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W Heagy

Publications and source records attributed to W Heagy.

11 recordsLinked to original sources
PubMed1992

Opioid receptor agonists and Ca2+ modulation in human B cell lines.

Opiates and opioid peptides have been shown to modulate lymphocyte functions; however, little attention has been given to the type of receptors or receptor signaling mechanisms that are involved. Receptor-mediated signaling via ionized free Ca2+ is an event thought to be important in the triggering of lymphocyte activities. We report use of the calcium indicator dye, indo-1, and flow cytometry to identify B lymphocyte calcium responses to physiologic concentrations of opioid peptides. The human B cell lines Nalm 6 and JY responded to the naturally occurring opioid pentapeptide methionine-enkephalin or other opiate receptor agonists with a rapid, dose-dependent rise in free cytoplasmic Ca2+. This opioid peptide effect on Ca2+ modulation was inhibited by the opiate receptor antagonist naloxone. The synthetic enkephalin analogue DAMGO with specificity for mu-type opiate receptors and the synthetic opiate receptor agonists U50,488H and U69,593 with selectivity for kappa-type sites also stimulated calcium responses when applied to the B cell lines. These studies provide evidence that human B cell lines express functional opiate receptors of the mu- and kappa-types and suggest that such receptors, coupled with Ca2+ modulation, are instrumental in the B cell response to opiates and endogenous opioid neuropeptides.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Inhibition of immune functions by antiviral drugs.

Immune functions were evaluated in vitro for PBMC isolated from healthy donors and cultured with the antiviral agents, 3'-azido-3'-deoxythymidine (AZT), ribavirin, ganciclovir, 2'3'-dideoxyinosine (ddI), or acyclovir. To identify methods for assessing the effects of antiviral drugs on immune cells, the PBMC response to mitogens, Con A, or phytohemagglutinin was evaluated from measurements of [3H]thymidine and [14C]-leucine incorporation, cell growth, cellular RNA, DNA, and protein levels, and the PBMC proliferative cycle (i.e., progression from G0----G1----S----G2 + M). At clinically relevant concentrations, AZT, ribavirin, or ganciclovir diminished PBMC responsiveness to mitogen. The numbers of proliferating cells in G1, S, and G2 + M phases of the cell cycle, DNA content, and [3H]thymidine uptake were decreased in cultures treated with AZT, ribavirin, or ganciclovir. AZT or ribavirin but not ganciclovir reduced RNA and protein in the cultures and inhibited cell growth. Whereas AZT, ribavirin, or ganciclovir were antiproliferative, ddI or acyclovir had little, if any, effect on PBMC mitogenesis. The inhibitory effects of antivirals on immune cells may contribute to the immune deterioration observed in patients following prolonged use of the drugs.

Acyclovir↗
PubMed1990

Neurohormones regulate T cell function.

In this communication we show that T cell locomotion is affected by direct interaction with neurohormones. Opioid peptides, including beta-END, MET-ENK, LEU-ENK, and related enkephalin analogues enhanced migration of human peripheral blood T lymphocytes. Activity was dependent on the peptide NH2-terminal sequence, stimulated by enkephalin analogues with specificity for classical delta or mu types of opiate receptor, and inhibited by the opiate receptor antagonist naloxone. Our studies suggest that such neuropeptides stimulate T cell chemotaxis by interaction with sites analogues to classical opiate receptors. We propose that the endogenous opioids beta-END, MET-ENK, and LEU-ENK are potent immunomodulating signals that regulate the trafficking of immune response cells.

Amino Acid Sequence↗
PubMed1990

Use of IFN-gamma in patients with AIDS.

