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Biomedical subjects

R B Pollard

Publications and source records attributed to R B Pollard.

At least 55 records · Page 3Linked to original sources
PubMed1997

Inhibition of pulmonary metastasis by Z-100, an immunomodulatory lipid-arabinomannan extracted from Mycobacterium tuberculosis, in mice inoculated with B16 melanoma.

The anti-metastatic effect of Z-100, an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis, was investigated in mice bearing B16 melanoma cells. Treatment of BF10 mice implanted with high metastatic B16F10 melanoma cells with a 10 mg/kg dose of Z-100 resulted in the reduction of experimental pulmonary metastasis as compared with that of BF10 mice treated with saline. The number of pulmonary metastatic colonies in BF1 mice (mice implanted with low metastatic B16F1 melanoma cells) was greatly increased after the inoculation of CD4+ CD11b+ CD281+ TCR alphabeta+ type 2 T cells (F10-Th2 cells) derived from BF10 mice, while only a few metastatic colonies were demonstrated in lungs of BF1 mice inoculated with naive CD4+ T cells. However, the numbers of metastatic colonies in BF1 mice were not increased when they were inoculated with the F10-Th2 cell fraction derived from Z-100-treated BF10 mice and the generation of F10-Th2 cells in BF10 mice was effectively suppressed by the Z-100 treatment. These results suggest that Z-100 inhibits pulmonary metastasis of B16 melanoma through the regulation of tumor-associated Th2 cells, which are a key cell in the acceleration of tumor metastasis.

Animals↗
PubMed1997

CD4- CD8- TCR alpha/beta+ suppressor T cells demonstrated in mice 1 day after thermal injury.

We have described previously that CD8+ CD11b+ TCR gamma/delta+ type 2 T cells (BA-type 2 T cells) and suppressor macrophages (Sup-Mł) are generated in spleens of mice 3 to 5 days (Sup-Mł) and 4 to 9 days (BA-type 2 T cells) after thermal injury. In the present study, an additional suppressor T cell, characterized as CD3+ CD4- CD8- TCR alpha/beta+ T cells (double negative suppressor T cells, DN Sup-T cells), was demonstrated in mice 1 day after thermal injury. DN Sup-T cells inhibited the proliferation of lymphocytes stimulated with allogeneic cells or a lectin in a mixed lymphocyte reaction, and produced both type 1 and type 2 cytokines (interferon-gamma, interleukin-2, interleukin-4, and interleukin-10) when they were stimulated in vitro with anti-CD3 monoclonal antibody. These results suggest that DN Sup-T cells express phenotypic properties similar to natural suppressor cells and cytokine-producing profiles different from type 1 (Th1 cells and CTLs) and type 2 T cells (Th2 cells and CD8+ type 2 T cells). DN Sup-T cells may play a role on the burn-associated immunosuppression appearing in the acute phase of thermally injured individuals.

Animals↗
PubMed1997

Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus.

The antiviral effect of glycyrrhizin (GR), an active component of licorice roots, was investigated in mice infected with influenza virus A2 (H2N2). When mice that had been exposed to 10 50% lethal doses of the virus were treated intraperitoneally with 10 mg of GR per kg of body weight 1 day before infection and 1 and 4 days postinfection, all of the mice survived over the 21-day experimental period. At the end of this period, the mean survival time (in days) for control mice treated with saline was 10.5 days, and there were no survivors. The grade of pulmonary consolidations and the virus titers in the lung tissues of infected mice treated with GR were significantly lower than those in the lung tissues of infected mice treated with saline. GR did not show any effects on the viability or replication of influenza virus A2 in vitro. When splenic T cells from GR-treated mice were adoptively transferred to mice exposed to influenza virus, 100% of the recipients survived, compared to 0% survival for recipient mice inoculated with naive T cells or splenic B cells and macrophages from GR-treated mice. In addition, the antiviral activities of GR on influenza virus infection in mice were not demonstrated when it was administered to infected mice in combination with anti-gamma interferon (anti-IFN-gamma) monoclonal antibody. These results suggest that GR may protect mice exposed to a lethal amount of influenza virus through the stimulation of IFN-gamma production by T cells, because T cells have been shown to be producer cells of IFN-gamma stimulated with the compound.

