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J L Fahey

Publications and source records attributed to J L Fahey.

At least 19 recordsLinked to original sources
PubMed2001

Impaired response to HAART in HIV-infected individuals with high autonomic nervous system activity.

Neurotransmitters can accelerate HIV-1 replication in vitro, leading us to examine whether differences in autonomic nervous system (ANS) activity might promote residual HIV-1 replication in patients treated with highly active antiretroviral therapy. Patients who showed constitutively high levels of ANS activity before highly active antiretroviral therapy experienced poorer suppression of plasma viral load and poorer CD4(+) T cell recovery over 3-11 months of therapy. ANS activity was not related to demographic or behavioral characteristics that might influence pathogenesis. However, the ANS neurotransmitter norepinephrine enhanced replication of both CCR5- and CXCR4-tropic strains of HIV-1 in vitro via chemokine receptor up-regulation and enhanced viral gene expression, suggesting that neural activity may directly promote residual viral replication.

Adult↗
PubMed2001

Idiopathic CD4+ T cell lymphocytopenia evolving to monoclonal immunoglobulins and progressive renal damage responsive to IL-2 therapy.

Idiopathic CD4+ T cell lymphocytopenia was unexpectedly detected in a 33-year-old, otherwise healthy young woman with no HIV or other viral infection, autoimmune, or neoplastic disease or increased susceptibility to infection. CD4+ T cell levels were 60-140/microl over a 3.5-year period. Following an uneventful pregnancy, the patient developed anemia and interstitial nephritis associated with a plasma cell dyscrasia with a monoclonal IgA gammopathy and a shifting immunoglobulin pattern that included IgG and IgA monoclonal proteins and increased urinary light chains. Osteolytic lesions were never detected and bone marrow aspirations revealed up to 10% atypical plasma cells. Various therapies often used in treating multiple myeloma only temporarily controlled the increasing renal damage. IL-2 therapy of 600,000 to 1 million units subcutaneously daily resulted in increased CD4+ T cells to normal levels, a decrease in the gammopathy, a return of renal function, energy, and weight gain, and apparently normal health status sustained for 2 years. The findings are compatible with a potentially fatal but nonmalignant immunoregulatory disorder that can be controlled by IL-2 administration.

Adult↗
PubMed2000

Thalidomide in low intermittent doses does not prevent recurrence of human immunodeficiency virus-associated aphthous ulcers.

A multicenter, double-blind, randomized, placebo-controlled study was conducted to determine the safety and efficacy of thalidomide in reduced, intermittent doses for preventing recurrences of oral and esophageal aphthous ulcers in patients with human immunodeficiency virus (HIV) infection. Forty-nine HIV-infected patients whose ulcers previously had healed as a result of thalidomide therapy were randomly assigned to receive either 100 mg of oral thalidomide or placebo 3 times per week for 6 months. Ulcers recurred in 14 (61%) of 23 thalidomide-randomized patients, compared with 11 (42%) of 26 placebo-randomized patients, with no significant difference in the median time to recurrence of ulcers (P=.221). There were no changes in plasma levels of HIV RNA, tumor necrosis factor (TNF)-alpha, and soluble TNF receptor II at the time of ulcer recurrence. Adverse events among patients treated with thalidomide included neutropenia (5 patients), rash (5 patients), and peripheral sensory neuropathy (3 patients). Thalidomide in lower intermittent doses is ineffective at preventing recurrence of aphthous ulcers in HIV-infected persons.

Anti-HIV Agents↗
PubMed2000

Distinct categories of immunologic changes in frail elderly.

Immune changes and their relationships in a frail elderly population (N=116, age 70-103, median 86 years) were defined in comparison to a healthy younger group. Previous immune studies in the elderly have generally focused on one or few parameters without correlation analyses. Furthermore, the study populations have been active elderly in relatively small numbers. A total of 33 immune parameters representing many aspects of the immune system were quantified. Most changes in the frail elderly were parallel to those reported in active elderly. A classification tree analysis revealed that increased plasma activation markers (neopterin and sTNF-R) and increased CD28 expression on CD8 T cells and proliferative response separated the aged and control populations. Statistical procedures utilizing principal components analyses, partial correlations and exploratory factor analyses all indicated that immunologic parameters in frail elderly are grouped in three major clusters of immunologic results. These involved (a) increased plasma levels of neopterin and sTNF receptor indicating elevated IFNgamma and TNF cytokine activity; (b) increased proportion of mature (CD45RO) versus naïve (CD45RA) T cells; and (c) a diverse group of related changes including impaired proliferative response, reduced T cells, CD28 and CD25 expression, B cell percentage and lower CD4:CD8 ratios and increased HLA-DR expression. These findings emphasize that several different groups of immune parameters but not 33 independent immune changes, occurred in the aged population.

