Transforming growth factor-beta in the regulation of the immune response.
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Antibody Formation↗
Biomedical subjects
R B Pollard
Publications and source records attributed to R B Pollard.
Human immunodeficiency virus replication: modulation by cellular levels of cAMP.
HIV infection is associated with qualitative and functional immune deficiencies. It has been shown that the in vitro infection of CD4+ cells with HIV was associated with sustained elevation of cAMP and cGMP. In the present report the role of cAMP on HIV replication in MT-4 cells was investigated. The MT-4 cells were infected with HIV (strain 3b), in the presence or absence of agents that increase intracellular levels of cAMP, through different mechanisms. At selected times postinfection, HIV replication was measured by reverse transcriptase activity or HIV P24Ag in culture supernatants. Forskolin (FK, an activator of adenylate cyclase 1-100 microM), Isobutyl-methylxanthine (IBMX, a phosphodiesterase inhibitor, which indirectly increases intracellular levels of cAMP, 30-100 microM) and dibutyryl (db) cAMP (0.1-10 microM) enhanced HIV replication, in a dose-dependent manner. FK, IBMX, and db cAMP enhanced HIV replication by 2- to 10-fold, 4- to 7-fold, and 2- to 6-fold, respectively. Intracellular levels of cAMP were measured by radioimmunoassay and were also enhanced. Since cAMP exerts its catalytic effects through activation of protein kinase (PK) A the effect of H-8 (a specific inhibitor of the cAMP dependent PK A) on HIV replication was simultaneously examined. The H8 at doses of 0.1 to 10 microns inhibited HIV replication by 25 to 99.9%. Moreover H9 inhibited HIV replication in peripheral blood mononuclear cells by more than 90%. The replication of HIV appears to be a cAMP-dependent event, and PK A could possibly be a target for the development of anti-HIV therapies.
1-Methyl-3-isobutylxanthine↗
Disseminated herpes zoster in the immunocompromised host: a comparative trial of acyclovir and vidarabine. The NIAID Collaborative Antiviral Study Group.
Seventy-three immunocompromised patients with disseminated herpes zoster were evaluated in a double-blind controlled trial of acyclovir (n = 37) versus vidarabine (n = 36) therapy. Acyclovir was administered at 30 mg/kg/day at 8-h intervals and vidarabine was given as a continuous 12-h infusion at 10 mg/kg/day for 7 days (longer if resolution of cutaneous or visceral disease was incomplete). No demographic differences existed between treatment groups. No deaths attributable to varicella-zoster virus infection occurred within 1 month of treatment. Neither rates of cutaneous healing, resolution of acute neuritis, and frequency of postherpetic neuralgia nor adverse clinical and laboratory events differed between treatment groups. Acyclovir recipients were discharged from the hospital more promptly than vidarabine recipients (P = .04, log rank test). These data indicate that disseminated herpes zoster is amenable to therapy with either acyclovir or vidarabine; resultant mortality is low.
Acyclovir↗
Preventive effect of a synthetic immunomodulator, 2-carboxyethylgermanium sesquioxide, on the generation of suppressor macrophages in mice immunized with allogeneic lymphocytes.
The effect of 2-carboxyethylgermanium sesquioxide (Ge-132) on the generation of splenic suppressor macrophages (S-M phi) in C3H/He mice (H-2k) immunized with allogeneic spleen cells from C57Bl/6 mice (H-2b) was investigated. We have previously demonstrated that S-M phi expressing I-J antigen, which appeared during alloimmunization, inhibited cytotoxic T lymphocyte (CTL) generation in the MLR and the elimination of these S-M phi before subjection to the MLR resulted in more effective generation of CTL. The CTL activity, which was determined in vivo by the Winn's test, was markedly enhanced when immunized mice received a 100 mg/kg dose of Ge-132. The compound was found to be the most efficacious when injected simultaneously with the immunization. The activity of allospecific CTL co-cultured with M phi fractions obtained from immunized mice in a 4-h 51Cr-release assay was shown to be 31% lysis of the target cells as compared with 90% lysis of the target cells in effector cells co-cultured with normal M phi fractions. In contrast, effector cells co-cultured with M phi fractions from Ge-132-treated immunized mice lysed 95% of the target cells. Analysis of the level of I-J antigen expression on macrophages (M phi) obtained from mice 7 days after immunization revealed a > 2.5-fold increase, whereas I-A antigen expression remained constant when compared with splenic M phi from naive mice. In contrast, the opposite effect on I-J and I-A antigen expression was observed in splenic M phi from alloimmunized mice treated with Ge-132. These results suggest that Ge-132 could regulate CTL generation in alloimmunized mice by preventing the generation of I-J+ S-M phi.
