Biomedical subjects

J L Fahey

Publications and source records attributed to J L Fahey.

At least 91 records · Page 5Linked to original sources

PubMed1989

Serum neopterin changes in HIV-infected subjects: indicator of significant pathology, CD4 T cell changes, and the development of AIDS.

Serum neopterin is a metabolite of dihydroneopterin triphosphate, which is produced from GTP during immune activation. A study was undertaken in homosexual male subjects followed at 6 month intervals for 3 or more years to determine the value of serum neopterin changes induced by HIV infection. The significance of serum neopterin levels in evaluating prognosis of HIV-infected individuals was also assessed. Serum neopterin was found to be a useful indicator of the presence of HIV infection. Stratification of 29 HIV seroconverters showed a strong inverse correlation between the serum neopterin rise and the blood CD4 T cell fall in the first year following HIV infection. Thus, a small increase in neopterin (less than 5 nmol/L) at the time of HIV seroconversion was associated with minimal CD4 T cell reduction and a large increase (greater than 12 nmol/L) was associated with a much greater CD4 T cell fall. Neopterin levels were markedly different (lower) in individuals with little or no CD4 T cell fall when compared with those with moderate or marked rates of T cell fall. This relationship between serum neopterin and the CD4 T cell level was further confirmed by an evaluation of both parameters in a group of 799 seropositive homosexual men. In this analysis, serum neopterin was shown to have a significant predictive value for the development of AIDS within 3 years. Furthermore, when serum neopterin and CD4 T cell measurements were considered together, the prognostic value of the combination was significantly greater than either alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗

PubMed1988

Fractionated total body irradiation and high dose cyclophosphamide: a preparative regimen for bone marrow transplantation for patients with hematologic malignancies in first complete remission.

We treated 73 patients with hematologic malignancies in first complete remission (acute lymphoblastic leukemia = 23 patients; acute non-lymphoblastic leukemia = 25 patients; chronic myelogenous leukemia in first chronic phase = 20 patients, and high grade lymphoma = five patients) with a uniform preparative regimen consisting of fractionated total body irradiation (1,320 cGy) and high dose cyclophosphamide (100 mg/kg), followed by allogeneic bone marrow transplantation. By radiation dosimetry we demonstrated that the calculated doses were delivered accurately and reproducibly. Actuarial survival rates (+/- SEM) in complete remission were as follows: Acute lymphoblastic leukemia = 74 +/- 9%; acute nonlymphoblastic leukemia = 50 +/- 11%; and chronic myelogenous leukemia = 55 +/- 11%. Actuarial relapse rates for these three diagnoses were 19 +/- 9%, 17 +/- 11%, and 0% respectively. Three of the five lymphoma patients are alive in complete remission at 22+, 28+, and 54+ months. Overall probability of survival for the 73 patients was 59 +/- 7%. Interstitial pneumonia, usually associated with cytomegalovirus infection and graft-versus-host disease, and relapse of the underlying malignancy were the major causes of death.

Adolescent↗

PubMed1988

Selective decrease in Leu8-negative T cell subpopulations following treatment with recombinant interferon-alpha 2a (rIFN-alpha 2a).

The effects of in vivo treatment with recombinant human IFN-alpha 2a (rIFN-alpha 2a) on the distribution of T cell subpopulations were examined in 21 patients with renal cell adenocarcinoma, using two-color flow cytometry with anti-Leu8 in combination with anti-Leu2 and anti-Leu3. Other parameters indicative of immune status, such as the number and percentage of total (CD3) T cells, in vitro proliferation to mitogen, and spontaneous immunoglobulin secretion, were also measured, prior to the initiation of treatment with rIFN-alpha 2a, and during treatment. Total T cell number decreased after treatment with rIFN-alpha 2a, to a low of 54% of mean pretreatment values after 4 weeks. The CD4/CD8 ratio did not change appreciably following treatment with rIFN-alpha 2a. However, the number of Leu8-negative T cells, within both the CD4 and the CD8 T cell populations, decreased more than the number of Leu8-positive T cells. An increase in spontaneous immunoglobulin-secreting cells followed treatment with rIFN-alpha 2a.

Antibodies, Monoclonal↗

PubMed1988

Immunomodulating effects in vitro of interleukin-2 and interferon-gamma on human blood and bone marrow mononuclear cells.