The tolerance and toxicity of interferon-gamma (IFN-gamma) was assessed in a phase I/II study of 21 patients with acquired immune deficiency syndrome (AIDS). A highly purified preparation of human recombinant E. coli-produced IFN-gamma was given i.v. twice weekly for an 8 week period. Patients were enrolled in the study in groups of four or five; the initial group received an IFN-gamma dose of 0.03 mg/m2 and subsequent groups received higher IFN-gamma doses of 0.3, 1, or 3 mg/m2. Toxicity resulting from IFN-gamma was minimal and the therapy was well tolerated even at the maximum dose (3 mg/m2). No patients developed antibodies that neutralized IFN-gamma. Clinical responses were observed in 3 of 17 patients with Kaposi's sarcoma (KS). A complete clinical response was achieved in one individual and a partial, temporary regression of KS lesions was observed in two other patients. HIV p24 antigen was decreased in plasma samples obtained from six of nine patients with initially detectable HIV protein. These data suggest that IFN-gamma should be considered as a therapeutic agent, possibly with other antivirals, in the treatment of patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Recombinant human gamma interferon enhances in vitro activation of lymphocytes isolated from patients with acquired immunodeficiency syndrome.

Decreased responses to antigens and lectins are a characteristic feature of peripheral blood lymphocytes isolated from patients with the acquired immunodeficiency syndrome (AIDS). The in vitro addition of recombinant gamma interferon (IFN-gamma) to cultures of peripheral blood lymphocytes obtained from patients with AIDS resulted in an augmented proliferative response [( 3H]thymidine uptake) to phytohemagglutinin (PHA) and an enrichment in CD4+ and CD8+ T lymphocytes. In AIDS cultures stimulated with PHA, IFN-gamma increased the release of T-cell growth factors and enhanced the expression of interleukin-2 receptors on activated lymphocytes. Responsiveness to PHA was augmented, albeit to a lesser extent, by IFN-gamma in cultures derived from normal donors. Proliferation to microbial antigens including herpes simplex virus, cytomegalo virus, and Candida albicans was increased by IFN-gamma in cultures established from a group of AIDS patients with Kaposi's sarcoma who had no history of opportunistic infection.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Ribavirin treatment of the acquired immunodeficiency syndrome (AIDS) and the acquired-immunodeficiency-syndrome-related complex (ARC). A phase 1 study shows transient clinical improvement associated with suppression of the human immunodeficiency virus and enhanced lymphocyte proliferation.

STUDY OBJECTIVE: To assess safety, tolerance, and the clinical and laboratory effects of oral ribavirin in patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. DESIGN: Three uncontrolled phase I trials of increasing duration: 14 days, 8 weeks, and 12 months. SETTING: Outpatient clinic of a university-referral hospital. PATIENTS: All patients were antibody-positive for the human immunodeficiency virus (HIV) by radioimmunoprecipitation assay, all had recovered from Pneumocystis carinii pneumonia, and none had Kaposi sarcoma at entry. Nine of ten patients with AIDS had less than 100 CD4+ lymphocytes/mm3 at entry and all patients with the AIDS-related complex had fewer than 200 CD4+ lymphocytes/mm3. Five patients with AIDS and five with the AIDS-related complex entered the 14-day trial. All but two patients with AIDS went on to the 8-week trial, along with seven additional patients with AIDS. Five surviving patients with AIDS and 3 patients with the AIDS-related complex went on to the 1-year study. INTERVENTIONS: Oral ribavirin, 1200 mg twice daily for 3 days was given, followed by 300 mg twice daily for 11 days. During an 8-week trial, a loading dose of oral ribavirin was administered for 3 days, followed by a dose of 300 mg twice daily for 8 weeks. Prolonged regimen of a 3-day loading dose was given, followed by a dose of 300 mg twice daily for 1 year. MEASUREMENTS AND MAIN RESULTS: Ribavirin treatment was well tolerated, with anemia requiring transfusion in one of the ten patients with AIDS receiving the drug for 8 weeks; no other significant toxicity occurred. Six of nine patients initially positive for HIV-1 in blood became negative during ribavirin treatment. Six of nine patients with AIDS had a twofold improvement in lymphoproliferative response to at least one lectin with ribavirin treatment. Mean survival from first episode of P. carinii pneumonia was 17.3 months in patients with AIDS receiving 8 weeks of ribavirin and 21.2 months in patients with AIDS receiving prolonged treatment. CONCLUSIONS: Oral ribavirin, 600 mg daily, was well tolerated and safe in the patients with severe AIDS and the AIDS-related complex. Ribavirin therapy merits extensive evaluation in a multicenter controlled trial to assess its efficacy.

