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Biomedical subjects

A R Hayward

Publications and source records attributed to A R Hayward.

At least 37 records · Page 2Linked to original sources
PubMed1995

Frequency and cytokine phenotype of blood T cells from premature infants responding to staphylococcal enterotoxin B.

The responder cell frequency (RCF) of premature (< 1900 g birth weight) infants' blood lymphocytes, which proliferate in cultures stimulated by staphylococcal enterotoxin B, falls from 1:3400 to about 1:8000 during the first 2 wk of life. Term infants, in contrast, show no fall in RCF. The reduced RCF in the premature infants affected cells that make interferon-gamma more than cells making IL-4. The reduced RCF was accompanied by a fall in the fraction of V beta 3+ T cells that entered cell cycle in stimulated cultures. The RCF of premature infants' T cells was increased in cultures supplemented with irradiated monocytes from adults. Addition of IL-4 (but not IL-2, IL-6, or indomethacin) increased the RCF and fraction of cells entering cell cycle of the premature infants. The data suggest that postnatal environmental factors limit the ability of premature infants' monocytes to support a T-cell response to staphylococcal enterotoxin B in vitro and that this limitation is overcome by adding IL-4.

Cell Cycle↗
PubMed1994

Clinical application of responder cell frequency estimates with four years of follow up.

Limiting dilution cultures have been used to estimate the frequency of T cells which respond to antigen stimulation in vitro, but nothing is known of the reproducibility of this assay when applied to human blood. We developed a simplified form of limiting dilution culture in which blood mononuclear cells were diluted in round bottom 96-well plates and cultured for 10 days. The assay was used to estimate the frequency of blood mononuclear cells proliferating in response to varicella-zoster virus antigen. 250 subjects aged 25-87 years were studied: 95 of these subjects had annual measurements repeated over a 4 year period. The coefficients of variation for intra-assay replicates was 5%, and for inter-assay comparisons was 17.6% and 26% for tests at a 1 or 3 month interval respectively. For subjects studied at 1 year intervals the coefficient of variation was 42% with the total variability equally distributed between the variation between subjects and the variation within subjects. These data provide the first quantitative data to validate limiting dilution cultures for the long term in vitro measurement of human T cell responses.

Adult↗
PubMed1994

Vaccinating guinea pigs with recombinant glycoprotein D of herpes simplex virus in an efficacious adjuvant formulation elicits protection against vaginal infection.

Guinea pigs were immunized with glycoprotein gD-2t in SAF-m or saline, then challenged with herpes simplex virus, type 2 (HSV-2). Animals given gD-2t in SAF-m had higher anti-gD-2t antibodies, fewer and less severe vaginal lesions, and decreased ganglionic latency compared to animals given gD-2t in saline. Leucocytes from animals vaccinated with gD-2t in SAF-m had greater proliferative responses to gD-2t in vitro than cells from control animals. MHC II-restricted, gD-2t-specific cytotoxic T cells were induced in guinea pigs vaccinated with gD-2t in SAF-m. Thus, immunization of guinea pigs with gD-2t in SAF-m markedly reduced the incidence and severity of primary HSV-2 by eliciting both humoral and cell-mediated responses.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1994

Immune response to secondary immunization with live or inactivated VZV vaccine in elderly adults.

Healthy varicella zoster virus (VZV) immune subjects > 55 years old, were immunized with 4,000 PFU of Oka strain VZV live vaccine or a similar amount of heat-inactivated vaccine. A subset of each group was also immunized with tetanus toxoid (TT) 3 months before receiving the VZV vaccine. The live and inactivated VZV vaccine groups had similar ages, sex distribution, and previous immunity to VZV. The live and inactivated VZV vaccines elicited similar increases in the frequency in blood of VZV-specific T cells, in vitro interferon-gamma production, and serum antibody levels both 3 and 12 months after immunization. Individuals with the highest responder cell frequency (RCF) at entry had the highest postimmunization RCF following either vaccine. There was no correlation at entry between the RCF to TT or RCF to VZV. There was a weak (P = 0.05) correlation in the incremental response to TT and VZV among individuals who responded to both vaccines. Entry variables that did not correlate with the response included percent of T cells or the CD45R0 (memory) T cell subset in blood, serum antibody levels, or amount of interferon-gamma production. The results indicate that the inactivated vaccine is safe for VZV-immune subjects and boosts their antibody and T-cell responses as effectively as the live vaccine for at least 1 year following immunization.

