Biomedical subjects

J L Fahey

Publications and source records attributed to J L Fahey.

At least 19 recordsLinked to original sources

PubMed1992

Immune changes in HIV-1 infection: significant correlations and differences in serum markers and lymphoid phenotypic antigens.

Human immunodeficiency virus type 1(HIV-1) induces extensive immune cell alterations which can be detected by changes both in serum levels of soluble immune activation products and in several lymphoid phenotypic markers. The current studies were conducted in 70 HIV-1 seropositive subjects to determine whether changes among four important serum immune activation markers (neopterin, beta-2 microglobulin, soluble CD8, and soluble IL-2 receptor) and seven lymphoid phenotypic markers (CD38, HLA-DR, CD57, CD11b, CD45RA, leu8, and CD71) reflect similar or disparate aspects of immune pathology. On the basis of correlation coefficient calculation, four groups of related markers (Fig. 1) were identified: Group A, sIL-2R was related to group B where serum neopterin, beta 2M, sCD8 levels, and lymphocyte CD38 antigen expression correlated closely. Loss of CD45RA or Leu 8 antigens in group C correlated with group B and D markers increase. HLA-D in group D was a more distantly related immune activation marker. Phenotypic markers CD57, CD11b, and CD71 did not correlate with the immune activation processes reflected by the serum and phenotypic marker groups A-D. Correlations between serum and certain lymphoid phenotypic markers were generally stronger later in HIV-1 infection when CD4 levels were less than 500/mm3. This study provides information for selecting markers for investigating immune changes in HIV-1 infection and immune-related diseases. Many serum and lymphoid phenotypic markers reflect related aspects of immune dysregulation. However, some markers can indicate different aspects of disease.

ADP-ribosyl Cyclase↗

PubMed1992

Beta-endorphin blunts phosphatidylinositol formation during in vitro activation of isolated human lymphocytes: preliminary report.

We have previously described the regulatory effect of beta-endorphin on three human cytotoxic cell populations. We confirmed the variable nature of these effects on human natural killer cell (NK) activity, showed mixed effects on the generation of cytotoxic T lymphocyte (CTL) activity, and demonstrated the reproducible suppression of lymphokine-activated killer cell (LAK) activity. We and others also observed mixed effects of beta-endorphin on the proliferative response to mitogens and in mixed leukocyte reactions. In the study reported here, we test the effects of beta-endorphin on the formation of phosphatidylinositol during cell activation. 32P-radiolabeled peripheral blood mononuclear cells obtained from normal adult donors and CD2-depleted subpopulations were activated with phytohemagglutinin or in a NK, LAK, or CTL protocol in the absence or presence of recombinant beta-endorphin. The total lipidic extract was analyzed by thin-layer chromatography and autoradiography. The results of these studies indicate that beta-endorphin blunts the formation of phosphatidylinositol by about 20% in the four systems studied and in all the donors tested. This effect is dose-dependent and is blocked in part by the opioid antagonist, naltrexone, suggesting involvement of the opioid receptor.

Adolescent↗

PubMed1992

Immunological variability associated with experimentally-induced positive and negative affective states.

Functional and phenotypic immunological parameters were examined immediately before, after, and 30 minutes after experimentally-induced short-term positive (happiness) and negative (anxiety, depression) affective states and a neutral state, in five healthy subjects. Results indicated that all affective states induced more immune fluctuations (regardless of the direction) than the neutral state. Furthermore, among the affective states, anxiety induced the most immunological variability and depression the least.

Adult↗

PubMed1992

Status of immune-based therapies in HIV infection and AIDS.

As our understanding of HIV disease pathogenesis progresses, approaches to immune-based therapy are evolving. Initial therapies aiming to alter immune function in patients with HIV infection have had mixed results. Clinical benefit in the trials so far has not been dramatic, although the studies are still at an early stage, and the correct protocols for the various agents or combinations of agents have yet to be established. As might be expected, where apparent benefit has occurred, it has been more obvious in those patients whose immune system was still intact.