ADP-ribosyl Cyclase↗
PubMed2000

Increased natural killer-cell mobilization and cytotoxicity during marital conflict.

Natural killer (NK) cells are reproducibly mobilized into the circulation in response to intense physical exercise or acute psychological stress, and altered expression of adhesion molecules potentially contributes to NK-cell mobilization. Studies of leukocyte mobilization during acute stress have used psychological stressors which facilitate tight experimental control but have limited applicability to everyday life. We therefore used a laboratory model of marital conflict as an experientially meaningful acute stressor to elucidate relationships among conflict, cardiovascular reactivity, and altered leukocyte phenotype and function. Forty-one ethnically diverse, nondistressed, healthy married couples were asked to discuss a specific problem in their marriage for 15 min. Blood pressure and heart rate were measured before, during, and after the discussion, and blood was remotely drawn at the same time points to quantify numbers of specific leukocyte subsets, NK-cell adhesion molecule expression, and NK cytotoxicity. Couples responded to the conflict task with cardiovascular reactivity; increases in the percentages of circulating NK cells and CD8(+) T cells and decreases in the percentage of circulating CD4(+) T cells; decreases in the percentage of NK cells that express L-selectin; and increases in NK-cell cytotoxicity without a commensurate increase in per-cell cytotoxicity. Rapid downregulation or shedding of L-selectin (CD62L) from NK cells did not contribute to their mobilization during conflict. Instead, CD62L(-) NK cells were mobilized while CD62L(+) NK cells were selectively retained in the vascular marginating pool and/or in extravascular tissue. From a broader perspective, the data support the hypothesis that altered trafficking of specific leukocyte subsets is an integral component of the fight-or-flight response to an acute stressor.

Adult↗
PubMed2000

Need for an external proficiency testing program for cytokines, chemokines, and plasma markers of immune activation.

An external evaluation program for measuring the performance of laboratories testing for cytokines and immune activation markers in biological fluids was developed. Cytokines, chemokines, soluble cytokine receptors, and other soluble markers of immune activation (CSM) were measured in plasma from a healthy human immunodeficiency virus (HIV)-seronegative reference population and from HIV-seropositive individuals as well as in supernatant fluids from in vitro-stimulated human immune cells. The 14 components measured were tumor necrosis factor (TNF) alpha, gamma interferon, interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, Rantes, MIP-Ia, MIP-Ibeta, soluble TNF receptor II, soluble IL-2 receptor alpha, beta(2)-microglobulin, and neopterin. Twelve laboratories associated with the Adult and Pediatric AIDS Clinical Trial Groups participated in the study. The performance features that were evaluated included intralaboratory variability, interlaboratory variability, comparison of reagent sources, and ability to detect CSM in the plasma of normal subjects as well as the changes occurring in disease. The principal findings were as follows: (i) on initial testing, i.e., before participating in the program, laboratories frequently differed markedly in their analytic results; (ii) the quality of testing of a CSM in individual participating laboratories could be assessed; (iii) most commercial kits allowed distinction between normal and abnormal plasma CSM levels and between supernatants of stimulated and unstimulated cells; (iv) different sources of reagents and reference standards frequently provided different absolute values; (v) inexperienced laboratories can benefit from participating in the program; (vi) laboratory performance improved during active participation in the program; and (vii) comparability between analyses conducted at different sites can be ensured by an external proficiency testing program.

Adult↗
PubMed2000

Cytokine gene expression occurs more rapidly in stimulated peripheral blood mononuclear cells from human immunodeficiency virus-infected persons.