Mononuclear cells (MNC) derived from peripheral blood (PBMNC) of 23 normal donors and 4 AIDS patients, and from bone marrow (BMMNC) of 15 normal donors were incubated at 37 degrees C in culture medium alone or in the presence of either natural or recombinant human interleukin-2 (IL-2) or recombinant human interferon-gamma (IFN-gamma; 1-1,000 U/ml). The cultured cells were washed on days 1, 4 or 7 and tested for various immune functions in vitro and for cell surface phenotype. IL-2, but not IFN-gamma, was found mitogenic for both PBMNC and BMMNC. The natural killer (NK) activity of both PBMNC and BMMNC was the only function tested that was markedly augmented (over 100-fold compared to medium control) by both lymphokines. Pretreatment of PBMNC with IL-2 at greater than or equal to 10 U/ml profoundly suppressed (up to 90%) various functions, such as mitogenic responses (phytohemmagglutinin, concanavalin A, pokeweed mitogen), allogeneic mixed leukocyte reaction, antibody production and T cell colony formation in agar. In contrast, some BMMNC functions were elevated at low doses of IL-2 and IFN-gamma, and significant suppression of BMMNC was seen only with high doses of IL-2 (greater than or equal to 100 U/ml) and IFN-gamma (1,000 U/ml). IL-2 was by far more effective than IFN-gamma in both the amplification of NK activity and the suppression of most of the other functions. IL-2, but not IFN-gamma, was found to activate/induce suppressor cells and increased the proportion of Leu-2+ (CD8) cells in PBMNC; the suppressive effect was time- and dose-dependent. The IL-2-induced suppression could be diminished by inclusion of anti-IL-2 antibody during the pretreatment phase. Similar suppressive effects were noted in PBMNC from AIDS patients. These findings suggest that: (a) high-dose IL-2 may elicit immunosuppression which can be mediated by nondiscriminative highly cytotoxic cells (i.e. lymphokine-activated killer cells) and/or by noncytotoxic, nonspecific suppressor cells, and (b) that PBMNC respond differently to the lymphokines than do BMMNC.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Patterns of CD4+ cell changes after HIV-1 infection indicate the existence of a codeterminant of AIDS.

Successive interval slopes of CD4+ cells each constructed from levels at three consecutive 6 month visits were compared over 3 years of follow-up among 565 persistently HIV-1 antibody-positive, 326 persistently antibody-negative, and 51 seroconverting homosexual men who had at least 500 CD4+ cells/mm3 at baseline and completed the first three 6 month visits. "Change" was defined as a difference between two successive interval slopes. Sixty-two percent of seroconverters meeting these criteria experienced a shift in one or more of their successive CD4+ interval slopes, the majority (56%) from a level slope to a negative slope (decreasing numbers of CD4+ cells), a significantly greater proportion than that observed among seronegatives (30%, p less than 0.0001). Fifty-eight percent of the seropositives maintained level interval slopes over the 3 years of follow-up. The majority (59%) of those men experiencing a shift went from a level to a negative interval slope, a significantly greater proportion than observed among seronegatives (30%, p less than 0.0001). The observed patterns of change in interval slopes are consistent with the laboratory observation that CD4+ cells must be activated to replicate HIV-1. The use of the interval slope strategy provides a method to identify a temporal focal point at which to examine possible codeterminants that trigger the production of HIV-1 and the subsequent decline in CD4+ cells.

AIDS Serodiagnosis↗

PubMed1988

Predictors of decline in CD4 lymphocytes in a cohort of homosexual men infected with human immunodeficiency virus.

Longitudinal data on four visits scheduled at 6 month intervals were available on a cohort of 1,827 homosexual men who were human immunodeficiency virus (HIV) seropositive at entry. To identify predictors of the rate of decline of CD4 T-lymphocytes, we used an autoregressive model that relates CD4 counts to predictor variables, while adjusting for previous CD4 counts. Significant predictors of steeper decline of CD4 counts were high CD8 count, low hemoglobin, low platelets, high serum IgA, high cytomegalovirus (CMV) antibody, and low HIV antibody. Using the fitted model, a subject with an initial deficit of 314 CD4 cells (median value of study sample) with respect to seronegative subjects and with average values in all other predictors is estimated to lose approximately 53 cells in a 6 month period (95% C.I. = 45-61 cells). Contrasting this estimate to the one obtained with similar methods in intravenous drug users, it is suggested that a faster rate of decline is present among i.v. drug users. This analysis provides evidence that several covariates in addition to previous number of CD4 counts have significant predictive power for estimating the decline in CD4 counts in HIV seropositive subjects.