Adoptive Transfer↗
PubMed1996

Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E2 in human monocytes.

Cytomegalovirus (CMV) has been associated with immunosuppression. Previously CMV was reported to interfere with signal transduction pathways in T cells. In this report the mechanisms underlying CMV-mediated immunosuppression were examined. Supernatants of CMV (Strains C-87, AD-169)-infected primary human monocyte (MO) cultures inhibited mitogenic T cell proliferative responses by > 95%. The inhibitory activity was observed 24 h through day 7 postinfection. The infection of MO was associated with a sustained elevation of intracellular levels of cAMP and the release of arachidonic acid (AA) and its metabolite PGE2 (activator of adenylate cyclase) in culture supernatants. The AA release was incidentally associated with TNF-alpha production. Monoclonal antibodies to TNF-alpha and pentoxyphylline (inhibitor of TNF synthesis) inhibited both AA and PGE2 release. The release of AA required protein synthesis and occurred under conditions consistent with the expression of CMV immediate early genes. Treatment of MO cultures at time of infection with 100 microM indomethacin or 1 microg of TNF-alpha mAb abolished the CMV-induced T cell inhibitory activity of the supernatants by 100%. These data suggest that TNF dependent release of AA and PGE2 contributes to CMV-induced immunosuppression.

Antibodies, Monoclonal↗
PubMed1996

2-Carboxyethylgermanium sesquioxide, a synthetic organogermanium compound, as an inducer of contrasuppressor T cells.

2-Carboxyethylgermanium sesquioxide (Ge-132), a synthesized organogermanium compound with immunomodulating activities, was shown to be an inducer of anti-suppressor T cells in normal mice. The suppressor cell activity of T6S cells, a clone of burn-induced CD8+ IL-4-producing suppressor T cells, was clearly inhibited when a mixed lymphocyte-tumor cell reaction of the clone was conducted with splenic mononuclear cells from mice treated orally with a 100 mg/kg dose of Ge-132. The activity of anit-suppressor cells was demonstrated in spleens of mice 2 days after treatment with Ge-132 and reached its peak on day 3. The anti-suppressor cells induced by the compound were of a contrasuppressor T cell-linage, because they were characterized as CD4+ CD28+ TCRalpha/beta+ Vicia villosa lectin-adherent T cells. These cells produced IFN-gamma but did not produce IL-2, IL-4, IL-6 or IL-10 in their culture fluids. CD4+ anti-suppressor T cells induced by Ge-132 may be different from other subsets of CD4+ T cells because Th1 and Th2 cells generated in our laboratory did not adhere to Vicia villosa lectin-coated petri dishes, and each produced specific cytokines. Th1 cells produced IFN-gamma and IL-2 while Th2 cells produce IL-4 and IL-10 in vitro. These results suggest that Ge-132 may be useful as an inducer of contrasuppressor T cells in immunocompromised individuals bearing suppressor T cells. To eliminate suppressor T cells from immunocompromised hosts may result in improved resistance from various opportunistic infections.

Animals↗
PubMed1996

Interleukin-12 protects thermally injured mice from herpes simplex virus type 1 infection.

Severe burn injury is associated with increased susceptibility to severe herpesvirus infections. Type 2 cytokines [interleukin (IL)-4 and IL-10] released from burn-associated CD8+ type 2 T cells (BA-type 2 T cells) have been shown to play a role in the increased susceptibility of thermally injured mice (TI-mice) to herpes simplex virus type 1 (HSV-1) infection. Because IL-12 has been shown to inhibit the generation of type 2 T cells, murine rIL-12 was injected into TI-mice exposed to HSV-1 to determine whether IL-12 could influence HSV-1 infections in individuals bearing type 2 T cells. rIL-12 improved the resistance of TI-mice or mice inoculated with T6S cells (a BA-type 2 T cell clone) against HSV-1 infection. Type 2 cytokines were detected in sera of TI-mice or mice inoculated with T6S cells (T6S-mice). However, treatment of TI-mice or T6S-mice with rIL-12 inhibited type 2 cytokine production in the sera of these mice. All TI-mice exposed to a lethal dose of HSV-1 survived when they were treated with a mixture of monoclonal antibodies (mAbs) against type 2 cytokines. Staphylococcal enterotoxin A [an interferon-gamma (IFN-gamma) inducer] stimulated serum IFN-gamma production in TI-mice and T6S-mice treated with rIL-12, whereas no IFN-gamma was produced in mice treated with saline. These results suggest that IL-12 has the potential to protect TI-mice infected with a lethal dose of HSV-1 via a shift to type 1 T cell responses from type 2 T cell responses.