Evaluation of cytokine gene expression following in vitro stimulation is one means of examining the dysregulation of the immune system in human immunodeficiency virus (HIV) infection. We have assessed differences in the immune status of non-HIV-infected (HIV-) and HIV-infected (HIV+) individuals by evaluating the kinetics of the expression of cytokine genes. We compared detailed time courses of cytokine mRNA expression in HIV- and HIV+ peripheral blood mononuclear cells (PBMC) and found that there is a significant shift (P<0.01) for all cytokines examined (interleukin 2 [IL-2], IL-6, IL-10, gamma interferon, and tumor necrosis factor alpha [TNF-alpha]) to an earlier time of mean peak mRNA expression by HIV+ PBMC (between 4 and 8 h) compared to HIV- PBMC (8 h) in response to either phytohemagglutinin (PHA) or anti-CD3 stimulation. Additional studies showed that although PHA-stimulated HIV+ PBMC showed decreased median IL-2, IL-4, and TNF-alpha mRNA levels, they typically demonstrated more rapid kinetics (increased mean 4-h/24-h cytokine mRNA ratios), with significant differences for IL-4 (P<0.05) and TNF-alpha (P<0.005), compared to HIV- PBMC. The use of fresh or frozen cells gave comparable cytokine mRNA data; however, the secretion of some cytokine proteins (IL-2 receptor, IL-10, and TNF-alpha) appeared to be reduced in HIV+ PBMC that had been frozen and thawed. Our studies demonstrate that the kinetics of cytokine gene expression can reveal additional dysregulation of the immune system in HIV infection, suggesting that PBMC of HIV-infected persons exist in an activated state in vivo that permits them to express cytokine genes more rapidly than a normal PBMC.

Cells, Cultured↗
PubMed1999

Worry affects the immune response to phobic fear.

Worry, the cognitive enumeration and anticipation of potential future negative events, is associated with autonomic dysregulation, which may in turn have implications for the immune system. People endorsing high (n = 7) and normal levels of trait worry (n = 8) were briefly exposed to a phobic stimulus and the autonomic and immune responses and recovery were assessed. A time-matched control group (n = 6) was not exposed to any stimulus. Both worry groups showed increased heart rate and skin conductance in response to phobic fear. However, only the normal worry group showed a concomitant increase in natural killer cells in peripheral blood. Patterns of change during the follow-up period suggested that phobic fear had disrupted a normal circadian increase in natural killer cells. Adrenergic and hypothalamus-pituitary-adrenal mechanisms may be responsible for the differences between high and normal worry groups in their natural killer cell response to and recovery from phobic fear.

Adult↗
PubMed1999

The prognostic significance in HIV infection of immune activation represented by cell surface antigen and plasma activation marker changes.

One hundred and eighteen HIV-infected homosexual men without AIDS and 40 control seronegative homosexual men were assessed for 23 parameters reflecting immune activation to determine prognostic significance for occurrence of AIDS. Samples cryopreserved in 1987-1989 were analyzed, with AIDS occurrence determined by mid-1992. Cell surface antigens assessed on the major lymphocyte subsets were HLA-DR, CD38, CD71, and CD25. Soluble serum molecules assessed were tumor necrosis factor alpha, soluble TNFalpha receptor II, soluble IL-2 receptor alpha, neopterin, and beta2-microglobulin. Using a proportional hazards model, prognostic markers included decreased CD4 number and percentage; increased sIL-2R, neopterin, and beta2M; increased percentage HLA-DR+ total lymphocytes and CD4+ cells; increased CD38+ total lymphocytes and CD8+ cells; increased CD71+ total lymphocytes and CD4+ cells; and decreased CD25+ total lymphocytes and CD19+ cells. After adjustment for CD4 cell levels, sIL-2R, neopterin, beta2M, and CD25+ CD19 cells remained significant, indicating that additional information about AIDS risk was provided by these markers.

ADP-ribosyl Cyclase↗
PubMed1999

Phenotypic and functional characteristics of circulating monocytes of elderly persons.

Aging is associated with impairment of immune functions. Age-dependent alterations in T-cells are well known. Although the pivotal role of monocytes in immune regulation by their production of proinflammatory and inhibitory cytokines is acknowledged, limited information is available on monocyte changes in aging. The present study focused on phenotypic changes in circulating monocytes in elderly subjects and in the level of cytokines they produce. The results demonstrated a significant expansion of CD14dim/CD16bright circulating monocytes in elderly. In contrast, the majority of circulating monocytes of healthy young individuals were CD14bright/CD16dim. The CD14dim/CD16bright monocytes are considered to have phenotypic evidence for activation. Furthermore, significant increases of constitutive production of monocytic cytokines including interleukin (IL)-1beta. IL-1 receptor antagonist, and IL-6 by nonstimulated monocytes from elderly was also indicative of activation. This was also observed when monocytes from elderly were cultured with autologous lymphocytes. However, after stimulation, significantly lowered IL-1beta production was observed and IL-6 and IL-10 tended to be higher in the elderly. Collectively, these results indicate that monocytes of aged individuals, in contrast to a younger population exhibit in vivo activation as well as imbalanced production of cytokines. Such age-related alterations in monocytes may contribute to impaired immune competence of aging.

Adult↗
PubMed1999

Psychosocial predictors of natural killer cell mobilization during marital conflict.