Aged↗
PubMed1994

Immune responses of elderly persons 4 years after receiving a live attenuated varicella vaccine.

Annually, for 4 years after a live attenuated varicella-zoster virus (VZV) vaccine was administered to 202 elderly (55 to > 87 years old) VZV-immune persons, the immune response of vaccinees was evaluated. Anti-VZV antibody levels were enhanced by vaccination for just 1 year. However, VZV-specific proliferating T cells in peripheral blood were increased in frequency from 1 in 68,000 to 1 in 40,000 at 1 year; VZV-responding T cells were still 1 in 51,000 4 years after vaccination. The calculated half-life of this enhanced immunity was 54 months. Age had little effect on response to the vaccine, but larger doses were associated with longer duration of enhanced immunity. Immunity in approximately 10%-15% of vaccinees, independent of dose, failed to increase with the vaccine. This might complicate the use of this vaccine for prevention or attenuation of herpes zoster in the elderly.

Age Factors↗
PubMed1994

Cytokine production in varicella zoster virus-stimulated limiting dilution lymphocyte cultures.

Human blood lymphocytes were stimulated with varicella zoster virus (VZV) antigen in limiting dilution cultures and the amounts of interferon-gamma (IFN-gamma) and IL-4 measured in the supernatants. The results indicate that up to 85% of proliferating cells of young adults produce IFN-gamma and up to 10% make IL-4. At limiting dilution, few if any wells were positive for both IFN-gamma and IL-4. The amount of IFN-gamma per well increased in the presence of antibody to IL-4, but anti-IFN-gamma not increase IL-4 production. The frequency of wells containing IFN-gamma was lower in subjects < 19 or > 55 years of age, and the amounts of IFN-gamma in positive wells was significantly lower in cultures of the older subjects' lymphocytes. The frequency of IL-4-making cells did not fall significantly with age. The data suggest that the age-related decline in the frequency of blood T cells which responds to VZV affects mainly the cells with a Th1-like cytokine phenotype.

Adolescent↗
PubMed1993

Herpes simplex virus interferes with monocyte accessory cell function.

HSV is a successful human pathogen that causes severe infections in immunocompromised adults and newborn humans. The possibility that HSV might evade host immune responses by interfering with accessory cell function was investigated in vitro using newborns' monocytes adhered to plastic. These cells lost their ability to present staphylococcal enterotoxin B to resting T cells in a stimulatory form after overnight culture with HSV. The interference with T cell proliferation required live virus and was abolished by heat- or UV inactivation. The T cell proliferative response was restored by the addition of IL-2. Furthermore, HSV-precultured monocytes had a reduced production of IL-1 alpha and TNF-beta after phorbol-ionomycin stimulation. Wild-type HSV and a HSV mutant lacking the primary virion host shutoff protein both interfered with IL-1 synthesis and presentation of staphylococcal enterotoxin B for T cell proliferation. These results suggest that HSV can interfere with the provision by human monocytes of costimulator factors that are essential for T cell stimulation. This effect of HSV may be due to secondary shutoff mechanisms that decrease host protein synthesis or secretion after HSV infection.

Antigen-Presenting Cells↗
PubMed1993

Prevention of diabetes but not insulitis in NOD mice injected with antibody to CD4.

Non-obese diabetic (NOD) mice were injected with a rat monoclonal antibody to CD4 from birth every two weeks through 6 months of age. These animals gained weight normally but < 11% of their spleen T cells were CD4+, compared with 28% of CD4+ in controls injected with polyclonal rat IgG. The reduction in CD4 cell percentage was associated with a reduction in the number of cells in the thymus and spleen following the injection. CD4+ cells which survived the injections were nevertheless able to enter cell cycle when stimulated by Con A. None of the CD4-treated NOD mice became diabetic by 6 months of age and none of the animals studied histologically at this time had insulitis. At 9 months of age (three months after stopping the CD4 injections) the mice made antibody to human IgG. At 1 year of age most of the male mice had insulitis, although none of the male or female mice had become spontaneously diabetic. Two thirds of animals injected with cyclophosphamide at 16 months became diabetic within 3 weeks. The results confirm that treatment with CD4 antibody in the first 6 months suffices to reduce the incidence of diabetes in NOD mice. The treatment does not prevent the subsequent development of insulitis in injected mice and does not prevent the accumulation of cells capable of causing overt diabetes after cyclophosphamide injection.

Animals↗
PubMed1993

Immune responses to varicella zoster virus infections in healthy children.

