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Biomedical subjects

T G Evans

Publications and source records attributed to T G Evans.

At least 19 recordsLinked to original sources
PubMed1999

Detection of intracellular antigen-specific cytokines in human T cell populations.

Determination of antigen-specific cytokine responses of T lymphocytes after vaccination is made difficult by the low frequency of responder cells. In order to detect these responses, the profile of intracellular cytokines was analyzed using flow cytometry after antigenic expansion. Peripheral blood mononuclear cells were stimulated with antigens for 5 days, further expanded with interleukin (IL)-2, and then restimulated on day 10. Cytokine production was detected by intracellular staining with monoclonal antibodies after saponin-based permeabilization. Influenza expansion resulted in specific interferon-gamma (IFN-gamma) production of 6%-20%, with less IL-4 production (0%-2%). Tetanus toxoid resulted in even greater production. IL-4 and IFN-gamma were produced mainly by memory cells of the CD45RO+ phenotype. IFN-gamma production was contributed by both CD4 and CD8 populations. These methods were then applied to a clinical trial of a candidate human immunodeficiency virus type 1 vaccine. Antigen-specific increases in IFN-gamma were measured, which corresponded to antibody production, lymphoproliferation, and skin testing.

AIDS Vaccines↗
PubMed1999

A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers.

Induction of CD8+ cytotoxic T cells is considered one of the important correlates for the protective efficacy of candidate human immunodeficiency virus type 1 (HIV-1) vaccines. To induce CD8+ cytotoxic T lymphocytes (CTLs) along with neutralizing antibody and CD4+ T cell help, a live canarypox virus construct expressing gp120, transmembrane gp41, the gag and protease genes, and sequences containing CTL epitopes in nef and pol was given simultaneously with, or followed by, rgp120 SF2. CD8+ CTLs were detected in 61% of volunteers at some time during the trial. Three to 6 months after the last immunization, the gene-specific responses were gag, 26/81; env, 17/77; nef, 12/77; and pol, 3/16. Simultaneous immunization with the canarypox vector and the subunit, beginning with the initial immunization, resulted in earlier antibody responses. In summary, a strategy of immunization with a canarypox vector expressing multiple genes of HIV-1 given with gp120 results in durable CD8+ CTL responses to a broad range of epitopes.

AIDS Vaccines↗
PubMed1998

Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and gp120 SF-2 recombinant vaccines in uninfected volunteers. NIAID AIDS Vaccine Evaluation Group.

OBJECTIVE: To determine the ability of live attenuated canarypox virus expressing HIV antigens to induce CD8+ cytotoxic T-cell responses and to prime for neutralizing antibody responses to boosting with purified recombinant gp120 subunit vaccine. DESIGN: A prospective, double-blind, randomized, immunogenicity and safety study was conducted in healthy adults at low risk for acquiring HIV infection and who were seronegative for HIV. METHODS: CD8+ cytotoxic T-cells directed against Env or Gag expressing target cells were measured after live recombinant canarypox-HIV-1 vaccine priming (vaccine given at days 0, 7, 14 and 21). Neutralizing antibodies were measured after subunit boosting (vaccine given at days 28 and 84). RESULTS: CD8+ CTL were induced in 64% of volunteers by the live recombinant canarypox-HIV-1 vaccine. All volunteers who received two doses of subunit vaccine after live recombinant canarypox priming developed neutralizing antibodies directed against laboratory strains of HIV-1 and seven out of eight volunteers tested developed neutralizing antibodies to the primary isolate, BZ167, but to none of eight other primary isolates. Unprimed controls had low or absent neutralizing antibodies after two doses of subunit vaccine. CONCLUSIONS: The live canarypox vector was safe, stimulated cytotoxic T-cells and primed for a vigorous neutralizing antibody response upon boosting with subunit gp120 vaccine. This vaccine combination should be evaluated further for inducing protection against HIV infection.

AIDS Vaccines↗
PubMed1998

Cytomegalovirus-specific IFNgamma and IL-4 are produced by antigen expanded human blood lymphocytes from seropositive volunteers.

The cytokine responses to cytomegalovirus (CMV) antigen in seropositive and seronegative individuals were measured using a combination of antigenic expansion and intracellular staining. Intracellular IFNgamma and IL-4 were produced in a dose-dependent manner by T cells in response to CMV only in the seropositive population. The potential for individual cells to produce both Th1 and Th2 cytokines simultaneously was clear, as IL-4 was most often produced in those cells with the highest IFNgamma production. The cytokine-specific nature of this response was demonstrated by fluorescence microscopy, which showed granular cytoplasmic staining, and at the mRNA level by ribonuclease protection assays. These methods expand our ability to evaluate the immune response to CMV, and can now be correlated to a number of clinical conditions.