AIDS Vaccines↗

PubMed1992

Different lymphoid cell populations produce varied levels of neopterin, beta 2-microglobulin and soluble IL-2 receptor when stimulated with IL-2, interferon-gamma or tumour necrosis factor-alpha.

Immune activation is central to many immune disorders. Clinical investigations have shown that immune activation can be quantified by measurements of soluble immune activation products in serum. Most in vitro studies of these immune activation products have focused on single products. In this study the specific cell sources and the major lymphokines inducing multiple activation products were investigated. In vitro addition of interferon-gamma (IFN-gamma) or IL-2 stimulated peripheral blood mononuclear cells to produce neopterin, beta 2-microglobulin (beta 2-M) and soluble IL-2 receptor (sIL-2R). These two lymphokines can act independently, because neutralizing antibodies to one of the lymphokines did not block the inducing activity of the other. Tumour necrosis factor-alpha (TNF-alpha) was also investigated and shown to be a less powerful inducer than IL-2 or INF-gamma. Separated lymphoid subpopulations responded differently to specific lymphokines. Monocytes produced only neopterin and only in response to INF-gamma. T cells released beta 2-M and sIL-2R in response to IL-2. B cells, however, were capable of producing all three immune activation products. Neopterin production in B cells was induced by either INF-gamma of IL-2, indicating that B cells have additional mechanisms for responding to lymphokines. To investigate whether these in vitro findings also occur in vivo, sera from patients who had received either rIL-2 or INF-gamma treatment were tested. INF-gamma administration led to substantial increases in serum neopterin but only a moderate beta 2-M increase and no increase in the serum sIL-2R levels. rIL-2 administration caused a substantial increase of all three serum immune activation products, consistent with our in vitro findings. The results confirm that increased serum levels of soluble immune activation products are indicators of increased cytokine production by lymphocytes and monocytes and also that B cells can be a prominent source of immune activation products.

B-Lymphocytes↗

PubMed1992

The effect of zidovudine treatment on serum neopterin and beta 2-microglobulin levels in mildly symptomatic, HIV type 1 seropositive individuals.

Sixty-one subjects with mildly symptomatic human immunodeficiency virus (HIV) infection were included in a double-blind, randomized, placebo-controlled trial of zidovudine (part of AIDS Clinical Trials Group protocol 016, ACTG 016) to evaluate changes in the serum immune activation markers neopterin and beta 2-microglobulin (beta 2M) as early markers of the antiviral effect of zidovudine on HIV type 1 (HIV-1) infection. The mean values of serum neopterin and beta 2M levels in 27 placebo-treated subjects tended to increase with time. The mean value of neopterin in 34 subjects receiving zidovudine decreased at 4 weeks (15.76 nmol/L before treatment to 12.73 nmol/L, p = 0.001). The maximum reduction was seen at 8 weeks of treatment (10.78 nmol/L, p less than 0.0001). Subsequently, the mean value of serum neopterin increased but remained below the pretreatment value for more than a year. Serum beta 2M levels decreased (from 3.01 to 2.69 mg/L at 4 weeks, p = 0.01) and reached the lowest level at 8 weeks (2.45 mg/L, p = 0.0002) in zidovudine recipients. The mean beta 2M level returned to pretreatment value at approximately 24 weeks of the treatment. There was a close correlation between changes from baseline in serum neopterin and beta 2M during the first 16 weeks of the zidovudine therapy, but not later. Subjects with greater reductions of serum neopterin or beta 2M tended to maintain lower levels of these markers with continued zidovudine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗

PubMed1992

Eleven lymphoid phenotypic markers in HIV infection: selective changes induced by zidovudine treatment.

