Search PubMed⌕ Search

Biomedical subjects

E L Morgan

Publications and source records attributed to E L Morgan.

At least 37 records · Page 2Linked to original sources
PubMed1987

The role of prostaglandins in C3a-mediated suppression of human in vitro polyclonal antibody responses.

Suppression of polyclonal antibody responses in human peripheral blood mononuclear cell cultures by human C3a appears to involve the release of endogenous prostaglandins from monocytes. C3a was found, under the experimental conditions employed, to activate the cyclooxygenase pathway of arachidonic acid metabolism with the release of large amounts of the prostaglandin E2 species. Suppression of the protein A-induced polyclonal antibody response by C3a is abrogated by the prostaglandin synthesis inhibitor indomethacin. In addition, physiologic amounts of exogenous PGE2 were able to inhibit polyclonal antibody secretion in a manner similar to the suppression observed when C3a was added to culture. These results suggest that C3a-induced release of prostaglandins could be a major element in immunosuppression induced by C3a.

Antibody Formation↗
PubMed1986

Antagonistic regulatory properties of the Fc region of immunoglobulin.

Coculture of human peripheral blood mononuclear cells with Fc fragments of human IgG, or the synthetic Fc region-derived peptide, p23, results in the release of oxidative products of arachidonic acid. Prostaglandin E was the major arachidonic acid metabolite found in the culture supernatants. Induction of polyclonal antibody production by Fc fragments and p23 is influenced by the concomitant production of prostaglandin E in culture. Addition of prostaglandin synthetase inhibitors, indomethacin and aspirin, to human peripheral blood mononuclear cell cultures resulted in a significant increase in the amount of polyclonal antibody produced. Moreover, addition of exogenous prostaglandin E to these cultures abrogated the ability of indomethacin to enhance Fc fragment-induced polyclonal antibody production. These results suggest that Fc fragments possess bifunctional immunoregulatory properties.

Adult↗
PubMed1986

Modulation of the immune response by anaphylatoxins.

Bioactive C3a and C5a fragments derived from the human complement compounds C3 and C5, respectively, possess immunoregulatory activities. C3a and C5a differentially influence in vitro immune function. C3a was found to be a potent suppressor of antigen-specific and polyclonal antibody responses. In contrast, C3a was unable to suppress antigen-or mitogen-induced B and T cell proliferation. Analyses of synthetic peptides based on the sequences of C3a revealed that the carboxy-terminal region of the molecule is responsible for immunosuppression. C3a-mediated suppression occurs through the activation of a nonspecific suppressor T cell pathway. In contrast to the results obtained with C3a, C5a was found to augment both in vitro humoral and cell-mediated immune responses. Regulation of immune function by complement components may form part of an in vitro nonspecific immunoregulatory network.

Adjuvants, Immunologic↗
PubMed1986

Lymphocyte activation by the Fc region of immunoglobulins.

The Fc region of Ig is required for numerous biological effector functions which include: opsonization, anaphylaxis, C fixation, catabolism of the Ig molecule, FcR binding, and immune regulation. To this latter point, the cellular and subcellular events involved in immune regulation by IC and Fc fragments of Ig have been the focus of numerous investigations. Characterization of cyanogen bromide cleavage fragments from a human IgG1 myeloma protein indicates that one biologically-active site is found in residues 335-357 of the CH3 domain of the molecule. Synthesis of the biologically-active region resulted in a peptide, termed p23, which stimulates mouse and human B cells to secrete polyclonal Ig and activates AA metabolic pathways. In contrast to these findings, p23 is unable to induce B cell proliferation or IL-1 secretion from macrophages. Analysis of data obtained with overlapping peptides, based on p23, suggests that the minimal active sequence needed for B cell differentiation is leu-pro-pro-ser-arg (residues 351-355). In contrast, only p23 or p23 minus the carboxyterminal glu356 and glu357 were able to induce PGE release. Release of biologically-active peptides derived from the Fc region of Ig into the cellular microenvironment may form the nucleus of a nonspecific in vivo immunoregulatory network. The specificity of peptide regulatory activities could reside in their effectiveness at high concentrations in the cellular microenvironment. The interaction of Fc region peptides with receptors on B cells, T cells, and macrophages/monocytes could result in a dynamic control of immune reactivity.