AIDS Serodiagnosis↗

PubMed1988

Clinical drawbacks of total lymphoid irradiation: the cons.

Success has been reported with use of total lymphoid irradiation (TLI) in organ transplant recipients and in patients with rheumatoid arthritis and other autoimmune diseases. In a well-conducted randomized double blind clinical trial, Cook et al have found that TLI was superior to sham irradiation of patients with multiple sclerosis (MS). However, it is clear from looking at this data that not all patients responded to TLI and that with time disease activity returned. Our own experience with TLI in two MS patients was very disappointing. Despite its apparent benefit in some conditions, considerable drawbacks are associated with TLI. These include high financial cost, unpleasant treatment-related side effects, and the possibility that more serious morbidity as well as mortality may be treatment-related. Furthermore, the optimum therapeutic regimen for TLI has not yet been established. Issues related to cumulative dose, dose per fraction, frequency of fractions, field of irradiation, and interaction with other therapies still need clarification. For these reasons we do not recommend TLI as a treatment for MS.

Humans↗

PubMed1987

Tumor immunology.

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Acquired Immunodeficiency Syndrome↗

PubMed1987

Antibodies to human immunodeficiency virus in human sera induce cell-mediated lysis of human immunodeficiency virus-infected cells.

The capacity of human immunodeficiency virus (HIV) antibody-positive sera from homosexually active men without acquired immune deficiency syndrome to lyse the HIV-infected T cell lines MOLT-4f and CCRF-CEM (CEM) in cooperation with lymphocytes from normal donors was investigated. Twenty-seven HIV antibody-positive sera, most of which enhanced the killing of HIV-infected MOLT-4f and CEM target cells by normal mononuclear cells were studied in detail. HIV antibody-positive sera resulted in lysis at dilutions as high as 1/10,000. HIV antibody-negative sera did not augment lysis of infected target cells. In addition, lysis of uninfected targets was not enhanced in the presence of HIV antibody-positive sera. Because fractionation of the HIV antibody-positive sera on a protein A affinity column resulted in recovery of the activity from the IgG fraction, the extra cytotoxic activity mediated by nonimmune cells in the presence of immune sera appears to be antibody-dependent. Furthermore, the cytotoxic effector cells were in the nonrosetting fraction of lymphocytes and expressed Leu-11 (cluster designation (CD)15) antigens, which is characteristic of cells participating in antibody-dependent cellular cytotoxicity reactions. The antibody specificity of the sera, determined by radioimmunoprecipitation, provides evidence that antibody-dependent cellular cytotoxicity can occur even when there are no detectable antibodies directed against gag proteins. Sera which lacked detectable antibodies to the envelope protein gp120 by radioimmunoprecipitation did not mediate antibody-dependent cellular cytotoxicity.

Adult↗

PubMed1987

Infection with the human immunodeficiency virus (HIV) is associated with an in vivo increase in B lymphocyte activation and immaturity.

The expression of phenotypic markers on B lymphocytes in patients with the acquired immune deficiency syndrome (AIDS), in human immunodeficiency virus (HIV) seropositive individuals, and in healthy seronegative donors was examined by two-color flow cytometry. Patients with AIDS and HIV-seropositive individuals showed an elevated percentage of B cells bearing an activation marker, the transferrin receptor, when compared with donors not infected with HIV. A decrease in the percentage of resting (Leu-8 positive) B cells was also seen in AIDS patients and HIV-seropositive individuals. An increased percentage of circulating, immature (CALLA-positive, CD10) B cells was seen in AIDS patients. These phenotypic changes were accompanied by an increased level of spontaneous IgG and IgM secretion, and increased cell size within the total B cell population and in some B cell subpopulations, in patients with AIDS and in HIV-seropositive people. These results demonstrate that phenotypic changes indicative of in vivo B cell activation and immaturity accompany the polyclonal production of Ig seen in HIV-infected individuals.

Acquired Immunodeficiency Syndrome↗

PubMed1987

Early effects of HIV on CD4 lymphocytes in vivo.

