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T cell-antigen-presenting cell interactions in human systemic lupus erythematosus. Evidence for heterogeneous expression of multiple defects.

Via CS, Tsokos GC, Bermas B, Clerici M, Shearer GM.

Department of Medicine, University of Maryland School of Medicine, Baltimore.

To assess interactions between T cells and APC in patients with SLE, PBL were stimulated in vitro and IL-2 production measured after stimulation with either a MHC-self-restricted Ag (influenza A virus) or an Ag which can use both MHC-self-restricted or unrestricted T cell activation pathways (HLA-alloantigen). SLE patients (n = 26) and controls (n = 8) were categorized as responder (+) or nonresponder (-) for each stimulus and grouped according to their paired response pattern. All controls responded to both influenza virus (Flu) or alloantigen (Allo) and were categorized as +/+. In contrast, SLE patient response patterns were heterogeneous with no evidence for a single SLE-associated defect. Instead, SLE patient responses fell into one of three different patterns: a) normal responses to both Flu and Allo (+/+), observed in nine (35%) patients; b) defective responses to Flu but intact Allo responses (-/+) observed in 12 (46%) SLE patients; and c) defective responses to both Flu and Allo (-/-), observed in five (19%) SLE patients. There was no statistically significant correlation between immune response pattern and the use of immunosuppressants. Further analysis of -/- SLE patients indicated defects in APC function and in both CD4+ and CD8+ T cell function. In contrast, cell depletion and add-back studies in -/+ SLE patients demonstrated defects in APC function only. Thus, similar to the well recognized clinical heterogeneity among SLE patients, our data support the concept that SLE patients are heterogeneous with respect to in vitro T cell-APC function, exhibiting responses ranging from normal function to defects in APC and in both T cell subsets. Prospective studies are in progress to determine the clinical relevance of these observations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8376810&dopt=Abstract flu, flu medicine, tamiflu



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Comparison of rapid diagnostic techniques for respiratory syncytial and influenza A virus respiratory infections in young children.

Dominguez EA, Taber LH, Couch RB.

Department of Microbiology, Baylor College of Medicine, Houston, Texas 77030.

We performed virus isolation tests for respiratory viruses on combined nasal wash-throat swab specimens collected from infants and children with acute respiratory illnesses presenting to a hospital clinic during a 3-month period of concurrent epidemics of respiratory syncytial virus (RSV) and influenza A virus (Flu A) infections. Virus isolation results were used to assess the utility of commercially available rapid diagnostic kits for these two viruses. The kits employed direct immunofluorescence (IF) of cells (Imagen for RSV and Flu A), indirect IF of cells (Baxter Bartels Microscan), and enzyme immunoassay (EIA) (Becton Dickinson Directigen for RSV and Flu A and Abbott TestPack for RSV). All testing was completed on 81 specimens from 80 subjects. Of the 81 specimens, 53 (65%) yielded a virus: RSV, 28%; Flu A, 25%; rhinovirus, 6%; and enterovirus, cytomegalovirus, herpes simplex virus, and adenovirus, 2 to 4% each. Among the tests, Bartels Microscan and Directigen Flu-A exhibited the highest sensitivities (87 and 75%) and efficiencies (94 and 94%) for RSV and Flu A, respectively. All the tests exhibited high specificity. Thus, optimal detection of RSV and Flu A among infants and children who presented to a hospital clinic required two different detection methods (IF and enzyme immunoassay) and kits from two different companies (Baxter [Bartels Microscan] and Becton Dickinson [Directigen]).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8408545&dopt=Abstract flu, flu medicine, tamiflu



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Limiting dilution analysis of interleukin-2-producing T cells responsive to recall and alloantigens in human immunodeficiency virus-infected and uninfected individuals.

Schulick RD, Clerici M, Dolan MJ, Shearer GM.

Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Peripheral blood mononuclear cells (PBMC) from individuals who were seropositive for the human immunodeficiency virus type 1 (HIV), and most without symptoms (HIV+) were compared with PBMC from healthy HIV-seronegative (HIV-) individuals for in vitro generated T helper cell (Th) responses. Th function in bulk culture and limiting dilution analysis was assessed by IL-2 production following stimulation with influenza A virus (FLU) or irradiated allogeneic PBMC (ALLO). We observed that the frequencies of FLU- and ALLO-stimulated Th cells were not appreciably different in the PBMC of HIV- individuals, and that they were also not different in the PBMC of those HIV+ individuals who responded to both FLU and ALLO in bulk culture. However, there was a severe drop in the Th frequency to FLU in HIV+ individuals who were unresponsive to FLU but responsive to ALLO by bulk culture. The PBMC of HIV+ individuals who were unresponsive by bulk culture to both FLU and ALLO exhibited a drastic reduction in the Th frequencies for both stimuli. These results demonstrate a concordance between Th functional analysis performed by limiting dilution and bulk culture. The results also indicate that the early selective loss in Th function to recall antigens is not likely to be due simply to a difference in frequencies of FLU- and ALLO-stimulated Th cells present prior to the onset of Th dysfunction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8436177&dopt=Abstract flu, flu medicine, tamiflu



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Analysis of T helper and antigen-presenting cell functions in cord blood and peripheral blood leukocytes from healthy children of different ages.