Adult↗
PubMed1998

Highly active antiretroviral therapy results in a decrease in CD8+ T cell activation and preferential reconstitution of the peripheral CD4+ T cell population with memory rather than naive cells.

OBJECTIVE: Highly active antiretroviral therapy (HAART) can produce marked increases in peripheral blood CD4+ T cells and decreases in HIV plasma RNA copy numbers. However, it is not clear whether these absolute changes will be accompanied by a recovery in the known naive CD4+ T cell depletion or a decrease in the marked CD8+ T cell activation. DESIGN: Twenty-nine patients were enrolled in studies of either nucleoside therapy alone or nucleoside therapy combined with a protease inhibitor (zidovudine + lamivudine + indinavir). One hundred and ninety-one examinations were carried out at three baseline time points and during 40 weeks of follow-up to evaluate the effect of HAART on CD4+ memory/naive phenotype and CD8+ T cell activation. METHODS: CD4+ and CD8+ T cell number, CD62L/CD45RA expression on CD4+ T cells and CD38 expression on CD8+ T cells were measured by three-color flow cytometry. RESULTS: Most protease inhibitor treated patients had a significant rise in CD4+ numbers. The marked rise in the CD4+ T cells seen in individuals in this study was not accompanied over a 40-week period by a change in the abnormally low CD4+ naive compartment, and thus was almost completely of memory phenotype. The CD38 expression on CD8+ cells fell during treatment, and decreased to a greater degree than the comparable rise in CD4+ T cell counts. This decrease continued in many patients after the CD4+ T cell rise or viral load decline had plateaued. CONCLUSION: HAART results in changes in activation to a greater extent than absolute changes in CD4+ T cell numbers, but is not accompanied by an increase in naive CD4+ T cells. Measurements of CD4+ T cell numbers alone may not allow appropriate interpretation of immune activation or immune competence in patients receiving those drugs.

Anti-HIV Agents↗
PubMed1998

Th1/Th2 cytokine responses following HIV-1 immunization in seronegative volunteers. The AIDS Vaccine Evaluation Group.

The Th1/Th2 profile that follows human vaccination may profoundly influence the subsequent course of disease after infection. However, the ability to detect IL-4 has been limited outside trials of live vaccination. By using methods in which memory effector cells are allowed to antigenically expand by short term culture, followed by low-dose mitogenic stimulation, we have been able to follow the Th1/Th2 profile in HIV-1 volunteers enrolled in two phase I studies of HIV immunogens (a recombinant gp120 and a multivalent, octomeric V3 loop peptide). Antigen-specific interferon-gamma (IFN-gamma) could be detected in primary stimulation, but IL-4 was observed only after antigenic expansion and restimulation. In both of these studies the responses after initial immunizations were dominated by IFN-gamma, with IL-4 appearing only after multiple rounds of immunization, and IL-4 was temporally related to antibody production. Concomitant with the IL-4 production, the amount of supernatant IFN-gamma declined. Antigen-specific IL-10 was not detected in either study. Such techniques, which have been shown to correlate with outcomes in immunotherapy, may prove useful as future surrogates of human vaccine response.

AIDS Vaccines↗
PubMed1998

Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium.

Disseminated Mycobacterium avium complex (MAC) infection continues to be a common opportunistic infection in patients infected with human immunodeficiency virus (HIV). The optimal therapy for disseminated MAC infection is unclear. We compared azithromycin plus ethambutol with clarithromycin plus ethambutol in the treatment of disseminated MAC infection in HIV type 1-infected patients, examining the frequency of bacteremia clearance, time to clearance, and study drug tolerance after 16 weeks of therapy. Fifty-nine patients for whom blood cultures were positive for MAC were enrolled in the study from 10 university-affiliated Veterans Affairs Medical Centers. Thirty-seven patients were evaluable for determination of quantitative bacteremia and clinical outcomes. Clearance of bacteremia was seen at the final visit in 37.5% of azithromycin-treated patients and in 85.7% of clarithromycin-treated patients (P = .007). The estimated median time to clearance of bacteremia was also significantly different between the two treatment arms: 4.38 weeks for clarithromycin recipients vs. > 16 weeks for azithromycin recipients (P = .0018). Only one isolate developed macrolide resistance during therapy. Abatement of symptoms, other laboratory-evident abnormalities, and adverse effects were similar in the two groups. At the doses used in this study, clarithromycin/ethambutol produced a more rapid resolution of bacteremia than did azithromycin/ethambutol, and clarithromycin/ethambutol was more effective at sterilization of blood cultures after 16 weeks of therapy.