This study examined how specific emotions relate to autonomic nervous and immune system parameters and whether cynical hostility moderates this relationship. Forty-one married couples participated in a 15-min discussion about a marital problem. Observers recorded spouses' emotional expressions during the discussion, and cardiovascular, neuroendocrine, and immunologic parameters were assessed throughout the laboratory session. Among men high in cynical hostility, anger displayed during the conflict was associated with greater elevations in systolic and diastolic blood pressure, cortisol, and increases in natural killer cell numbers and cytotoxicity. Among men low in cynical hostility, anger was associated with smaller increases in heart rate and natural killer cell cytotoxicity. These findings suggest that models describing the impact of stress on physiology should be refined to reflect the joint contribution of situational and dispositional variables.

Adult↗
PubMed1999

Stability of plasma levels of cytokines and soluble activation markers in patients with human immunodeficiency virus infection.

Cytokine and immune activation marker levels in plasma are valuable measurements of immune status and treatment effects in human immunodeficiency virus (HIV) infection and AIDS. Five populations representing various stages of disease were studied: controls, 2 AIDS groups with <50/mm3 CD4 cells, and 2 groups of HIV-positive subjects-1 with stable CD4 T cells (median, 545/mm3) and 1 with >100/mm3 CD4 cell decline in 1 year. Relatively stable levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor (R)II, soluble interleukin-2R, neopterin, and beta2-microglobulin (beta2M) were documented over 5-8 weeks in patients with AIDS and for 1-4 years in the other groups. beta2M was generally the most stable marker. Interferon-gamma levels, however, fluctuated substantially. Individuals, whether normal or HIV-positive, maintain characteristic plasma levels of cytokines and immune activation markers. Thus, documented changes, in excess of the variability observed in this study, are likely to be significant indicators of change in disease status or effects of therapy.

Adult↗
PubMed1999

Thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group.

A multicenter, double-blind, randomized, placebo-controlled clinical trial was conducted to determine the safety and efficacy of thalidomide for treating esophageal aphthous ulceration in persons infected with human immunodeficiency virus (HIV). Twenty-four HIV-infected patients with biopsy-confirmed aphthous ulceration of the esophagus were randomly assigned to receive either oral thalidomide, 200 mg/day, or oral placebo daily for 4 weeks. Eight (73%) of 11 patients randomized to receive thalidomide had complete healing of aphthous ulcers at the 4-week endoscopic evaluation, compared with 3 (23%) of 13 placebo-randomized patients (odds ratio, 13.82; 95% confidence interval, 1.16-823.75; P=.033). Odynophagia and impaired eating ability caused by esophageal aphthae were improved markedly by thalidomide treatment. Adverse events among patients receiving thalidomide included somnolence (4 patients), rash (2 patients), and peripheral sensory neuropathy (3 patients). Thalidomide is effective in healing aphthous ulceration of the esophagus in patients infected with HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Variables that affect assays for plasma cytokines and soluble activation markers.

Cytokines and soluble immune activation markers that reflect cytokine activities in vivo are increasingly being measured in plasma, serum, and other body fluids. They provide useful diagnostic and prognostic information as well as insight into disease pathogenesis. Assays of neopterin, beta2-microglobulin, soluble interleukin-2 receptor, and soluble tumor necrosis factor receptor type II as well as of the cytokines tumor necrosis factor alpha and gamma interferon (IFN-gamma) were evaluated by using serum and plasma samples of human immunodeficiency virus (HIV)-positive and HIV-negative subjects. Many factors were found to influence the outcomes of these assays. Substantial differences in apparent levels of analytes were frequently found when enzyme-linked immunosorbent assay (ELISA) kits from different manufacturers were used. In some cases, differences were found in the standards provided by separate manufacturers. Furthermore, the analytic results from different lots of ELISA kits supplied by single manufacturers differed by as much as 50%. The need for uniformity in the standards for quantitative assays was clearly illustrated. International reference standards are available for cytokines but not for soluble cytokine receptors or soluble activation markers. Marker levels in serum or in plasma were similar except those for IFN-gamma. Most of the analytes were stable under several storage conditions. Thus, batch testing of frozen stored samples is feasible. The findings indicate that for longitudinal studies, the levels of cytokines and immune activation markers in plasma or serum should be measured by using preverified reagents from one manufacturer. The quality of laboratory performance can have an impact on clinical relevance. Proficiency testing and external quality assurance programs can help to develop the needed consensus.

Antigens, CD↗
PubMed1998

Prognostic significance of plasma markers of immune activation, HIV viral load and CD4 T-cell measurements.