AIDS-Related Complex↗
PubMed1985

Blocking of CTL-mediated killing by monoclonal antibodies to LFA-1 and Lyt-2, 3. II. Evidence that trypsin pretreatment of target cells removes a non-H-2 molecule important in killing.

We sought additional evidence for an inverse relationship between functional CTL-target cell affinity on the one hand, and susceptibility of the CTL-mediated killing to inhibition by alpha LFA-1 and alpha Lyt-2,3 monoclonal antibodies on the other hand. Previously, we experimentally reduced affinity by pretreating the target cells with papain. This removed most of the class I H-2 antigens, had little effect on the ability of allospecific CTL to recognize and kill these targets, but dramatically reduced the initial strength of CTL-target cell adhesion, and increased by more than 10-fold the susceptibility of the killing to inhibition by alpha Lyt-2,3 and alpha LFA-1 MAb. In the present report, we find that pretreating the target cells with trypsin, like papain, does not significantly change the susceptibility of the target cells to killing by allospecific CTL in a 2-hr assay, and increases by about 10-fold susceptibility of the killing to inhibition by alpha LFA-1. Unlike papain, however, trypsin does not consistently increase blocking by alpha Lyt-2,3, does not remove class I H-2 antigens from the target cell, and does not substantially reduce the strength of initial CTL-target adhesion formation (estimated by post dispersion lysis after a 5-min conjugate-forming incubation). These results show a functional difference between LFA-1 and Lyt-2,3. Both papain and trypsin produced similar 10-fold increases in susceptibility to blocking by alpha LFA-1. In contrast, susceptibility to inhibition by alpha Lyt-2,3 was increased nearly 100-fold by papain, but was not consistently affected by trypsin. Thus, the above-mentioned inverse relationship holds for alpha Lyt-2,3 but not for alpha LFA-1. Our results are consistent with the hypothesis that Lyt-2,3 but not LFA-1 participates in recognition of class I H-2 antigens. Possibly LFA-1 participates in an adhesion-strengthening process that follows T cell recognition, and which may also be used by other LFA-1 expressing leucocytes in intercellular interactions. Finally, our results suggest (for the first time in the mouse system) that an unidentified non-H-2 "trypsin-sensitive counter blocking" molecule on the target cell plays an important role in CTL-target cell interaction.

Animals↗
PubMed1978

Interaction of glutathione analogues with Hydra attenuata gamma-glutamyltransferase.

gamma-Glutamyltransferase activity was studied in extracts of the cnidarian Hydra attenuata. The binding of gamma-glutamyl peptide analogues to the enzyme was studied by observing their effects on heat denaturation and their inhibition of p-nitroaniline release from gamma-glutamyl p-nitroanilide. Neither position-1 analogues, in which the gamma-glutamyl moiety was changed to a beta-aspartyl (beta-Asp-Abu-Gly) or an alpha-glutamyl (Glu-Abu-Gly) linkage, nor glutamate protected the enzyme against inactivation at 58 degrees C. GSH (reduced glutathione), gamma-Glu-Abu-Gly and gamma-Glu-Met on the other hand did prevent heat denaturation. GSH and analogues of GSH were competitive inhibitors of p-nitroaniline release, but those analogues in which glycine was replaced by 2-aminoisobutyrate, phenylalanine, leucine or tyrosine had Ki values that were approximately five times those of analogues with the cysteine residue replaced.

Amino Acids↗