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Biomedical subjects

A R Hayward

Publications and source records attributed to A R Hayward.

At least 19 recordsLinked to original sources
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↗
PubMed1991

Major histocompatibility complex restriction of T-cell responses to varicella-zoster virus in guinea pigs.

Varicella-zoster virus (VZV), adapted to grow in guinea pig fibroblasts, was injected subcutaneously into Hartley, strain 2, and strain 13 guinea pigs. Serum immunoglobulin G antibodies were detected 2 weeks later, and T-cell proliferative responses by blood lymphocytes were found 3 weeks after injection. The proliferating cells bound the 155 antibody, which defines a CD4-like subset of guinea pig T lymphocytes. VZV-infected fibroblasts of human, Hartley, and strain 13 origin elicited equivalent amounts of proliferation, which was quantitatively greater than that obtained with an extracted VZV antigen. Uninfected (control) human or guinea pig fibroblasts did not elicit T-cell proliferation. The proliferative response to VZV required the presence of autologous (strain 2 or 13) antigen-presenting cells and was blocked by the addition of an anti-class II major histocompatibility complex antibody. Effector cells obtained from in vitro cultures mediated class II-restricted cytotoxicity to L2C cells incubated with VZV. Class I-restricted responses were obtained only by cross-priming strain 2 animals with strain 13 peritoneal exudate cells which had been preincubated with VZV. The data indicate that guinea pigs resemble humans in that class II-restricted T cells with specificity for VZV are more readily cultured from blood than are class I-restricted cells.

Animals↗
PubMed1990

T cell proliferative response to interleukin 2: different frequency of responders among CD45R0 and CD45RA subsets.

A proportion of human blood T cells is known to proliferate in cultures containing 10 or more units/ml of interleukin (IL)2, in the absence of exogenously added antigen. A possible explanation for this phenomenon is that the IL2 serves to maintain the proliferation of memory T cells which have recently been activated by antigen in vivo. To test this possibility we therefore separated T cells according to their CD45 (common leukocyte antigen) phenotype into the CD45RO and CD45RA subsets which are associated with memory and naive status, respectively. The frequency of responder cells in limiting dilution analysis of adult MNC was 1:1625 CD45RO cells, 1:2405 for CD45RA cells, and 1:1642 for unseparated cells. CD45RA cells from newborns had a 1:1850 frequency of responders. The IL2 responder cells were predominantly CD3+ TcR alpha beta +, with a minor component of TcR delta cells. There were no differences in the frequency of T cells using V beta 5 and V beta 8 between responding and nonresponding cells. The data argue against a requirement for prior sensitization for a proliferative response to IL2 and give no evidence that the subset of T cells which responds to IL2 differs in phenotype from nonresponsive cells.

Adult↗
PubMed1990

V beta 5 and V beta 8 memory T cells in adults and infancy: co-ordinated increase in response to early antigen stimulus.

Blood mononuclear cells (MNC) expressing the T cell receptor V beta gene families were identified with the monoclonal antibodies 1C1 (V beta 5) or Mx6 (V beta 8). These cells were typed for expression of the T200 common leucocyte antigen with the CD45RA antibody defining the 220-kD variant (which characterizes naive cells) and the UCHL1 antibody which defines the 180-kD variant (characterizing memory cells). Of adult MNC, 3 +/- 0.44% stained for V beta 5 and 4.12 +/- 0.26% stained for V beta 8; similar results were obtained in a group of infants aged less than 3 months, who were exposed to antigen stimulus in the form of infection and/or blood transfusion. While the total percentages of V beta 5 and V beta 8 cells in the blood of adults were not correlated, the proportions of these cells expressing CD45RO was positively correlated. A similar trend which did not reach statistical significance was present in a group of infants. A minority of the infants studied showed transient deviations from the mean established for adults. The results suggest that naive and memory T cell populations have similar frequencies of V beta 5 and V beta 8 expressing cells, and that age does not affect the frequency of usage of either of these V beta families.

Adult↗
PubMed1990

T-cell responses to predicted amphipathic peptides of varicella-zoster virus glycoproteins II and IV.

Four peptides from the predicted amino acid sequences of varicella-zoster virus (VZV) glycoproteins II and IV selected for potential amphipathicity and a terminal lysine residue were synthesized. The peptides elicited weak proliferative responses by T cells with the CD4+ UCHL1+ CD45R- phenotype from the blood of VZV-immune individuals. The frequency of responder cells in individuals with specific response to peptides was 1:80,000 or fewer blood mononuclear cells, and the number of peptides responded to did not correlate with the proliferative response to VZV antigen. Of 40 peptide-specific T-cell clones obtained by limiting dilution, 10 were restimulated by extracted VZV antigen in the presence of autologous antigen-presenting cells. A total of 50% of these clones lysed HLA class II-positive lymphoblasts which had been preincubated with the appropriate peptide, and 2 of 15 cytotoxic clones lysed lymphoblast targets superinfected with VZV. The data indicated that T cells with specificity for putative VZV peptides may readily be cultured from the subset of blood mononuclear cells which bears the phenotype associated with memory.

Adult↗
PubMed1989

Neonatal injection of CD3 antibody into nonobese diabetic mice reduces the incidence of insulitis and diabetes.