Adjuvants, Immunologic↗
Recombinant human interferon beta ser protects against zidovudine-induced genetic damage in AIDS patients.
This study was conducted to evaluate the in vivo genotoxicity of zidovudine (ZDV) in patients with Acquired Immune Deficiency Syndrome (AIDS). Patients with this disease who were non-smokers and on ZDV (1200 mg/day) as their only medication for 4 weeks to 7 months were studied. Patients with AIDS who had not received ZDV served as a negative control. Whole blood cultures were initiated by conventional methods with PHA 1:50 dilution. In addition, for each culture there was an untreated control and a recombinant interferon-beta (rIFN-beta)-treated culture. The IFN-treated cultures were exposed to 10, 100, 1000, or 10000 units of rIFN-beta for the entire incubation period. The cells were harvested at 72 h and stained with a fluorescence plus Giemsa method which permits the determination of the number of division cycles a cell has completed. One hundred metaphases from first division cells were scored from each culture for chromosome aberrations that were mainly from the chromatid-type, i.e. chromatid, chromosome, and isochromatid breaks. The frequency of breaks in the ZDV and no ZDV group was 8.29 +/- 2.65 and 0.5 +/- 0.29 per 100 cells respectively (P less than 0.05). Cultures from ZDV patients that were incubated with 100 and 1000 units of rIFN-beta, however, showed a frequency of 1.3 +/- 0.71 and 1.9 +/- 1.08 respectively, which was significantly lower than observed in the cultures not exposed to IFN (P less than 0.05). At the highest dose of rIFN-beta utilized no aberrations were detected.(ABSTRACT TRUNCATED AT 250 WORDS)
Acquired Immunodeficiency Syndrome↗
Metabolic interaction of recombinant interferon-beta and zidovudine in AIDS patients.
Zidovudine (AZT), the only currently approved drug for treatment of human immunodeficiency virus (HIV) in AIDS, is known to be metabolized by mammalian systems to a variety of metabolites including 3'-azido-3'-deoxy-5'-O-glucuronide (GAZT). Interferons (IFNs) are known to alter the microsomal enzyme system responsible for the metabolism of some compounds. The aim of the present study was to investigate the effect of combination therapy of recombinant (r) IFN-beta and AZT on the rates of metabolism of AZT in AIDS patients. AZT was given orally (200 mg every 4 h) for 8 weeks prior to initiation of rIFN-beta therapy (45 X 10(6) U/day, s.c.). Serum samples from 8 patients were obtained prior to and at days 3 and 15 following initiation of rIFN-beta therapy. Serum was analyzed by high-performance liquid chromatography (HPLC) for both AZT and GAZT. The serum data were analyzed by a computer-assisted pharmacokinetics program that calculates rates of AZT metabolism. The half life for AZT was increased approximately two-fold by day 15. The rate of metabolism of AZT was diminished from 1.43 h-1 prior to IFN-beta therapy, to 0.4 h-1 and 0.05 h-1 at days 3 and 15, respectively. The volume of distribution of AZT was 2 l/kg at day 0 and increased to 3.2 and 3.5 l/kg on days 3 and 15, respectively. In conclusion, the results indicate that rIFN-beta inhibits the rate of AZT metabolism in AIDS patients.
Acquired Immunodeficiency Syndrome↗
Comparative disposition and whole-body autoradiographic distribution of [2-14C]azidothymidine and [2-14C]thymidine in mice.