OBJECTIVE: To evaluate the prognostic significance for AIDS occurrence of plasma levels of immune activation markers in comparison with and in conjunction with HIV viral load and CD4 T-cell measurements. DESIGN: A retrospective analysis was conducted of three plasma activation markers, the soluble tumor necrosis factor (TNF) receptor II (TNF-RII), neopterin and soluble interleukin-2 receptor levels, and of CD4 T-cell levels and plasma HIV viral load. SUBJECTS: The participants were 659 men taking part in the University of California Los Angeles Multicenter AIDS Cohort Study who were HIV-seropositive but AIDS-free in 1985. MAIN OUTCOME MEASURE: Clinically defined AIDS within 3 years. Failure time statistical regression models for the time to development of AIDS were used to assess prognostic capacity of the parameters alone and in combination. RESULTS: All the markers had prognostic capability. The levels of the three plasma activation markers correlated well with each other (median r = 0.61). They related less well with HIV RNA plasma levels (median r = 0.50) and least well with CD4 cell levels (median r = 0.36). Furthermore, plasma marker levels were shown to be able to stratify patients for prognosis within all the major categories of CD4 T-cell and HIV RNA levels. CONCLUSIONS: Plasma levels of soluble TNF-RII and other soluble markers of immune activation have prognostic capabilities which are different from HIV and CD4 T-cell levels. Combination of a single plasma activation marker measurement (such as soluble TNF-RII) with CD4 T-cell levels improved the prognostic capability of each. A new graphic technique for presenting prognostic capability indicated that plasma soluble TNF-RII and CD4 cell levels are better prognostic factors than HIV plasma level with CD4 cells < 200 x 10(6)/l. Inexpensive tests for one of the plasma activation markers, such as soluble TNF-RII or neopterin, can be useful for evaluations of HIV disease course, especially when expensive equipment, technical expertise and funding required for flow cytometry and for HIV load measurements are not readily available.

Antigens, CD↗
PubMed1998

Norepinephrine accelerates HIV replication via protein kinase A-dependent effects on cytokine production.

To explore the role of sympathetic nervous system activation in HIV pathogenesis, we examined the effect of the neuroeffector molecule norepinephrine (NE) on HIV-1 replication in quiescently infected PBMCs that were subsequently activated with Abs to CD3 and CD28. NE accelerated HIV-1 replication at concentrations ranging from 10(-8) to 10(-5) M. This effect could be mimicked by protein kinase A (PKA) activators (forskolin or dibutyryl-cAMP) and abrogated by beta-adrenoreceptor antagonists or the PKA inhibitor rp-cAMP, indicating transduction via the adrenoreceptor signaling pathway. NE reduced cellular activation and altered the production of several HIV-modulating cytokines: IL-10 and IFN-gamma were markedly suppressed; TNF-alpha, IL-1beta, IL-2, IL-4, and IL-6 were mildly suppressed; and levels of IL-12 were not significantly altered. The addition of either exogenous IFN-gamma or IL-10 abrogated the effect of NE on virus production. Thus PKA-dependent suppression of cytokine production appears to mediate the enhancement of HIV-1 replication by NE.

Adenylyl Cyclases↗
PubMed1998

Quantification of cytokine mRNA in peripheral blood mononuclear cells using branched DNA (bDNA) technology.

Changes in the patterns of cytokine expression are thought to be of central importance in human infectious and inflammatory diseases. As such, there is a need for precise, reproducible assays for quantification of cytokine mRNA that are amenable to routine use in a clinical setting. In this report, we describe the design and performance of a branched DNA (bDNA) assay for the direct quantification of multiple cytokine mRNA levels in peripheral blood mononuclear cells (PBMCs). Oligonucleotide target probe sets were designed for several human cytokines, including TNFalpha, IL-2, IL-4, IL-6, IL-10, and IFNgamma. The bDNA assay yielded highly reproducible quantification of cytokine mRNAs, exhibited a broad linear dynamic range of over 3-log10, and showed a sensitivity sufficient to measure at least 3000 molecules. The potential clinical utility of the bDNA assay was explored by measuring cytokine mRNA levels in PBMCs from healthy and immunocompromised individuals. Cytokine expression levels in PBMCs from healthy blood donors were found to remain relatively stable over a one-month period of time. Elevated levels of IFNgamma mRNA were detected in PBMCs from HIV-1 seropositive individuals, but no differences in mean levels of TNFalpha or IL-6 mRNA were detected between seropositive and seronegative individuals. By providing a reproducible method for quantification of low abundance transcripts in clinical specimens, the bDNA assay may be useful for studies addressing the role of cytokine expression in disease.

Cytokines↗