Low circulating CD4 cell numbers and CD4 cell dysfunction are distinguishing features of HIV-mediated disease. The current study delineates the in vivo effects of HIV on distinct functional subsets of CD4 cells in homosexually active men who have been infected with HIV for different lengths of time, and examines the capacity of lymphocytes from these men to proliferate in vitro in response to soluble antigen. Although peripherial blood mononuclear cells from most acquired immune deficiency syndrome (AIDS) patients did not proliferate in response to either tetanus toxoid or Candida albicans, cells from most HIV seropositive men without AIDS, many of whom had been infected for more than 18 mo, responded normally to both. Non-responsiveness in HIV-infected men without AIDS was a late event and was associated with longer duration of infection, lower CD4 cell numbers, and subsequent development of AIDS. A defect in this response was observed in only one of 19 HIV seropositive men whose CD4 levels were greater than 300/mm3, but in eight of 10 with levels less than 300/mm3. The defect could not be attributed to a selective depletion of defined CD4 subpopulations that respond to soluble antigen. Dual-color immunofluorescent flow cytometry indicated that 4B4+, 2H4-, and HB-11- CD4 cells were not lost at a faster rate than other CD4 subsets.

Acquired Immunodeficiency Syndrome↗

PubMed1987

Correlation of clinical and immunologic states in multiple sclerosis.

Cyclophosphamide was administered to 14 patients with chronic progressive multiple sclerosis on an intermittent escalating dosage schedule adjusted to maintain numbers of peripheral blood B lymphocytes and helper/inducer (CD4) T cells below the fifth percentile of the normal population. Peripheral blood B cells, T cells, suppressor/cytotoxic (CD8) T cells, CD4 cells, and FcR+-bearing cell numbers and percentages were monitored at one-week to two-week intervals. Clinical status was assessed by neurologic examinations at approximately four-week intervals. Regression analysis revealed a statistically significant correlation between changes in immunologic status and changes in clinical state. The immunologic changes preceded the neurologic changes. Increases in percent of CD8 cells and decreases in percent of CD4 cells forecast improved clinical course. These findings, coupled with other studies, strongly suggest a pathogenetic role for helper and suppressor T cells in the production of clinical signs of multiple sclerosis.

B-Lymphocytes↗

PubMed1987

Cyclophosphamide 'pulses' in chronic progressive multiple sclerosis. A preliminary clinical trial.

To our knowledge, this is the first clinical trial in multiple sclerosis (MS) demonstrating the feasibility of directing immunomodulating therapy by monitoring immunologic results. Cyclophosphamide was administered at monthly intervals, escalating the dose until there was a significant reduction in both the number of blood B lymphocytes and helper/inducer (CD4) T cells of 14 patients with chronic progressive MS. The frequency and severity of adverse effects led us to conclude that the regimen is too toxic for the long-term treatment of patients with MS.

Adult↗

PubMed1987

Increased spontaneous immunoglobulin secretion associated with cyclophosphamide-induced immune suppression.

Spontaneous immunoglobulin (Ig) secretion by cells from multiple sclerosis (MS) patients (in the progressive phase) treated with monthly pulse doses of cyclophosphamide (CY) (1000-1600 mg/M2) was measured using the protein A plaque assay, to evaluate the effect of CY treatment on B-cell function. Surprisingly, an increase, rather than a decrease, in Ig-secreting cells was seen following CY treatment. CY-treated MS patients averaged 1380 +/- 535 spontaneous total (IgM + G + A) Ig plaque-forming cells (PFC) per 1 X 10(6) peripheral blood mononuclear cells (MNC), measured at 15-22 days after monthly CY administration, while healthy adults had 280 +/- 47 Ig PFC/10(6) MNC, and MS patients not treated with CY had 300 +/- 43 Ig PFC/10(6) MNC. The observed increase was due to an increase in IgG and IgA PFC. PFC levels remained elevated for 4 weeks following CY treatment, decreasing to control levels by 7-8 weeks post-CY. A small increase in serum IgG level was noted after greater than 12 months of pulse CY therapy; no increase was seen in CSF IgG levels. A preferential decrease in the number of CD4+ T cells was also seen in the CY-treated MS patients. We propose that the observed increase in the number of spontaneous Ig PFC was due to the CY-induced disruption of the CD4+ T cell-mediated control of in vivo activated B cells.

Antibody-Producing Cells↗

PubMed1987

Administration of monthly pulses of cyclophosphamide in multiple sclerosis patients. Delayed recovery of several immune parameters following discontinuation of long-term cyclophosphamide treatment.