Azidothymidine (AZT) is the only approved drug for treatment of acquired immunodeficiency syndrome caused by human immunodeficiency virus. The drug is known to be metabolized by mammalian systems. The objectives of this study were: 1) to investigate the biologic fate of AZT using whole-body autoradiography; and 2) to compare the biologic fate of AZT with that of the parent molecule thymidine (dThd). Male Sprague-Dawley mice were given (intravenously) a tracer dose of [2-14C]AZT (273 microCi/kg) or [2-14C]dThd (218 microCi/kg). Treated animals were sacrificed at various time periods (2 min, 5 min, 4 hr and 24 hr) and processed for whole-body autoradiography. Tissue distribution of radioactivity in the autoradiographs was quantitated using computer-aided image analysis. The elimination of AZT and dThd was also examined by radiochemical analyses of urine, feces and expired air of treated animals over a 24-hr period. Twenty-four hr following AZT treatment, the radioactivity excreted in urine, feces and in exhaled air (as 14CO2) accounted for 86, 4.6 and 3.7% of the dose, respectively. Within 2 min after administration of AZT, maximum radioactivity was detected in the kidney. The brain, spinal cord and testes were conspicuous because of virtual lack of radioactivity. All other parenchymatous organs (liver, lung, heart and spleen) had apparent similar levels of radioactivity that were higher than those in the connective tissues. At a later time period (4 hr), the radioactivity in most organs was eliminated except in the renal medulla, contents of gastrointestinal tract, urinary bladder and mouth cavity.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Role of natural killer cells and macrophages in the nonspecific resistance to tumors in mice stimulated with SMANCS, a polymer-conjugated derivative of neocarzinostatin.
Copoly(styrene-maleic acid)-conjugated neocarzinostatin (SMANCS), a lipophilic derivative of the proteinaceous antitumor antibiotic neocarzinostatin, has been reported to stimulate a nonspecific resistance to tumors (NSRT) in solid tumor-bearing mice, in addition to its chemotherapeutic antitumor effect through the arrest of DNA synthesis by direct DNA strand scission. In the present study, splenic or peritoneal effector cells were used to investigate the ability of SMANCS to augment natural killer (NK) cell activity and to generate cytostatic macrophages (A-M phi). Splenic NK cell activity augmented by SMANCS was characterized by cytotoxicity to various target cells, nylon wool nonadherence, and sensitivity to treatment with anti-asialo-GM1 antiserum or monoclonal anti-Thy-1.2 antibody followed by complement. The A-M phi generated by SMANCS stimulation were characterized by their adherence to a plastic surface coated with fetal calf serum and their ability to phagocytize carbonyl-iron. The maximum level of NK cell activity in the spleens of mice was detected 3 days after i.v. injection of SMANCS, and the highest activity of the peritoneal A-M phi was demonstrated in mice 4 days after SMANCS treatment. On the other hand, the NSRT of mice stimulated with SMANCS was not detectable in mice treated with carrageenan or trypan blue, whereas SMANCS-stimulated NSRT was observed in mice treated with anti-asialo-GM1 antiserum. The NSRT that was stimulated with SMANCS was also demonstrated in mice homozygous for the beige mutation and their non-beige littermates, when NK cell-resistant EL-4 thymoma was used as a tumor target. These results suggest that the expression of NSRT of mice stimulated with SMANCS may require the function of A-M phi, although NK cell activity was also augmented in spleens of mice by administration of SMANCS.
Animals↗
Induction of interleukin 3 and tumor resistance by SSM, a cancer immunotherapeutic agent extracted from Mycobacterium tuberculosis.