AIDS-Related Opportunistic Infections↗
PubMed1997

Effect of foscarnet cream on experimental UV radiation-induced herpes labialis.

A topical 3% foscarnet cream formulation was evaluated for its ability to treat experimental UV radiation (UVR)-induced herpes labialis in a double-blind study. Healthy adult volunteers with a history of sunlight-induced herpes labialis were randomly assigned at four centers to receive either foscarnet cream (n = 152) or a vehicle control (n = 150). Following measurement of the minimal erythematous dose (MED), the subjects' lips were exposed to 4 MEDs of UV light. Subjects applied the cream on the UVR-exposed area approximately eight times daily beginning immediately after UVR exposure and continuing for 7 days, or until all lesions had a minimum of 4 days of treatment. There were no significant differences between groups in the percentages of subjects that developed any lesion, aborted lesions (did not progress beyond a papule), immediate lesions (developed within 48 h of UVR), or delayed classic lesions (developed 48 h to 7 days after UVR). Treatment with foscarnet significantly reduced the mean lesion area (49 versus 81 mm2; P = 0.01), the maximum lesion area (80 versus 141 mm2; P = 0.01), and the time to healing (P = 0.03) of the delayed classic lesions (n = 78). There was also a trend for a decrease in the mean duration of these lesions (156 versus 191 h; P = 0.08) and the duration of pain (3.9 versus 4.3 days; P = 0.06) in foscarnet-treated subjects. There were no clinically significant adverse reactions. These data suggest that topical foscarnet can be efficacious and deserves further evaluation for the treatment of herpes labialis.

Adolescent↗
PubMed1996

The use of oral dehydroepiandrosterone sulfate as an adjuvant in tetanus and influenza vaccination of the elderly.

Elderly individuals often exhibit a poorer immune response and shorter duration of immunity to vaccines than younger persons. Improvement in vaccine response has been demonstrated when administering the hormone dehydroepiandrosterone sulfate (DHEAS) as an adjuvant in animal trials. Two separate, randomized double-blinded vaccine trials were therefore conducted using DHEAS as an oral adjuvant in individuals age 65 or older. Sixty-six individuals were randomized to DHEAS, 50 mg po bid for 4 days, or a placebo capsule. Tetanus vaccination was given immediately before the fifth dose. At entry the level of protective antibody was age-dependent (P = 0.009), and by 28 days post-vaccination most individuals had protective levels of antibody, with no difference noted between treatment groups. In the second study, 67 individuals received placebo capsules or DHEAS immediately before and 24 h after influenza vaccination. The number of individuals who developed protective titers (> or = 1:40) was not different in the two groups. The mean log increase in HAI response was greater in the DHEAS group to all three vaccine components, although this did not achieve significance. Minimal side-effects of DHEAS administration were noted. Given the trend toward improved response in the elderly to influenza, larger trials using DHEA as an adjuvant in vaccines that are neoantigens may be indicated.

Adjuvants, Immunologic↗
PubMed1996

Cost effectiveness and cost utility of preventing trachomatous visual impairment: lessons from 30 years of trachoma control in Burma.

AIMS/BACKGROUND: This paper reports on the findings of a cost and effectiveness study of the trachoma control programme (TCP) in Burma. The TCP began in 1964 employing non-surgical interventions (community education and mass treatment with topical antibiotics) and surgical correction of trichiasis. METHODS: Fixed and variable costs of the TCP are assessed over 30 years (1964-93) and apportioned to either surgical or non-surgical interventions. The change in the prevalence of trachoma blindness during this period is used to calculate cases of visual impairment prevented by the TCP. The years of life saved because of premature mortality averted and from living in a handicapped state are added to yield a single measure of utility called handicap adjusted life years (HALYs). RESULTS: The cost effectiveness of the TCP is $54 per case of visual impairment prevented: $193 and $47 for surgical and non-surgical interventions respectively. The cost utility of the TCP is $4 per HALY averted: $10 and $3 for surgical and non-surgical interventions respectively. Results are highly sensitive to the 1965 prevalence of blindness, the choice of discount rate, and the effectiveness of both interventions. CONCLUSIONS: Thirty years of trachoma control in Burma are associated with a remarkable decline in trachomatous blindness. Both surgical and non-surgical interventions are cost effective means of preventing trachomatous visual impairment. Discussion focuses on methodological limitations and implications for research and policy.