HIV infection induces substantial changes in the expression of many lymphocyte phenotypic markers as well as depletion of CD4 lymphocyte numbers. A comprehensive study was undertaken to determine whether seven lymphocyte phenotypic changes associated with HIV infection (increased CD38, HLA-DR, CD57, and CD71 and decreased CD11b, CD45RA, and leu-8) are altered by zidovudine (ZDV) administration. Levels of the four major lymphoid subsets (CD4, CD8, B, and NK cells) and changes in the serum activation markers neopterin and beta 2-microglobulin (beta 2M) were also measured. Elevated pretreatment expression of CD38 and CD71 was reduced significantly toward normal at 2 weeks by ZDV; however, CD38 and CD71 returned to pretreatment levels at different rates. The kinetics of CD38 reduction and the return to pretreatment levels were similar to those of serum neopterin and beta 2M. HLA-DR decreased in many but not all subjects. CD4 lymphocytes showed a transient increase, most evident at 8 weeks of treatment. Lymphoid phenotypes that did not show significant changes after ZDV therapy included CD57, CD11b, CD45RA, and leu-8 markers as well as CD8 T cells, CD20 B cells, and CD56 NK cells. The fact that some lymphocyte phenotypic markers change toward normal with ZDV treatment and others do not indicates that complex processes underlie immune perturbations of HIV infection. Several phenotypic markers (CD38, CD71, and HLA-DR) that are susceptible to short-term effects of ZDV (but with changes that differ from CD4 T cell changes) are surrogate marker candidates for evaluation in anti-HIV treatment.

Biomarkers↗

PubMed1992

Acute lymphoid changes and ongoing immune activation in SIV infection.

Two features of simian immunodeficiency virus (SIV) infection are emphasized: a transitory decrease in CD4 T cells in the first 2 weeks of infection followed by CD8 T-cell rise, and immune cell activation occurring by 4 weeks and persisting throughout the illness. The short-term changes included a fall in CD4 T cells by 2 weeks with partial recovery by 4 weeks and a CD8 rise that starts at 2 weeks. Subsequent characterization of CD4 T cells showed reduced expression of HLA-DR and CD25 (IL-2 receptor alpha chain) antigens later in SIV infection. Immune cell activation is evident in increased serum levels of neopterin and soluble CD8 antigen. Serum beta 2-microglobulin changes are less marked. Activation of CD8 T cells is reflected by increased percentages of cells expressing HLA-DR antigen. The B-cell numbers increased late in the course of SIV infection. Increased expression of the CD78 (Leu 21) activation phenotype was also seen in some monkeys. The immune activation changes (serum neopterin levels) induced by SIV infection in rhesus macaques appear to be associated with duration of illness, although the number of monkeys observed until death were too few for conclusive data. Thus, immune activation as well as T-cell deficiency may reflect significant immunopathogenic processes in SIV-induced disease.

Animals↗

PubMed1991

Preferential reductions in lymphocyte sub-populations induced by monthly pulses of chlorambucil: studies in patients with chronic progressive multiple sclerosis.

Thirty-three patients with chronic progressive multiple sclerosis (MS) were assigned to intervention groups receiving monthly pulses of chlorambucil (CB) for about one year. The monthly doses ranged from 0.4 to 1.5 mg/kg. Administration of CB resulted in preferential reduction in different lymphocyte subsets which was dose- and time-dependent. The number of B-cells (CD20) decreased more rapidly than NK-cells (CD16, CD56, CD16+CD56+) or T-cell (CD3) and T-cells subsets (CD4 and CD8). At 1.2 mg/kg, CB administration resulted in a preferential drop of T-suppressor/cytotoxic cells (CD8) compared with T-helper cells (CD4), and of the less mature "virgin" CD4 cells (CD4+CD45RA+) compared with "memory" CD4 cells (CD4+CD45RA-). The expression of activation markers (transferrin receptor, CALLa, HLA-Dr and CD38[OKT10]) within CD4, CD8 or CD20 lymphocytes was not altered by CB administration. Our data, which show that CB administration results in a preferential fall in B-cell numbers, contrast with the effects of long-term administration of the related immunosuppressive drugs, azathioprine and cyclophosphamide.

Antigens, CD↗

PubMed1991

Differential effect of beta-endorphin on three human cytotoxic cell populations.