Interleukin 3 (IL-3) activity was demonstrated when inguinal lymph node cells obtained from Bacillus Calmette-Guérin-sensitized mice (BCG-ILNC) were stimulated in vitro with SSM, an immunomodulator extracted from Mycobacterium tuberculosis. The IL-3 activity was first detected on Day 1 in culture fluids of BCG-ILNC stimulated with SSM, reached a peak on Day 3, and then gradually decreased. The activity was completely neutralized by treatment with anti-murine IL-3 monoclonal antibody (mAb). When BCG-ILNC were treated with anti-Thy 1.2 or anti-Lyt 1.2 mAb followed by complement, IL-3 was not produced in the culture fluids. However, IL-3 in the culture fluids was detected when BCG-ILNC were treated with anti-Lyt 2.2 mAb, anti-asialo-GM1, or anti-mouse immunoglobulin antiserum followed by complement. These results suggested that Lyt 1+ T-cells appeared to be required for the production of IL-3 from BCG-ILNC stimulated with SSM. In addition, low but significant IL-3 activity was also observed in sera of mice treated with SSM. However, serum IL-3 activity was not detected in mice treated with both SSM and Thy 1.2 or Lyt 1.2 mAb, whereas the activity was induced by SSM in mice treated with anti-Lyt 2.2 mAb or anti-asialo-GM1 antiserum. On the other hand, the in vivo growth of IMC tumors inoculated in BALB/c x DBA/2 F1 mice was significantly decreased by intralesional injection of culture fluids containing IL-3, as well as by SSM itself. This antitumor activity of the culture fluids was not altered when it was treated with mAbs for interleukin 1, interleukin 2, or anti-mouse gamma-interferon antiserum. The antitumor activity of the fluid was only eliminated when it was treated with anti-mouse IL-3 mAb. Since nonspecific resistance to tumors in mice stimulated with SSM appears to require Lyt 1+ T-cells, these results suggest that, in part, nonspecific resistance to tumors of mice stimulated with SSM may be developed through IL-3, which was produced by Lyt 1+ T-cells after SSM stimulation.
Animals↗
Depletion of macrophages expressing I-J antigen results in efficient generation of alloreactive cytotoxic T lymphocytes.
The role of suppressor macrophages (S-M phi) produced during generation of cytotoxic T lymphocytes (CTL) stimulated with allogeneic lymphocytes was investigated. Splenic CTL from C3H/He mice (H-2k) were generated by in vivo immunization and subsequent in vitro stimulation by splenic lymphocytes from C57B1/6 mice (H-2b) in mixed lymphocyte reaction (MLR). In addition to in vitro standard 51Cr release assay, the CTL activity was mainly measured in vivo using the Winn assay against EL-4 thymoma cells in B6C3F1 mice (H-2b/k). In mice injected with CTL plus EL-4 cells survival rate was 20% compared with no survival of mice treated with normal spleen cells plus EL-4 cells. The antitumor activity of the CTL was significantly increased when immunized mice were treated with a 5 mg/kg ip dose of indomethacin at the time of immunization (80% survival). Macrophages were depleted from spleen cells of immunized mice by plastic adherence or carbonyl-iron treatment, replaced with an equivalent number of M phi from normal mice, and then introduced into a 5-day MLR. When the antitumor activity of the cells isolated from this MLR was measured in the Winn assay, 90-100% survival in EL-4-bearing mice was observed. In contrast, none of the mice inoculated with EL-4 alone and 20% of the mice that received CTL obtained after alloimmunization followed by MLR in addition to EL-4 survived. These results of CTL activity were confirmed by in vitro cytotoxicity tests. When the M phi isolated from spleens of immunized mice were analyzed for I-Jk antigen expression, a 2.5-fold increase was detected, compared with splenic M phi obtained from normal C3H/He mice. In contrast, Ia and I-Ak antigen expression was equivalent in M phi isolated from normal or immunized C3H/He mice. When immune spleen cells were treated with anti-I-Jk antiserum followed by complement and then, subjected to the MLR, the antitumor activity of CTL was significantly enhanced (80% survival). However, treatment of these cells with anti-I-Ak antiserum and complement did not alter CTL activity. These data suggest that the increase of S-M phi expressing I-Jk+ antigen to be induced during alloimmunization results in suppression of allospecific CTL-generation in MLR.
Animals↗
Patterns of interferon-gamma production by peripheral blood mononuclear cells from patients with human immunodeficiency virus infection.