The immune responses to varicella zoster virus were studied in 67 otherwise normal children participating in a placebo-controlled trial of acyclovir for the treatment of chickenpox. No differences were observed between acyclovir and placebo groups. Children were studied longitudinally, at onset of chickenpox, and at 1 month, 3 months, 1 year, and 3 years after infection. These data help define the natural history of the immune response to chickenpox in children.

Acyclovir↗
PubMed1993

Degeneration of aortic valve allografts in young recipients.

Aortic allograft fibrocalcification and valvular insufficiency have been observed in patients less than 3 years of age at initial replacement of the left ventricular outflow tract. From June 1985 through May 1992, 47 children have undergone aortic root replacement with cryopreserved aortic valve allografts. Thirty-three children were 3 years of age or older and 14 were less than 3 years of age at operation. In the older patient group, there were three (9%) hospital deaths and one child underwent cardiac transplantation 30 hours after aortic root replacement because of left ventricular failure. Clinical follow-up of the 29 surviving older children is from 4 months to 6.6 years (mean 3.0 years). One patient was lost to follow-up. Two children (7%) have required reoperation, but primary allograft degeneration was not observed. In the younger patient group, there were three (21%) hospital deaths. Follow-up ranged from 2.5 months to 4.7 years (mean 2.3 years). Among 11 operative survivors, one late death resulted from a pulmonary embolus. Seven of 10 (70%) remaining allograft recipients had progressive allograft calcification or insufficiency. Six of them have required reoperation to explant the allograft, and one child is currently receiving cyclosporine therapy with the original valve allograft. The cause of allograft failure is possibly immunologic. The prevalence of early aortic valve allograft degeneration has prompted the consideration of nonviable allografts or xenografts, pulmonary autografts, or minimal immunosuppression as alternatives when left ventricular outflow tract reconstruction is necessary in children less than 3 years of age.

Adolescent↗
PubMed1992

Immune response to split-product influenza vaccine in preterm and full-term young children.

Humoral and cellular immune responses to two doses of influenza antigens were measured in children 6-48 months of age. These vaccinees comprised a previously unimmunized cohort of 18 healthy full-term children and 15 sick preterm children with bronchopulmonary dysplasia and an additional 30 ex-preterm children who were reimmunized. Half of the reimmunized cohort were recovered from bronchopulmonary dysplasia and half had active bronchopulmonary dysplasia. Antibody response was measured by haemagglutination inhibition (HI) and ELISA, and cellular immunity was measured by enumerating memory T cells. Six weeks after immunization, ELISA antibody levels were significantly higher in previously unimmunized full-term vaccinees than in previously unimmunized sick preterm infants (p less than 0.002). No difference was found between sick and recovered reimmunized children. By HI testing greater than 90% of children in both cohorts developed titres greater than or equal to 1:32, and these were generally maintained for at least 20 weeks. T-cell proliferative responses to influenza antigen were greater in the full-term children than in the preterm children (p less than 0.02), irrespective of state of health or prior immunization status. Split-product vaccine was immunogenic in all the cohorts studied; however, factors such as prematurity, health status and previous influenza immunization played important roles in the magnitude of some responses.

Antibodies, Viral↗
PubMed1992

Reduced incidence of insulitis in NOD mice following anti-CD3 injection: requirement for neonatal injection.

The incidence of diabetes in NOD mice is reduced following a single neonatal injection of the anti-CD3 antibody, 145.2C11. We now show that the reduction in incidence is greater when the antibody is given in the first than in the third week of life. Anti-CD3 antibody injected in macro-aggregated form did not protect the recipients from insulitis and protection was diminished when elimination of the antibody was accelerated by injecting anti-hamster IgG. Protection was not reversed when anti-CD3 injection was followed by anti-CD4 and anti-CD8. Animals neonatally injected with anti-CD3 were not protected from the induction of diabetes following transfer of spleen cells from diabetic donors. These results contrast with the view that anti-CD3-mediated protection from diabetes depends on a long-lived change in recipient T cells. The findings are consistent with immunosuppression alone being an adequate explanation for the effect of anti-CD3 antibody on susceptibility to diabetes in NOD mice.

Animals↗
PubMed1992

Immune response of elderly individuals to a live attenuated varicella vaccine.