Recovery of various components of the immune system was followed in eight patients with multiple sclerosis who had received monthly pulses of cyclophosphamide (CY) for approximately one year. CD8 cell numbers and NK and ADCC functions recovered in 1-2 months; B cells and FcR+ cell numbers recovered in 2-4 months. The recovery of CD4 cells and total T cell numbers, CD4/CD8 ratio and proliferative responses to PHA took more than 4 months. The impaired proliferation was not attributable to low IL-2 receptor expression. Once immunosuppression has been achieved pulse administration of CY at 2- to 4-month intervals may be feasible for long-term maintenance treatment.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1987

Ras related oncogene protein as a tumor marker in transitional cell carcinoma of the bladder.

An oncogene related protein has been detected in the urine of patients with transitional cell carcinoma (TCC). This is a 55 kilodalton protein (p55) which is immunologically related to the ras oncogene product p21. Sixteen patients with TCC (55%) and none of the controls exhibited high level of p55 expression (greater than or equal to 3X the level of background). There were ten cancer patients (35%) who had 2X the level of background and three patients (10%) who had the level of background. In contrast, there were two non-cancer patients with 2X level of expression (9%) and the remainder (91%) had the background level of p55 expression. The expression of the marker (p55) tends to correlate with tumor grade and stage and is elevated in patients with a history of multiple recurrences. The ras oncogene has been identified in the tissues of a wide variety of cancers and is not a marker which is specific for any single cancer. The identification of its related gene product in the urine may be useful as a marker for TCC.

Antigens, Neoplasm↗

PubMed1987

Detection of onco-fetal bladder antigen in urine of patients with transitional cell carcinoma.

Studies of antigens associated with transitional cell carcinoma were extended by using murine IgM monoclonal antibody E7, developed earlier by this laboratory. These antibodies react preferentially with human bladder tumors and transitional cell carcinoma (TCC) cell line 647V. We now report that monoclonal antibody E7 detected the presence of antigen in midgestational and third trimester amniotic fluids, and in urine of patients with advanced transitional cell carcinoma. Western blot analysis showed that the antigen present in amniotic fluids consists of a sharp band with molecular weight greater than 200 kdaltons. A similar molecular weight pattern was seen with the solubilized membrane of 647V. A sensitive and convenient sandwich ELISA was developed and the urine of patients with bladder cancer was assayed for the presence of the E7 antigen. Antigen was detected in the urine of patients with advanced transitional cell carcinoma but not in the urine of normal adults or in urine from patients with prostate cancer, renal cell carcinoma, or benign prostate hyperplasia. An inhibition enzyme immunoassay was developed with monomeric forms of the E7 antibody and confirmed the presence of antigen in the urine of patients with TCC. We conclude that the E7 antigen is an onco-fetal antigen expressed in patients with transitional cell carcinoma of the bladder.

Antibodies, Monoclonal↗

PubMed1987

Predictors of clinical AIDS in young homosexual men in a high-risk area.

One hundred and sixty-seven homosexual men in Los Angeles characterized by HIV antibody, T-cell numbers, titres to cytomegalovirus (CMV), and specific sexual practices were followed for two years for immune changes and for more than three years for development of clinical AIDS. Thirty-five per cent had antibody to HIV at baseline. The mean level of T-helper (Th) cells was significantly lower and of T-suppressor (Ts) cells significantly higher in HIV seropositives than in seronegatives. The annualized incidence of HIV seroconversion was 7%. Eight men developed AIDS, an attack rate of 14% in those with HIV antibody at baseline. A number of observations were made: T-cell alterations, except a transient elevation in Ts cells, were unusual in the absence of HIV antibody; a seropositive man with a T-cell alteration was significantly less likely to revert to 'within normal limits' than was a seronegative man; a steady decline in the number of Th cells preceded onset of clinical AIDS; the number of Ts cells remained higher in men subsequently developing AIDS than in other seropositive men; clinical AIDS occurred only in men with HIV antibody whose CMV antibody levels were above the median for the group (1:1600); and the attack rate for clinical AIDS was 50% in men with HIV antibody and elevated CMV who at baseline had either: fewer than 325 Th cells/cc, or whose Th/Ts ratio was below 0.8 (but whose levels of Th and Ts cells were within normal limits).(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