Animals↗
PubMed1996

Immunotherapy of CMV infections.

Immunotherapy has not only become the accepted standard for some CMV infections, but also remains an area of active investigation for the treatment and prophylaxis of CMV infections. Polyclonal immunoglobulin administration has improved the survival of CMV pneumonitis in BMT recipients, and monoclonal anti-CMV antibodies, notably MSL-109, appear to increase the time to relapse of CMV retinitis in patients with AIDS. The adoptive transfer of CMV-specific CD8 cells is under investigation as another CMV prophylactic strategy in BMT recipients, and it is hopeful that this methodology can be applied to the therapy of established CMV infections.

Animals↗
PubMed1996

In vitro induction of anti-type 2 T cells by glycyrrhizin.

Glycyrrhizin (GR), an active component of licorice roots, has been previously shown to induce the generation of anti-type 2 T cells (anti-BI2T cells), which are able to counteract the activity of burn-induced CD8+ type 2 T cells (BI2T cells), in thermally injured and normal mice. In the present study, anti-BI2T cells were generated in vitro in cultures of spleen cells stimulated with GR. Anti-BI2T cells were induced in vitro when splenic mononuclear cells (SMNC) were stimulated in vitro for 24 to 72 h with 0.1-10 micrograms/ml of GR. Anti-BI2T cell activity was detected when suppressor macrophages (M phi) were depleted from SMNC after stimulation with GR. However, the GR-stimulated generation of anti-BI2T cells required the participation of M phi or their sonicated fractions. Anti-BI2T cells induced in vitro by GR were identified as Vicia villosa lectin adherent IFN7 producing-CD4+ T cells lacking the ability to produce IL-2, IL-4 or IL-10. These results indicate that anti-BI2T cells are generated by GR in vitro. M phi are not only necessary for the generation of anti-BI2T cells induced by GR but also inhibit their activity.

Animals↗
PubMed1996

Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS.

The study objective was to obtain preliminary information regarding the safety and efficacy of amphotericin B (AmB) lipid complex (ABLC) in the treatment of AIDS-associated cryptococcal meningitis. Of 55 patients randomly assigned to 6 weeks of therapy with ABLC (1.2-5.0 mg/[kg.d], with ascending doses for three sequential cohorts) or AmB (0.7-1.2 mg/[kg.d]), 46 received > or = 12 doses. Transfusion requirements, mean decreases in hemoglobin level, and mean increases in creatinine level were significantly greater with AmB than with ABLC. The total number of adverse events, infusion-related events, and occurrences of hypomagnesemia and hypokalemia associated with each form of therapy were similar. Among 21 recipients of ABLC at a dosage of 5 mg/kg (daily for 2 weeks and then thrice weekly for 4 weeks), symptoms and signs resolved for 18 (86%). Of those receiving > or = 12 doses of ABLC, cultures converted to negative for 8 (42%), were undeterminable for 3 (16%), and remained positive for 8 (42%) despite resolution of symptoms. Although preliminary, these data suggest ABLC has significant activity in patients with AIDS-associated cryptococcal meningitis. Because this formulation has less hematologic and renal toxicity than does AmB, further evaluation of ABLC is warranted.

AIDS-Related Opportunistic Infections↗
PubMed1995

Small amounts of exogenous IL-4 increase the severity of encephalitis induced in mice by the intranasal infection of herpes simplex virus type 1.