A number of immune parameters have been described as impaired in AIDS patients. The patterns of interferon-gamma (IFN-gamma) production by peripheral blood mononuclear cells (PBMC) from AIDS-related complex (ARC) and AIDS patients in response to specific and nonspecific mitogens and their relationship to proliferative responses, interaction with exogenous interleukin 2 (IL-2), and absolute CD4 cell counts were studied. The PBMC were exposed to phytohemagglutinin (PHA) or cytomegalovirus (CMV) antigen (Ag) and/or 10 units of IL-2. At selected times, culture supernatants were tested for IFN-gamma production by radioimmunoassay and at identical times proliferative responses were determined by [3H]thymidine uptake. IFN-gamma production in response to PHA or CMV Ag was inhibited significantly and appeared dependent on absolute CD4 cell counts. Proliferative responses were also similarly decreased. While IFN-gamma production to PHA was severely inhibited in PBMC only from patients with less than 100 CD4 cells/mm3, equivalent inhibition in response to CMV Ag was observed only in those with CD4 counts less than 600/mm3. IL-2 enhanced the PHA and CMV Ag-induced IFN production significantly by 2.8- and 5.3-fold respectively. Therefore, the administration of IL-2 might improve certain cell-mediated immune responses.
CD4-Positive T-Lymphocytes↗
Magnetic resonance imaging and neuropsychological findings in human immunodeficiency virus infection.
Neurobehavioral functioning and magnetic resonance imaging (MRI) were investigated in 25 patients with various Centers for Disease Control (CDC) stages of human immunodeficiency virus (HIV) infection and in a control group of seven normal subjects. Unequivocal slowing of information processing speed and cerebral atrophy were related to the stage of HIV infection, with patients in CDC group IV exhibiting the most abnormal findings. Slowing of response speed was directly related to the severity of cerebral atrophy.
Adult↗
Stimulation of non-specific resistance to tumors in the mouse using a poly(maleic-acid-styrene)-conjugated neocarzinostatin.
The development of non-specific resistance to tumors following stimulation with poly(maleic-acid-styrene)-conjugated neocarzinostatin (SMANCS), a polymer-conjugated derivative of neocarzinostatin, was investigated in mice. The growth of syngeneic solid tumors (Meth-A fibrosarcoma and RL male 1 leukemia) inoculated into BALB/c mice was suppressed after one treatment with SMANCS at doses ranging from 0.14 mg/kg to 3.4 mg/kg i.v. 24 h before tumor implantation. Since previously observations concerning SMANCS have shown that it disappeared within 1.5 h after i.v. administration in mice and that it was inactivated quickly in plasma, SMANCS evidently inhibited tumor growth by mediating non-specific resistance. In addition, the non-specific resistance to tumors stimulated by SMANCS could be passively transferred to untreated mice by serum which was shown to contain interferon (IFN) from 12 h to 20 h after SMANCS administration. However, the resistance was not produced by serum prepared from mice at 8 h or 32 h after administration presumably because of the observation that the interferon activity was only demonstrated from 12 h to 28 h after SMANCS stimulation. When the serum specimens were treated with anti-IFN-gamma antiserum, the antitumor activity of the sera was abrogated. However, no significant change was detected in the antitumor activity of the specimens following treatment with anti-IFN-alpha/beta antiserum. Treatment of mice with SMANCS and anti-IFN-gamma antiserum together resulted in the elimination of the non-specific resistance to tumors. The IFN induced in the sera of mice by SMANCS was shown to be 57% IFN-gamma and 41% IFN-alpha/beta. Half of the interferon produced in SMANCS-stimulated mice could be eliminated by treatment with anti-IFN-gamma, and treatment of SMANCS-stimulated mice with both anti-IFN-gamma and anti-IFN-alpha/beta antisera resulted in a total absence of detectable interferon. These findings suggest that while the administration of SMANCS induces both IFN-gamma and IFN-alpha/beta production, in this case, it is only the former which mediates the non-specific resistance to tumors.
Animals↗
Tremor induced by trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome (AIDS).
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Acquired Immunodeficiency Syndrome↗
Suppressor Lyt 2+ T-cells demonstrated in mice late after thermal injury.
