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T Doan

Publications and source records attributed to T Doan.

12 recordsLinked to original sources
PubMed1999

Differences in the effectiveness of delivery of B- and CTL-epitopes incorporated into the hepatitis B core antigen (HBcAg) c/e1-region.

Work from a number of laboratories including our own has shown that foreign B-epitopes inserted into the c/e1-region of Hepatitis B core antigen (HBcAg) elicit powerful antibody responses when mice are immunised with the recombinant core particles. In the present study, we wished to take advantage of the immunodominance of the c/e1-region to deliver cytotoxic T-lymphocyte (CTL) epitopes as a recombinant HBcAg vaccine. Our results indicated that recombinant HBcAg containing CTL epitopes of the E7 protein of human papillomavirus failed to prime E7-directed CTL responses when used to immunise mice for antigen processing through either the endogenous pathway via a Salmonella typhimurium vector, or through the exogenous pathway by parenteral immunisation with recombinant core. Hydropathicity plots predict that the presumed surface location of the hydrophilic c/e1-region within the core particle may alter following insertion of hydrophobic residues constituting the CTL epitopes, thereby compromising their presentation to the afferent immune system. Our data indicate that while the c/e1-region has a powerful adjuvanting effect for inserted B-epitopes, it does not serve this function for inserted CTL epitopes. These findings have generic implications for the development of CTL inducing vaccines using HBcAg as a vaccine vehicle.

Amino Acid Sequence↗
PubMed1999

Human papillomavirus type 16 E7 oncoprotein expressed in peripheral epithelium tolerizes E7-directed cytotoxic T-lymphocyte precursors restricted through human (and mouse) major histocompatibility complex class I alleles.

Mice which coexpress human papillomavirus type 16 E7 and HLA A2.1 in peripheral squamous epithelium and thymic cortical epithelium are tolerant at the cytotoxic T-lymphocyte (CTL) level to E7 epitopes restricted through HLA A*0201 and H-2(b) (T. Doan, M. Chambers, M. Street, G. J. Fernando, K. Herd, P. Lambert, and R. Tindle, Virology 244:352-364, 1998). Here we used bone marrow-reconstituted radiation chimeras to distinguish whether E7-directed CTL tolerance was mediated peripherally by E7 expression in skin or centrally by E7 expression in thymus. In chimeric mice expressing E7 in skin and reconstituted with E7-naïve bone marrow and E7-naïve thymus, CTL responses to vaccine-administered E7 epitopes were not restored, i.e. , the mice remained tolerant. In contrast, chimeric mice not expressing E7 in skin and reconstituted with E7-naïve bone marrow and E7-expressing thymus had full E7-directed CTL responses. These results demonstrate that E7 protein expression in peripheral squamous epithelium is sufficient to tolerize the E7-directed CTL precursor repertoire. The data have implications for E7-mediated tumorigenesis and for the development of E7-based immunotherapeutic strategies, since peripheral immunological tolerance of tumor-associated antigens may create a barrier to effective immunotherapy.

Animals↗
PubMed1998

Presenilin-1 mutations associated with familial Alzheimer's disease do not disrupt protein transport from the endoplasmic reticulum to the Golgi apparatus.

Mutations in genes encoding presenilin-1 (PS1) and presenilin-2 (PS2) have been linked to familial forms of Alzheimer's disease (AD). Cells expressing mutant presenilins produce elevated levels of Abeta42, the major amyloid peptide found in AD plaques. The mechanism whereby this occurs remains unknown, but the localization of presenilins to endoplasmic reticulum (ER) and Golgi compartments has suggested that they may function in intracellular trafficking pathways involved in processing beta-amyloid precursor proteins (APP). To test this possibility, we coexpressed PS1(wt), PS1(M146L), or PS1(L286V) in HEK293 cells together with the LDL receptor, a classic glycoprotein marker that undergoes post-translational O-glycosylation in the Golgi compartment. Pulse-chase analysis of the receptor indicated that mutant presenilins had no effect on ER-->Golgi transport. Similar results were obtained when the studies were carried out with cells expressing the Swedish variant of APP (SWAPP751) instead of the LDL receptor. Moreover, secretion of the soluble exodomain polypeptide fragments of SWAPP751 that arise from alpha-secretase and beta-secretase cleavage was not markedly affected by the PS1 mutants. Despite the lack of discernible effect of the PS1 mutants on trafficking of proteins through the Golgi apparatus, they caused a substantial increase in the proportion of Abeta42 relative to total Abeta in the culture medium. The results suggest that mutant forms of PS1 cause elevated production of Abeta42 by a mechanism that is independent of a major disruption of exocytic trafficking of APP.