Over 80% of nonobese diabetic (NOD) mice develop lymphocytic infiltrates of their pancreatic islets (insulitis) by 6 wk of age and 50% of the females are diabetic by 6 mo of age. The incidence of insulitis in NOD mice injected once as neonates with 250 micrograms of the CD3 antibody, 145.2C11, was 8% at 10 wk of age, increasing to 25% at 32 wk of age. Fewer than 10% of these animals developed diabetes by 8 mo of age. Neonatal administration of 145.2C11 reduced the proliferative responses of spleen cells to mitogen stimulation 2 and 4 wk postinjection and expression of TCR was reduced 1 to 5 wk postinjection. The percentage of CD4 and CD8 cells in the spleen was transiently reduced after injection and the frequency of Pgp-1+-high cells (putative memory cells) was increased 2 to 4 wk postinjection, suggesting that in vivo administration of the antibody caused some T cells to divide as well as transiently reducing T cell numbers. IL-2R expression was not detected on spleen cells in the 4 wk after antibody injection. The phenotypic and functional changes after neonatal CD3 antibody injection resolved by 8 wk of age. The control and injected mice grew normally and made equivalent IgG antibody responses to injected human IgG. Neonatally injected 145.2C11 antibody was cleared from the circulation with a terminal half-life approximating to 21 days but greater than 90% of antigen binding activity was lost 6 days after injection. Protection from diabetes did not follow neonatal elimination of T cells with CD4 and CD8 antibodies, nor the injection of a TCR subset antibody, F23.1. Our data suggest that the neonatal T cell repertoire is open to modulation by a single injection of a CD3 antibody and they offer a new experimental approach to immunotherapy in an animal model of type 1 diabetes.

Animals↗
PubMed1989

Ontogeny of expression of UCHL1 antigen on TcR-1+ (CD4/8) and TcR delta+ T cells.

The frequency of blood mononuclear cells expressing the 180-kDa splice variant of the common leukocyte antigen identified by the UCHL1 monoclonal antibody (a characteristic of post-thymic cells which have been through a cycle of stimulation) rose in a logarithmic relationship to age between birth and 16 years. At birth only a low frequency of CD4+ (negative for CD 25) and no CD8+ T cells expressed UCHL1. The subsequent increase in UCHL1 expression occurred in parallel on T cells expressing alpha/beta receptors and gamma/delta receptors, suggesting that these subsets participated in post-thymic proliferation in proportion to their numbers in blood. The frequency of UCHL1 expression on CD8 cells was 5-15% less than on CD4 cells.

Age Factors↗
PubMed1989

Inhibition of varicella-zoster virus in vitro by human peripheral blood mononuclear cells.

A functional in vitro assay of cell-mediated immunity to varicella-zoster virus (VZV) is described. This procedure uses an enzyme-linked immunosorbent assay (ELISA) to measure the inhibitory effect of human peripheral blood mononuclear cells on VZV antigen production by VZV-infected cell monolayers. When mononuclear cells from VZV-immune, tetanus-immune donors were stimulated with either VZV antigen or tetanus toxoid they reduced VZV antigen production. In contrast, mononuclear cells from VZV-nonimmune, tetanus-immune donors reduced VZV antigen only when stimulated with tetanus toxoid, but not when stimulated with VZV antigen. Cell-free supernatants recovered from the VZV inhibition assays contained the anti-VZV activity. The magnitude of the anti-VZV activity of the supernatants equalled the inhibition observed when the stimulated mononuclear cells were added to the VZV-infected monolayers. Treatment of either mononuclear cells or supernatants with anti-interferon gamma antibody indicated that their VZV inhibitory capability was largely due to the production of interferon gamma by stimulated mononuclear cells.

Adult↗
PubMed1989

A cytotoxic monoclonal islet cell surface antibody from the NOD mouse.

Monoclonal antibody (Mab) 1.93B7 was obtained by fusion of spleen cells from a diabetic NOD mouse with P3X63Ag8.653 myeloma cells and screening for complement mediated lysis of rat insulinoma (RIN) cells. Immunofluorescence studies revealed that this Mab binds to RIN cells but not to the rat pituitary tumour line GH3. The binding of Mab 1.93B7 to RIN cells was abolished by trypsin but not by neuraminidase treatment of the cells, suggesting that the antigen recognized is a protein. Mab 1.93B7 bound to approximately 30% of mouse (BALB/c) and rat islet cells which had been subjected to trypsin digestion and incubated as a single cell suspension for 12h to allow reexpression of trypsin sensitive antigens. Since Mab 1.93B7 is potentially pathogenic, as suggested by its reactivity to primary islet cells and its complement fixing capacity, we injected it into BALB/c and NOD mice. Cytotoxic activity against RIN cells was detected in the serum of the animals injected with Mab 1.93B7, but the Mab did not exert a diabetogenic action and failed to reverse diabetes when administered at onset in NOD mice. No modification of the course of spleen cell mediated transfer of diabetes in NOD mice was observed when the Mab was administered from the time of spleen cell inoculation to the appearance of glycosuria. The implications of the lack of an effect in vivo of Mab 1.93B7 under the conditions employed are discussed.

Animals↗
PubMed1988

Nicotinamide protects target cells from cell-mediated cytolysis.

Nicotinamide in concentrations of 5 mM and greater protected fibroblast target cells from lysis by lymphokine-activated killer cells (LAK cells). Protection was concentration dependent and was exerted at the level of the target cell. Nicotinamide did not interfere with effector-target cell conjugate formation or with the calcium dependent triggering step of the lytic process. Target cell lysis in cultures without nicotinamide was accompanied by fragmentation of target cell DNA. The DNA of target cells cultured with LAK cells in the presence of nicotinamide remained intact. 3-Aminobenzamide which, like nicotinamide, inhibits poly(ADP-ribose) synthetase but is not a precursor of NAD, was an effective inhibitor of target cell lysis while nicotinic acid, an alternative precursor of NAD in cells, was not. The data point to a central role for poly(ADP-ribose) synthetase in the events leading up to DNA fragmentation and the release of 51Cr from target cells damaged by lymphokine-activated killer cells.

Benzamides↗