We have examined in vitro the effect of the proopiomelanocortin gene product, beta-endorphin (bE), on the cytotoxic activity of natural killer (NK) cells, lymphokine activated killer (LAK) cells and cytotoxic T-lymphocytes (CTL). Our studies show that bE reproducibly suppressed LAK cytotoxic activity in all donors tested. The effect of bE on the generation of CTL varied, and was negligible on CTL cytotoxic function. Our study also confirms the variable nature of the effects of bE on NK cytotoxicity. In all instances, the effects of bE were generally small, but could be blocked by opioid receptor antagonists, or by prior heat-inactivation of the peptide. The magnitude of the effects was greatest at low effector:target ratios in all of the three systems studied. These results support the emerging body of evidence that the neuroendocrine system may influence host defense mechanisms mediated by cytotoxic cells.

Adolescent↗

PubMed1991

Pituitary-adrenal-immune system in normal subjects and in patients with anorexia nervosa: the number of circulating helper T lymphocytes (CD4) expressing the homing receptor Leu8 is regulated in part by pituitary-adrenal products.

The association between plasma pituitary-adrenal (PA) hormones and the number of certain populations of peripheral blood lymphocytes (PBL) was examined in subjects with normal PA function and in patients with anorexia nervosa (AN). AN patients display several neuroendocrine dysfunctions, including hypercortisolemia. In the normal subjects there were positive correlations between adrenocorticotropic hormone (ACTH) and the number of PBL and helper T lymphocytes expressing the homing receptor Leu8 (CD4+Leu8+); there was a negative relationship between cortisol and these lymphocyte populations. These latter, inverse correlations did not occur in the AN patients, either while underweight or after weight recovery, with some persistence of hypercortisolemia. Administration of dexamethasone (DEX) suppressed cortisol levels and reduced, perhaps via a receptor-mediated mechanism, the number of circulating PBL and CD4+Leu8+ in the normal subjects but not in the AN patients. These results support the physiological relevance of PA-CMI interaction in subjects with normal PA function and indicate that the PA-CMI interrelationship is disrupted in AN patients with hypercortisolemia.

Adrenocorticotropic Hormone↗

PubMed1991

Serum increases and lymphoid cell surface losses of IL-2 receptor CD25 in HIV infection: distinctive parameters of HIV-induced change.

Lymphocyte activation induces production of soluble IL-2 receptor (sIL-2R) which is a large portion of the CD25 membrane molecule and which is detectable in serum. Serum sIL-2R is reported here to increase as a direct effect of the HIV infection and not to be due to secondary opportunistic infections. sIL-2R increased promptly after HIV seroconversion in 83% of 50 initially seronegative homosexual men. The sIL-2R serum levels stabilized in the third year after seroconversion and were then predictive of later CD4 T cell levels and development of AIDS. In two studies of 59 and 395 seropositive men, beta-2 microglobulin (B2M) and neopterin levels in serum correlated closely with each other but not with sIL-2R levels. Thus, increased production of sIL-2R may reflect pathological processes distinct from those determining B2M and neopterin increases. Membrane CD25 expression on peripheral blood lymphocytes, unexpectedly, was found to be decreased in HIV infection. This contrasted with the increased sIL-2R in serum. Investigations with sensitive flow cytometry technics showed that CD25 was expressed at reduced levels and averaged only 12% of lymphocytes from HIV-infected individuals in contrast to 25% in noninfected individuals. All major lymphoid populations showed reductions in CD25 positive cells. This reduction in lymphoid membrane CD25, however, was not inversely correlated with the increased serum levels of sIL-2R or with other parameters of immune deficiency or activation. Thus, surface CD25 loss and serum sIL-2R increase are separate and independent consequences of HIV infection.

CD4-Positive T-Lymphocytes↗

PubMed1991

Serum soluble CD8 molecule is a marker of CD8 T-cell activation in HIV-1 disease.