Alzheimer Disease↗
PubMed1998

Mice expressing the E7 oncogene of HPV16 in epithelium show central tolerance, and evidence of peripheral anergising tolerance, to E7-encoded cytotoxic T-lymphocyte epitopes.

In order to derive mice which expressed both the E7 open reading frame transgene of human papillomavirus type 16 in skin and MHC class 1 restriction elements for several E7-encoded cytotoxic T-lymphocyte (CTL) epitopes, K14.HPV16E7 mice which express E7 in basal keratinocytes were crossed to the F1 generation with A2.1 Kb transgenic mice which express the MHC binding cleft domains of human HLA A*0201, and murine H-2b. F1 mice (denoted K14E7 x A2.1) expressed E7 in the thymus at least as early as 2-5 days before birth. Immunisation of FVB x A2.1 control mice (transgenic for HLA A*0201 and H-2b but not for E7), with two HLA A*0201-restricted epitopes of E7 and one H-2b-restricted CTL epitope of E7, gave strong primary CTL responses recognising epitope-pulsed or constitutively E7-expressing syngeneic target cells. In contrast, in immunised K14E7 x A2.1 mice, the CTL responses to the H-2b epitope and one of the HLA A*0201 CTL epitopes were strongly down-regulated, and to the other HLA A*0201 epitope, completely abolished, as demonstrated by percentage specific killing by bulk splenocyte cultures in cytotoxicity assays, and by CTL precursor frequency analysis. In thymus-transplanted bone marrow radiation chimeras in which the immune system of K14E7 x A2.1 mice was replaced by a FVB x A2.1 immune system, specific immunisation did not result in reemergence of strong E7-directed CTL responses. In agreement with these in vitro findings, specific immunisation failed to significantly alter the course of E7-associated tumour development in K14E7 x A2.1 mice. These data are consistent with a model of central deletional CTL tolerance to E7-encoded epitopes recognised in the context of two distinct MHC class 1 restriction elements, and with the possibility of peripheral T-cell anergy maintained by expression of E7 in the skin.

Amino Acid Sequence↗
PubMed1996

An intervention program to reduce the hospitalization cost of asthmatic patients requiring intubation.

BACKGROUND: Asthma is the single disease that accounts for the largest proportion of total health care cost in the US. OBJECTIVE: To analyze whether an asthma management program affected the cost of subsequent asthma care for patients in whom intubation had been necessary. METHODS: We evaluated patients with asthma who (1) had required intubation for treatment of status asthmaticus; (2) were 45 years old or younger; (3) had regular follow-up visits in our clinic for 1 year after initial evaluation; and (4) had complete medical records 1 year before and 1 year after the intervention for our evaluation. Medical costs of asthma treatment for each patient were determined for 1 year before and 1 year after intervention. The program included patient education, regular outpatient visits, specialist care, and access to the Allergy Immunology emergency call service. The outcome measures were the total cost of care, inpatient hospitalizations, outpatient services, emergency services, and medicine costs. RESULTS: Nine patients [mean age 19.6 years (SD = 9.9)] fulfilled the criteria (six women and three men). The mean duration of asthma was 14.0 years (SD = 9.7). The mean total cost of care decreased from $43,066 to $4,914 (t = -4.53, P < .001) and inpatient hospitalization costs decreased from $40,253 to $1,926 (t = -4.50, P <.001). There was, however, no significant difference in the mean pre-intervention versus post-intervention cost of emergency services, outpatient services, or medicine costs. CONCLUSIONS: The intervention--which included education, specialist care, regular outpatient visits, and access to an emergency call service--significantly reduced the cost of asthma care in our population of patients intubated for asthma.

Adolescent↗
PubMed1994

Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: experience with 41 cases and a hypothesis regarding pathogenesis.