The Oka strain live attenuated varicella-zoster virus (VZV) vaccine was administered subcutaneously to 202 VZV-immune individuals who were 55 to greater than 87 years old. The dose administered varied from 1100 to 12,000 pfu. One cohort received 3000 pfu with a 3000 pfu booster 3 months later. The vaccine was well tolerated. VZV-specific immunologic responses were evaluated over a 24-month period. The mean anti-VZV antibody level was significantly increased for 12 months after vaccination. Interferon-gamma production in vitro by peripheral blood mononuclear cells (PBMC) of vaccinees was also increased for 6 months after vaccination. Most significantly, VZV-specific proliferating T cells in PBMC of vaccinees were increased in frequency from 1 in 68,000 to 1 in 40,000. This vaccine-enhanced frequency of VZV-responding T cells is similar to the frequency observed in 35- to 40-year-old adults. Dose and age of the vaccinees did not significantly influence the magnitude of the mean cell-mediated immune response. The data indicate that VZV immunity in the elderly can be boosted by active immunization. If the increased incidence of herpes zoster that accompanies aging results from the natural waning of immunity, active immunization may prevent or attenuate zoster in the elderly.

Aged↗
PubMed1992

Specific lysis of targets expressing varicella-zoster virus gpI or gpIV by CD4+ human T-cell clones.

Varicella-zoster virus (VZV)-specific CD4-positive T cells are known to lyse targets expressing VZV antigen, but little is known of the glycoprotein specificity or phenotype of these cells. To test the ability of T cells to distinguish between gpI and gpIV (which share an antibody-defined epitope), we prepared clones from blood from four healthy individuals by limiting dilution. Among 68 T-cell clones from four donors which were VZV specific in tests of proliferation, 30 lysed autologous Epstein-Barr virus-transformed lymphoblasts which had been superinfected with a recombinant vaccinia virus which included the whole VZV gpI sequence. These clones were characterized as major histocompatibility complex class II restricted by inhibition of their cytotoxicity with HLA-DR and CD4 monoclonal antibodies. Twenty-one clones lysed targets expressing gpIV. Fifteen of these clones lysed targets expressing gpI and gpIV. Four clones with gpI-gpIV specificity were examined in detail, and their dual specificity was confirmed by cold target inhibition. These four clones failed to kill target cells infected with a mutant gpIV recombinant vaccinia virus from which amino acid residues 212 to 354 had been deleted. This region includes one of the two gpIV decapeptides which have 50% homology with amino acids 111 to 121 of gpI. Our data confirm that T-cell-receptor-associated structures are required for specific lysis of VZV targets and indicate that (i) gpI-specific CD4 cytotoxic T cells outnumber gpIV-specific T cells in blood and (ii) 50% of gpI-specific T-cell clones also lyse gpIV-expressing targets.

CD4-Positive T-Lymphocytes↗
PubMed1992

Differential response of human thymus cells to CD2 antibodies: fragmentation of DNA of CD45RO+ and proliferation of CD45RO- subsets.

Human thymocytes bearing the CD45RO 'memory' cell phenotype do not proliferate in concanavalin A (Con A)-stimulated cultures and may be destined for intrathymic death. To determine whether this subset would exhibit characteristics of programmed cell death (apoptosis), we examined the integrity of the nuclear DNA by gel electrophoresis. DNA fragmentation was restricted to the CD45RO+ subset of human thymocytes following exposure to stimulating concentrations of anti-CD2 antibodies. Both CD45RO- and CD45RO+ subsets mobilized cytoplasmic Ca2+ following cell-surface CD2 ligation, but entry into the cell cycle and vigorous thymidine uptake were restricted to the CD45RO- subset. Our results provide a mechanism which may account for the failure of thymic CD45RO+ cells to respond to stimuli which elicit proliferation by the reciprocal CD45RA+ subset.

Antigens, CD↗
PubMed1992

Vitamin E supplementation reduces the incidence of diabetes but not insulitis in NOD mice.

The incidence of diabetes was reduced in non-obese diabetic (NOD) mice fed a diet containing 1000 IU/kg of vitamin E. Histologic examination of the islets of these mice, however, disclosed a frequency of insulitis that approximated the frequency found in animals fed conventional diets. The vitamin E-treated mice were not immunosuppressed, as judged by normal T cell subsets in the spleen and normal T cell proliferative responses to concanavalin A. NOD mice deprived of vitamin E were also protected from diabetes. However, these mice had delayed growth, reduced T cell numbers in the spleen, and impaired proliferative responses to mitogens, which is indicative of secondary immunodeficiency. The data are consistent with the view that antioxidant treatment may limit immunologically mediated damage to islet beta cells.

Animals↗