The effect of murine rIL-4 on the development of herpesvirus encephalitis (HSE) in mice infected intranasally with herpes simplex virus type 1 (HSV-1) was investigated. The mortality rates of mice infected with a 0.5 LD50 dose of HSV-1 were greatly increased after the administration of rIL-4 at doses ranging from 0.01 to 1.0 U/mouse 2 h before and 2, 4 and 6 days after the infection. In contrast, survival rates of mice exposed to a 5 LD50 dose of HSV-1 were clearly increased when these mice were treated with anti-IL-4 mAb. Cervical lymph node (CLN) cells and cerebrospinal fluid (CSF) cells from mice with HSE (HSE mice) produced IL-4 in their culture fluids when they were stimulated in vitro with HSV-1 Ag. Increased amounts of HSV-1 infection in mice resulted in the increased production of IL-4 in the culture fluids of local lymphocytes. However, significant amounts of IL-4 were not produced in serum specimens or in culture fluids of spleen cells from HSE mice. IL-4 production in culture fluids of CLN and CSF cells from HSE mice was clearly reduced after treatment of HSE mice with anti-IL-4 mAb. Furthermore, IL-4 production by CLN and CSF cells was greatly enhanced when the cells were prepared from HSE mice previously treated with rIL-4. The IL-4 was mainly produced from CD4+ T cells. These results demonstrate that small amounts of exogenous IL-4 increase the severity of HSE in HSV-1-infected mice through the increased production of IL-4 from local CD4+ T cells.

Administration, Intranasal↗
PubMed1995

HIV-induced TNF-alpha regulates arachidonic acid and PGE2 release from HIV-infected mononuclear phagocytes.

Arachidonic acid (AA) has been shown to interact with transmembrane signaling pathways involved in T-cell activation. The latter have been shown to be impaired in lymphocytes obtained from HIV-infected patients. In the present study, AA and its metabolite, PGE2, released from differentiating human mononuclear phagocytes in response to HIV infection, and their relationship to HIV replication and TNF-alpha production were examined. The macrophage (M phi) cultures were more permissive for HIV replication than monocyte (MO) cultures. AA release in response to HIV infection was observed in both MO and M phi with a peak at 24 hr postinfection (p.i.). This AA release was 3.8- and 6-fold that of uninfected MO and M phi cultures, respectively. Supernatants from MO and M phi cultures at the peak of AA production inhibited [3H]thymidine uptake of peripheral blood mononuclear cells in response to PHA by 45 and 54%. At 24 hr p.i., PGE2 production was increased in both MO and M phi cultures. This increase was associated with a 1.2- and 20-fold inhibition of IL-1 production, respectively. TNF release, however, increased through day 14 p.i. Treating mock-infected MO with recombinant TNF-alpha induced AA release. Monoclonal antibodies to TNF inhibited this release by 80%. TNF (0.01-0.4 microgram/ml) added exogenously to MO produced a biphasic pattern of AA release; while low concentrations were stimulatory, higher concentrations were inhibitory. Treating monocyte and macrophage cultures with mAb to TNF-alpha inhibited the HIV-induced release of AA and PGE2. These findings indicate that HIV-induced TNF-alpha regulates the release of AA and PGE2, which might provide insight into the mechanisms involved in the pathogenesis of HIV-related disorders.

Antibodies, Monoclonal↗
PubMed1995

CD4+ contrasuppressor T cells improve the resistance of thermally injured mice infected with HSV.

Modulation of burn-associated CD8+ CD11b+ T cell receptor gamma/delta+ suppressor T cells (BA2T cells) and improved resistance to herpesvirus infections was studied in thermally injured mice. The susceptibility of thermally injured mice to infection by herpes simplex virus (HSV) was approximately 100 times greater than it was in normal mice. The increased susceptibility of thermally injured mice to HSV infection was transferred to normal mice by BA2T cells, which appeared in spleens of mice 2-9 days after thermal injury. The suppressor cell activity of BA2T cells was effectively counteracted by CD4+ CD28+ T cell receptor alpha/beta+ Vicia villosa lectin adherent antisuppressor cells (designated as burn-induced contrasuppressor T cells; BCS cells), which were generated naturally in spleens of mice after the appearance of BA2T cells. The adoptive transfer of BCS cells to mice just after the injury improved the resistance of thermally injured mice to HSV infection to levels observed in normal mice. These results suggest that the increased susceptibility of thermally injured mice to HSV infection may be affected by BA2T suppressor cells and BCS cells may improve the resistance of thermally injured mice to HSV infection through the inhibition of BA2T suppressor cell activities.