Biological properties of suppressor cells mediating second suppressive state (S-SupS) of IFN-gamma responsiveness in mice following thermal injury were investigated by their ability to inhibit [3H]thymidine incorporation by allogeneic cell-stimulated mononuclear cells (MNC) prepared from spleens of unburned normal mice (N-mice). Kinetic studies indicated that the suppressor cells appeared at approximately 15 days post-burn and persisted until 40 days after thermal injury. This cell population from the spleens of thermally injured mice (TI-mice) was inactivated by anti-Thy 1.2 monoclonal antibody (mAb) plus complement (C). Treatment with antimouse immunoglobulin and anti-Lyt 1.2 mAb followed by C failed to abrogate the activity. However, it could be eliminated by treatment with anti-Lyt 2.2 mAb and C. In addition, when Thy 1+ or Lyt 2+ T cells were depleted from spleen cells containing suppressor cell activities by treatment with mAbs and C, the suppressor activity for IFN-gamma production by N-mice splenic MNC stimulated with concanavalin A was also eliminated. However, no alteration in the suppression of IFN production was observed when this splenic cell population from TI-mice was treated with anti-Lyt 1.2 mAb and anti-mouse Ig followed by C. Since it has been reported [1] that the suppressor cell in spleens of TI-mice could neither be removed by plastic adherence nor by carbonyl-iron treatment, this secondarily-generated suppressor cell was concluded to be a T cell possessing the Lyt 1-2+ phenotype. The present report describes the demonstration, following a generation of suppressor macrophages [2], of suppressor Lyt 2+ T cells spleen of mice late after thermal injury.
Animals↗
Relationship between the production of murine cytomegalovirus and interferon in macrophages.
Macrophages (M phi) harvested from the peritoneal cavities of mice after thioglycollate stimulation could be infected with murine cytomegalovirus (MCMV), although the efficiency of infection was low. Sequential measurements of interferon (IFN) production by virus-infected M phi were performed in an attempt to explain the characteristics of MCMV infection in the cell cultures. Infected M phi produced moderate amounts of IFN, which was completely neutralized by anti-IFN-alpha/beta serum. The IFN was detectable in cultures as early as 8 h after infection and was produced only by exposing M phi to infectious virus. Production increased until 48 to 72 h and preceded virus production, which was initially detected 72 h after infection. Treatment of the M phi cultures with anti-IFN-alpha/beta resulted not only in a marked increase in virus production, as well as a shortening of the long eclipse period of MCMV infection, but also induced increases in the number of M phi releasing MCMV (VR-M phi). Thus, the IFN produced in MCMV-infected M phi (MCMV-M phi IFN) appeared to suppress the production and spread of MCMV. The increase in the number of VR-M phi observed was more resistant to anti-IFN-alpha/beta treatment than the production of infectious virus. The antiviral effect of MCMV-M phi IFN on MCMV infection in mouse embryo fibroblasts was similar to that induced by IFN-alpha/beta. Therefore, MCMV-M phi IFN appeared to be more active in protecting against the spread of cell-free MCMV than of cell-associated virus. These differences in sensitivity to IFN action suggest that M phi may have a role in the latency of MCMV and that their production of IFN may facilitate the generation of latent infection.
Animals↗
Cytomegalovirus infections in renal, heart, heart-lung and liver transplantation.
Although infection with cytomegalovirus (CMV) continue to be recognized relatively frequently after organ transplantation, a decrease in their severity has been described with the use of newer immunosuppressive regimens. In particular whereas antithymocyte globulin was associated with an increase in morbidity and mortality, the use of cyclosporin A has resulted in a decrease in the frequency of symptomatic infections. Several sources of CMV infection in transplant recipients are: immunosuppression secondary to drug therapy can result in reactivation of the latent infection present before transplantation; blood transfusion, either pretransplant red blood cell transfusion or blood required at the time of surgery can also result in transmission of CMV and primary infection; the transplanted kidney or heart, particularly in situations in which seropositive organs are transmitted into seronegatives can serve as the vehicle for transmission. Recent data suggest that transmission of organ donor CMV can occur even in seropositive recipients. The clinical manifestations of CMV infection in transplant recipients range from asymptomatic or mild mononucleosis syndromes to severe infection. It is generally accepted that primary infections in patients who were seronegative before transplantation are more severe than reactivated infections. Involvement of multiple organ systems has been common, with retinitis, pneumonitis and gastrointestinal manifestations occurring most commonly. A specific CMV infection of the kidney has also been described but its manifestations are variable. The association of CMV infections with rejection remains controversial in human transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Acyclovir↗
Endoscopic evolution of gastric Kaposi's sarcoma.
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Adult↗