Clerici M, DePalma L, Roilides E, Baker R, Shearer GM.

Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

The development of antigen-specific functional T lymphocyte immunity in infants and children is an area of immunology that needs elucidation. Leukocytes from cord blood (CBL) and from PBL of children of different ages who were in the hospital for minor surgical procedures were compared with PBL from healthy adults for their ability to generate T helper cell (Th) responses assessed by in vitro proliferation and IL-2 production after stimulation with: influenza A virus (FLU); tetanus toxoid (TET); adult allogeneic PBL that were either undepleted (ALLO) or depleted of adherent antigen presenting cells (ALLONW); and PHA. CBL generated Th responses to ALLONW, ALLO, and PHA, but not to FLU or TET. PBL from infants between 6 and 13 mo of age responded to ALLO and PHA; none responded to FLU or ALLONW, and two of four responded weakly to TET. PBL from children between 13 and 26 mo of age responded to all stimuli except FLU, to which only one child responded marginally. PBL from children older than 36 mo responded to all stimuli at levels comparable to those of PBL from adults. The use of undepleted and adherent cell-depleted CBL and PBL from children of different ages as allogeneic stimulators of responses generated by PBL from adults indicated that the antigen presenting function of CBL and PBL from children 13 mo or older are sufficiently developed to present alloantigen, whereas PBL from children younger than 13 mo are not. Therefore, our results indicate that age-dependent differences exist in both T helper and antigen-presenting functions of CBL and PBL from children of different ages. Surprisingly, CBL appear to be more efficient in antigen-presenting function than PBL from children younger than 13 mo. These findings are important for establishing developmental parameters of T helper cell immunity relevant for pediatric infection and transplantation in infants and children.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8514891&dopt=Abstract flu, flu medicine, tamiflu



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A factor from CD8 cells of human immunodeficiency virus-infected patients suppresses HLA self-restricted T helper cell responses.

Clerici M, Roilides E, Via CS, Pizzo PA, Shearer GM.

Experimental Immunology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Defective in vitro T helper cell (Th) function can occur in asymptomatic human immunodeficiency virus (HIV)-seropositive (HIV+) individuals. A characteristic, early finding is the loss of an in vitro response to recall antigens, such as influenza A virus (FLU), despite an intact Th response to alloantigen (ALLO). To determine whether suppressor cells and/or inhibitory factors could contribute to this HIV-associated Th immunodeficiency, coculture studies were performed using peripheral blood leukocytes (PBLs) from monozygotic twins, one of whom was HIV-infected (HIV+) and one of whom was uninfected (HIV-seronegative, HIV-). In vitro Th function was measured as interleukin 2 production or proliferation to FLU and ALLO. Two pairs of twins were repetitively studied. A single HIV+ individual with multiple samples of cryopreserved PBLs over 6 years (including a HIV- specimen) was also studied. PBLs from the HIV+, but not from the HIV-, individuals demonstrated defective in vitro Th function in response to FLU but not to ALLO. PBLs from HIV+ individuals could induce a similar defect in the Th function of syngeneic or autologous HIV- PBLs. This suppression was generated by CD4-depleted, but not by CD8-depleted, PBLs. A suppressive factor from CD8+ cells of HIV+ donors was generated by 24-hr unstimulated cultures of HIV+ PBLs. This factor inhibited FLU but not ALLO responses of autologous, syngeneic, or allogeneic HIV- PBLs. This suppressive effect could not be explained by HIV infection or replication during the culture period. These results demonstrate that selective abrogation of Th function to recall antigens in HIV+ individuals is associated with an inhibitory factor produced by CD8+ T cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1388269&dopt=Abstract flu, flu medicine, tamiflu



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Psychology and decision making: modelling health behavior with multiattribute utility theory.

Carter WB.

Department of Health Services, School of Public Health and Community Medicine, University of Washington, Seattle 98195.

The success of much of dental practice is linked to patient behavior. Understanding the issues that influence patients' decisions when they choose to not follow preventive or therapeutic dental recommendations is instrumental to improving adherence, and ultimately, to improving dental health outcomes. Multiattribute Utility Theory (MAU) provides a methodology for systematically exploring these issues. It is based on a well-established body of knowledge in the psychological literature, and currently represents a state-of-the-art model for predicting behavior and delineating potentially modifiable behavioral determinants. Two examples are presented to illustrate how MAU can be used in clinical settings. In the first example, MAU is used to identify key reasons why nearly 70 percent high-risk patients did not obtain flu shots, a behavioral problem comparable to many confronted in dentistry. MAU correctly predicted the vaccination behavior of 82 percent of patients, and an intervention based on MAU findings nearly doubled vaccination rates. The second example used MAU to identify physician behaviors that influenced patients' satisfaction with an ambulatory care visit. MAU findings from this study identified specific behaviors in a provider's style that if modified may improve patient satisfaction. These MAU applications also emphasize the importance of soliciting the patient's perspective in clinical interactions since some of the most important determinants of patient behavior are not represented in traditional clinical decision models.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1487582&dopt=Abstract flu, flu medicine, tamiflu