Animals↗
PubMed1995

Glycyrrhizin (20 beta-carboxy-11-oxo-30-norolean-12-en-3 beta-yl-2-O-beta-D-glucopyranuronosyl-alpha-D-glucopyranosiduronic acid) improves the resistance of thermally injured mice to opportunistic infection of herpes simplex virus type 1.

The effect of glycyrrhizin (GR) on the resistance of thermally injured mice to opportunistic herpes simplex virus type 1 (HSV) infection was investigated. We have previously reported that the susceptibility of thermally injured mice or normal mice inoculated with T6S cells (a clone of burn-associated CD8+ CD11b+ TCR gamma/delta + type-2 suppressor T cells), to HSV infection was about 100 times greater than it was in normal mice. When thermally injured mice were treated i.p. with a 10 mg/kg dose of GR 2 and 4 days after infection of HSV, the resistance of these mice to HSV was improved to levels observed in normal mice. The adoptive transfer of splenic mononuclear cells (MNC) from normal mice treated with GR (GR-MNC) to thermally injured mice (recipients) resulted in the improved resistance of recipients to HSV infection. Normal mice inoculated with T6S cells and exposed to HSV had an 80% mortality rate, when given GR-MNC they had a 95% survival rate. The suppressor cell activity of T6S cells was clearly counteracted by GR-MNC in vitro in a mixed lymphocyte-tumor cell reaction. The type of cells responsible for anti-suppressor cells in GR-MNC was shown to be a CD4+ CD28+ TCR alpha/beta + Vicia villosa lectin-adherent T cell. These results suggest that GR may reverse the increased susceptibility of thermally injured mice to HSV infection through the induction of CD4+ contrasuppressor T cells.

Animals↗
PubMed1995

The data and safety monitoring board and acquired immune deficiency syndrome (AIDS) clinical trials.

The urgency of the Acquired immune deficiency syndrome (AIDS) epidemic has mandated that multiple therapeutic approaches be developed and that these approaches be evaluated through clinical trials. To oversee these trials, the National Institute of Allergy and Infectious Diseases (NIAID) has created three large clinical trial programs monitored by a Data and Safety Monitoring Board (DSMB). For each clinical trial, this Board uses a standardized approach employing contemporary biostatistical, medical, and ethical principles. The DSMB is responsible for reviewing interim data on clinical trial performance, treatment safety and efficacy, and overall study progress. If interim results provide convincing evidence of either excessive adverse effects or significant treatment benefit, the DSMB may recommend early termination of the trial to the NIAID and the study investigators. The responsibility, organization, and operating procedures of this DSMB are presented and illustrated through three clinical trials sponsored by NIAID and monitored by the Board. The rationale and operational model for the DSMB may be a useful example for the development of similar review processes in other HIV clinical trial settings.

Advisory Committees↗
PubMed1995

Zidovudine adherence among individuals with HIV infection.

The objective was to investigate the relationships among health beliefs, attitudes, and zidovudine compliance in individuals with HIV infection. A survey was administered to 52 individuals with HIV infection. The survey items, which reflected concerns expressed about zidovudine, were generated based on barriers to and benefits of zidovudine and the perceived susceptibility to and perceived severity of HIV as described by the health belief model (HBM). These items were expressed as attitudes and beliefs. Items were subjected to factor analysis, and survey results were correlated with laboratory data to predict adherence to their prescribed medication-taking regimen. Data indicated that 42.3% of the subjects were compliant with zidovudine. Factor analysis identified four dimensions: problems taking and scepticism about zidovudine; degree of concern about HIV; perceived severity of HIV; and physical barriers to taking zidovudine. Logistic regression analysis (forward conditional entry) identified those who were having problems taking zidovudine and who were sceptical about its effectiveness, and ethnicity as significant independent predictors of compliance, correctly classifying 75% of cases (p < 0.01). The fact that subjects who have problems taking zidovudine or are sceptical about the value of zidovudine are less compliant, and that this dimension is a significant predictor of compliance, suggests that non-compliance is related to attitudes and beliefs about zidovudine. This is consistent with the HBM, which holds that the balance between barriers and benefits of a health-related behaviour are significant determinants of outcome.

Adult↗