Evaluation of therapy for Stevens-Johnson syndrome was initiated as a retrospective analysis and then extended to a prospective series of patients treated with corticosteroids. This report extends the initial prospective study of patients with Stevens-Johnson syndrome treated with corticosteroids and evaluates the total series of 41 patients relative to outcome and the presumptive etiology. We propose that management of Stevens-Johnson syndrome requires corticosteroid therapy and that the survival of patients with Stevens-Johnson syndrome may depend on this therapy. No fatalities or adverse effects due to corticosteroids were noted. Stevens-Johnson syndrome due to a drug, a drug metabolite or viral infection may mimic a graft-versus-host reaction in which the patient rejects skin, mucous membrane, kidney or liver cells to which the drug, drug metabolite, or virus has bound. Corticosteroids suppress the inflammatory rejection until the activating agent has been eliminated.

Adolescent↗
PubMed1992

Cough variant asthma: usefulness of a diagnostic-therapeutic trial with prednisone.

Cough variant asthma is characterized as a persistent, nonproductive cough with minimal or no wheezing and dyspnea. The diagnosis can be overlooked or misdisagnosed. We describe the severity of cough, the misery of some patients who have this syndrome and the usefulness of a diagnostic-therapeutic trial in ten patients with cough variant asthma. We evaluated ten patients whose chief complaint was persistent nonproductive cough. During the course of evaluation, all patients received a diagnostic-therapeutic trial of prednisone for cough variant asthma after other major causes of cough had been excluded. The duration of cough ranged from 2 months to 20 years. Some patients had significant side effects from coughing including interference with social life, work and sleep, urinary incontinence, stool incontinence, hoarseness, and vomiting. After a diagnostic-therapeutic trial with prednisone, nine patients reported significant improvement of cough in three days. One patient required 2 weeks of therapy for optimal improvement. All were subsequently controlled primarily with inhaled conticosteroids. The diagnosis of cough variant asthma may not be made for a prolonged time. A short course of prednisone as a diagnostic-therapeutic trial can establish a diagnosis and be followed by an effective method of control of cough by inhaled corticosteroids.

Adolescent↗
PubMed1988

The Abbott IMx automated benchtop immunochemistry analyzer system.

We describe a new clinical laboratory instrument, the IMx, used to automate immunoassay testing in the clinical laboratory. The IMx incorporates a novel technology called Microparticle capture Enzyme ImmunoAssay (MEIA) for assays of high-molecular-mass analytes, and fluorescence polarization immunoassay (FPIA) for hapten assays. A front-surface fluorometer is used to quantify the enzymatic generation of fluorescent product at a rate proportional to the concentration of the analyte in an MEIA, and a fluorescence polarization optical system is used to quantify results in an FPIA. The microprocessor-based instrument uses a robotic arm with two degrees of freedom and a rotating carousel to process the samples for assay. One assay can be done on each of 24 patients' specimens in 30 to 40 min with "walk-away" automation. Calibration curves are stable for at least two weeks. Instrument control involves software-labeled "command keys," a numeric keypad, and an interactive display. Results are output to a thermal printer or computer interface.

Autoanalysis↗
PubMed1982

Maternal, fetal, and neonatal responses after epidural anesthesia with bupivacaine, 2-chloroprocaine, or lidocaine.

The effects of epidural analgesia on fetal heart rate, fetal heart rate variability, uterine activity, maternal blood pressure, newborn Apgar scores, neonatal acid base status, and the early neonatal neurobehavioral status were studied in 150 parturients during labor and delivery. Group I (n = 50) received 0.5% bupivacaine, group II (n = 50) received 2% 2-chloroprocaine, and in group III (n = 50) received 1.5% lidocaine. None of the three local anesthetics used had any significant effect on either base line fetal heart rate, beat-to-beat variability, or uterine activity. In cases in which monitoring of fetal heart rate was both technically satisfactory and continuous, late deceleration patterns were seen in 8 of 42, 0 of 34, and 3 of 47 of the fetuses in group I, II, and III, respectively. The difference in incidence of late deceleration patterns between groups I and II was statistically significant (p less than 0.025). Early neonatal neurobehavioral status did not differ among the three groups of neonates nor did any of the neonates in the three groups score lower than a control group of 20 neonates whose mothers did not receive any analgesia or medications for labor or delivery. It is concluded that epidural anesthesia as administered in this study has no significant effect on the base line fetal heart rate, uterine activity, or neurobehavioral status of the neonate, and that bupivacaine is associated with a higher incidence of what appears to be transient abnormalities of fetal heart rate.

Adolescent↗
PubMedDate not supplied

Sinusitis.

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Humans↗