To characterize CD8 T-cell activation during HIV-1 infection we measured serum soluble CD8 (sCD8) levels longitudinally in seroconverters and in individuals with established HIV infection who were in different stages of illness. CD8 T-cell activation occurs very early in HIV infection. Serum sCD8 levels were elevated in 91.5% of the first seropositive samples in seroconverters. Furthermore, CD8 T-cell activation persists throughout HIV infection. sCD8 predicted the occurrence of AIDS in HIV-seropositive individuals and so the addition of serum sCD8 levels to CD4 T-cell measurements increased the power in predicting the onset of AIDS. The serum level of sCD8 was particularly relevant to the prediction of subsequent CD4 T-cell fall relatively early in infection, for example, in the 3 years after seroconversion. However, later in HIV infection, for example within 2 years prior to development of AIDS, sCD8 levels were less predictive. sCD8 correlated with levels of beta 2-microglobulin and neopterin, which reflect activation of cell types other than CD8. Thus, serum sCD8 level can be a useful marker of specific CD8 T-cell activation, and is an independent predictor of prognosis in HIV infection.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia.

The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by allogeneic bone marrow transplantation (BMT) has been shown to be effective therapy for patients with acute and chronic leukemia. Therefore, we determined the long-term disease-free survival of patients who did not achieve a remission and were then treated with high-dose therapy and bone marrow allografting from matched sibling donors. Twenty-one patients (median age, 28 years) who did not achieve a remission with induction chemotherapy were subsequently treated with allogeneic BMT. After BMT, 90% achieved a complete remission. Six died of complications of the therapy, and six patients relapsed between 27 and 448 days after BMT. Nine patients (43%; median age, 25 years) are alive between 556 and 4,174 days after BMT. The cumulative probability of disease-free survival at 10 years is 43%. This study suggests that allogeneic BMT can be an effective therapy to achieve long-term control of acute leukemia, even in those patients who do not achieve a remission with primary therapy.

Adolescent↗

PubMed1990

HIV inhibits the early steps of lymphocyte activation, including initiation of inositol phospholipid metabolism.

Mechanisms accounting for HIV-associated suppression of lymphocyte proliferation were investigated. In previous work we demonstrated that purified and inactivated HIV-suppressed lymphoid cell proliferation. In this report we used an inactivated preparation of HIV obtained from infected CEM cells grown in serum free media and demonstrated that this HIV-associated suppression acted in the early steps of activation to inhibit the incorporation of radiolabeled phosphorus into phosphatidylinositol 4,5-bisphosphate and phosphatidic acid. Initially we showed that both purified CD4 and CD8 T lymphocyte subsets were affected and HIV-associated inhibition did not require the CD4 molecule. Impaired lymphocyte blastogenesis (decreased size and granularity and decreased expression of receptors to IL-2 and transferrin) in response to PHA indicated an effect of inactivated HIV on the early steps of activation. This was confirmed by time studies where 1) a 2 min HIV-pretreatment followed by washing before stimulation was sufficient to inhibit PHA induced proliferation of normal lymphocytes, and 2) addition of HIV to PHA prestimulated lymphocytes failed to inhibit proliferation, e.g., there was no effect on preactivated lymphocytes. HIV was mainly inhibitory of lymphocyte proliferation induced by PHA or mAb to the CD3 receptor. In contrast to the effect on the CD3/TiR, responses via the CD2 receptor were not suppressed, e.g., stimulation with the monoclonal antibodies T11(2) + T11(3). Inasmuch as responses by direct A23187 + PMA stimulation of intracellular pathways were also inhibited, it appears that the HIV-induced defect was not (or not only) membrane receptor mediated. The earliest (min) measurable event after stimulation was the initial increase in intracellular Ca2+ which was unaffected by HIV pretreatment. The next measurable event (min to h) of stimulation is a sustained increase in inositol phospholipid turnover. Pretreatment of mononuclear cells with inactivated HIV resulted in a decreased inositol phospholipid turnover as judged from decreased 32P incorporation into phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. This led to decreased generation of DAG as reflected in the reduced radiolabeling of its metabolite PA. Reduced availability of DAG presumably interferes with pkC activation and leads to decreased expression of receptors for IL-2 and transferrin and impaired proliferation.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1990

Effect of recombinant human granulocyte-macrophage colony-stimulating factor administration on the lymphocyte subsets of patients with refractory aplastic anemia.