Blindness↗
PubMed1996

Nitric oxide production in murine leishmaniasis: correlation of progressive infection with increasing systemic synthesis of nitric oxide.

Previous studies have shown that nitric oxide (NO) production is a major effector mechanism in the control of Leishmania major infection in the BALB/c and C3H murine models. The susceptibility of mice correlates with intrinsic NO production after infection. We have previously shown that blocking of systemic NO production with oral N-Omega-monomethyl-L-arginine results in decreased NO and exacerbated infection. The C3H mice also synthesize markedly more NO than BALB/c mice shortly after initial infection. We now show that late in infection, as the lesion size is increasing, the BALB/c NO production actually exceeds that seen during the curative stages of the C3H infection. In addition, treatment with meglumine antimoniate, which ameliorates but does not cure the BALB/c mouse, results in decreased systemic parasite load with a concomitant decrease in NO production. These results imply that in vivo, systemically measured levels of NO may in some circumstances reflect ongoing parasitic load, and that NO production is not always correlated with a curative response.

Animals↗
PubMed1995

Th1/Th2-like immunity and resistance to herpes simplex labialis.

To investigate potential immunologic mechanisms of resistance to recurrent herpes simplex labialis, we assayed serum antibody titers and cultured peripheral blood mononuclear cell (PBMC) cytokine production among patients with a history of frequent episodes (H+S+), herpes simplex virus (HSV)-seropositive individuals without a history of herpes labialis (H-S+) and HSV-seronegative persons (H-S-). In addition, H+S+ patients were exposed to experimental ultraviolet radiation (UVR) on the lips and the immunologic assay results compared among those who developed experimental lesions and those who did not. H+S+ patients were found to have higher median serum titers of HSV antibody and trends to lower levels of HSV-specific PBMC IFN-gamma and IL-2 than H-S+ control patients (123 vs 66, P = 0.04; 424 vs 548 pg/ml, P = 0.08; 14 vs 26 pg/ml, P = 0.14, respectively). Correlation of the results with the occurrence of experimental lesions showed the inverse: the subgroup of H+S+ patients with UVR-induced lesions had lower titers of antibody and trends to higher levels of IFN-gamma and IL-2 than H+S+ patients who could not be induced (93 vs 149, P = 0.02; 501 vs 347 pg/ml, P = NS; 26 vs 11 pg/ml, P = NS, respectively). The size and duration of UVR-induced lesions showed positive correlations with IFN-gamma and IL-2 levels (r = 0.60-0.67, P = 0.02-0.04). Although the small number of patients limited the power of this study, the overall pattern of the findings suggests that a Th1-like cytokine response (IFN-gamma and IL-2 production) may be associated with resistance to naturally occurring episodes of herpes labialis. The development and severity of experimental UVR-induced herpes labialis appears to be regulated differently and may involve an immunopathologic mechanism.

Antibodies, Viral↗
PubMed1995

Susceptibility to herpes labialis following multiple experimental exposures to ultraviolet radiation.

We studied susceptibility to herpes labialis by exposing 20 volunteers to experimental ultraviolet radiation (UVR) on three occasions at 3- to 4-month intervals. The number of patients who developed lesions after each session was 9/20 (45%), 9/20 (45%) and 14/20 (70%). Herpes simplex virus (HSV) was isolated from 21/29 (72%) of lesions sampled. Three patients never developed a lesion, 13 developed lesions on one or two of the three occasions, and 4 patients had a lesion following all three sessions. Seven of 33 (21%) lesions were 'immediate' lesions (developed within 48 h) and the others developed 3-7 days after UVR exposure (delayed lesions). Development of lesions correlated with historical susceptibility to sun-induced herpes labialis, but not with age, sex, years with herpes labialis, frequency of herpes labialis from all causes, or concurrent serum levels of cortisol, dehydroepiandrosterone, estradiol, progesterone or alpha 1-antitrypsin. Among normally menstruating females, a significant association was identified between the development of herpes labialis and the luteal phase of the menstrual cycle (8 cases of herpes labialis/11 attempts, RR = 14, P = 0.005). The lack of correlation between episodes of natural herpes labialis and susceptibility to experimental UVR-induced disease suggests that these events are controlled differently. The results of serial attempts to induce experimental herpes in each patient was most commonly inconsistent, indicating that individual patient susceptibility to UVR varies over time. While the explanation for this variation remains unclear, stages of the menstrual cycle may be important among women.

Adult↗