in splenic lymphocytes was increased in the infected, AZT-treated mice. In the intraperitoneal experiment, FV disease-induced death was prevented by treatment with all doses of AZT. Neutralizing antibody to FV was significantly reduced in all AZT-treated groups. Toxicologic manifestations of these AZT treatments included splenic enlargement and reduced hematocrit, although all treated, uninfected mice survived the treatments, gained weight, and displayed no significant effects on enumeration of T and B cells.

Animals↗

PubMed1989

Augmentation of ADCC and cytotoxic T-cell activity with ImuVert.

We previously reported that natural killer cell activity of peripheral blood mononuclear cells (PBMC) from healthy human subjects was augmented following in vitro incubation in ImuVert, a biologic response modifier derived from the bacterium Serratia marcescens. In the current investigation, we found that exposure of PBMC to ImuVert, 3-40 micrograms/ml, for 18 hr, resulted in significant and dose-dependent augmentation of three other types of cell-mediated cytotoxicity: K cell-mediated antibody-dependent cellular cytotoxicity (ADCC), monocyte-mediated ADCC, and cytotoxic T-cell activity against allogeneic PBMC. These and previous findings suggest that ImuVert may have a broad range of stimulatory effects on immune function.

Adult↗