Human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was administered to 14 patients with refractory aplastic anemia (AA). The effect of rhGM-CSF therapy on the lymphocyte phenotype; on the proliferative responses to the mitogen phytohemagglutinin, Candida albicans, and tetanus toxoid antigens; and on the natural killer (NK) activity of the circulating lymphocytes was studied. Samples were collected before (baseline) and twice during the rhGM-CSF administration. The absolute number of circulating lymphocytes remained relatively constant during the first period, but experienced a significant increase (P less than .001) during the second period. The increase was most prominent in the B cells (P less than .001), but the T cells (P less than .016) also increased. Detailed investigation of lymphocyte subsets showed an increase of the markers CD38 (Leu17), HLA-DR, and the transferrin receptor throughout the treatment course giving evidence of lymphoid cell activation. The NK cell activity was suppressed (P less than .008) throughout the treatment. However, proliferative responses to phytohemagglutinin, Candida antigen, and tetanus toxoid were unaffected. Although the mechanism is not yet defined, GM-CSF does induce activation and increase in absolute lymphoid cell number, especially B cells, together with a decrease in NK cytotoxicity. The implication of these immune cell changes in relation to host resistance to microorganisms remains to be established.

ADP-ribosyl Cyclase↗

PubMed1990

The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1.

We evaluated three cellular and five serologic markers that are affected by infection with the human immunodeficiency virus type 1 (HIV-1) for their ability to predict the progression to clinical acquired immunodeficiency syndrome (AIDS). The cellular markers were the number of CD4+ T cells, the number of CD8+ T cells, and the ratio of CD4+ T cells to CD8+ T cells. The serologic markers were the serum levels of neopterin (a product of stimulated macrophages), beta 2-microglobulin, soluble interleukin-2 receptors, IgA, and HIV p24 antigen. We evaluated the usefulness of these measures as markers of the progression to AIDS prospectively, over four years, in a cohort of 395 HIV-seropositive homosexual men who were initially free of AIDS. CD4+ T cells (expressed as an absolute number, a percentage of lymphocytes, or a ratio of CD4+ to CD8+ T cells) were the best single predictor of the progression to AIDS, but the serum neopterin and beta 2-microglobulin levels each had nearly as much predictive power. The neopterin level appeared to be a slightly better predictor than the beta 2-microglobulin level. The levels of IgA, interleukin-2 receptors, and p24 antigen had less predictive value. A stepwise multivariate analysis indicated that the best predictors, in descending order, were CD4+ T cells (the percentage of lymphocytes or the CD4+: CD8+ ratio), the serum level of neopterin or beta 2-microglobulin, the level of IgA, that of interleukin-2 receptors, and that of p24 antigen. The last three markers had little additional predictive power beyond that of the first two. We conclude that of the eight markers studied, progression to AIDS was predicted most accurately by the level of CD4+ T cells in combination with the serum level of either neopterin or beta 2-microglobulin. At least one of these two serum markers, which reflect immune activation, should be used along with measurement of CD4+ T cells in disease-classification schemes and in the evaluation of responses to therapy.

Acquired Immunodeficiency Syndrome↗

PubMed1990

A structured psychiatric intervention for cancer patients. II. Changes over time in immunological measures.

We evaluated the immediate and long-term effects on immune function measures of a 6-week structure psychiatric group intervention for patients with malignant melanoma. Along with a reduction in levels of psychological distress and greater use of active coping methods, the following immune changes were seen at the 6-month assessment point in the intervention-group patients (n = 35) compared with controls (n = 26): significant increases in the percent of large granular lymphocytes (defined as CD57 with Leu-7) and natural killer (NK) cells (defined as CD16 with Leu-11 and CD56 with NKH1) along with indications of increase in NK cytotoxic activity; and a small decrease in the percent of CD4 (helper/inducer) T cells. At the 6-week follow-up point, the majority of these changes were not yet observable. The results indicate that a short-term psychiatric group intervention in patients with malignant melanoma with a good prognosis was associated with longer-term changes in affective state, coping, and the NK lymphoid cell system. Affective rather than coping measures showed some significant correlations with immune cell changes.

Adaptation, Psychological↗