Amino Acid Sequence↗
PubMed1985

Binding and processing of immunostimulatory Fc gamma 1 fragments by the murine macrophage cell line P388D1.

Previous data from this laboratory indicated that human Fc gamma fragments induce murine B cells to proliferate and that the induction is macrophage-dependent. To further investigate the role of macrophages in this phenomenon, biologically active Fc gamma fragments from a human IgG1 myeloma protein and the murine macrophage-like cell line P388D1 were utilized. Fc gamma 1 fragments bound specifically and to a single class of receptor on P388D1 cells with a Ka value of 4 X 10(6) M-1 and to approximately 2.4 X 10(5) binding sites/cell. The binding was not effectively inhibited by two immunostimulatory Fc gamma 1 subfragments that were macrophage independent, i.e., pFc' fragments approximating the C gamma 3 domain of IgG1 and synthetic peptides representing residues 335-357 in IgG1. P388D1 cells were able to process Fc gamma 1 fragments but not intact IgG1 into subfragments that were able to induce lymphocyte proliferation in the absence of macrophages. The processing was rapid and resulted in active subfragments of several size classes. These findings not only further document the molecular and cellular events in these systems but underscore the usefulness of the P388D1 cell line in future studies on Fc fragment-induced lymphocyte regulation.

Animals↗
PubMed1985

Human C3a-mediated suppression of the immune response. II. Suppression of human in vitro polyclonal antibody responses occurs through the generation of nonspecific OKT8+ suppressor T cells.

C3a-mediated suppression of Ig secretion in human PBL cultures occurs through the activation of suppressor T cells. Incubation of T cell-enriched populations derived from peripheral blood or tonsil results in the activation of nonspecific OKT3+8+ suppressor T cells capable of inhibiting Fc fragment-induced Ig secretion in fresh autologous PBL cultures. Generation of OKT8+ suppressor T cells by C3a requires the interaction of T cells, adherent cells, and C3a. Activation of the suppressor-T-cell pathway is initiated early in culture. Incubation of the T-cell-enriched populations with C3a for 0.5 hr results in functional, transferable suppressor cells. Maximum suppression was achieved when C3a was allowed to interact with the cell population for 1-2 hr.

Antibody Formation↗
PubMed1985

Bifunctional lymphocyte regulation by human Fc gamma fragments and a synthetic peptide, p23, derived from the Fc region.

Fc fragments of human IgG1 and the synthetic peptide, p23, representing residues 335-357 in the CH3 domain of IgG1 were able to increase levels of secreted Ig in murine spleen cell cultures. B cell activation by Fc gamma fragments was macrophage- and T cell-dependent whereas activation by p23 was only T cell-dependent. Induction of Ig secretion by both stimulators was influenced by endogenous oxidative products of arachidonate, as evidenced by the augmentation of Ig levels in cell cultures treated with indomethacin (IM), a prostaglandin (PG) synthetase inhibitor. Both Fc gamma fragments and p23 were able to induce the release of PGE from splenic adherent macrophages and, in the former case, the release was inhibited by either IM or aspirin. Moreover, addition of either exogenous PGE1 or PGE2 reduced the levels of secreted Ig in Fc gamma fragment- or p23-stimulated cell cultures. These data suggest that B cell activation by Fc gamma fragments is influenced by the concomitant induction of suppressive PG.

Animals↗
PubMed1985

Bioactive complement fragments in immunoregulation.

Several fragments derived from complement components have been identified as potent effector substances in in vitro assays that measure cell proliferation and antibody synthesis. The anaphylatoxin C3a suppresses the immune response but fails to influence T- or B-cell proliferation. The factor C5a augments both antibody production and antigen-induced, but not mitogen-induced, T-cell proliferation. C3a-mediated suppression occurs through the activation of a suppressor T-cell cascade with macrophage collaboration. C5a-mediated enhancement, depending upon the in vitro system studied, acts at the level of the helper T cell and/or macrophage. A fragment generated from treating iC3b with kallikrein (c3d-K) has aided in defining a structural region of the C3b molecule that can influence the level of circulating leukocytes. The factor C3d-K is also capable of suppressing both specific and non-specific T-cell proliferative responses and mitogen-induced B cell growth. The mechanism of C3d-K action is defined as a direct effect on "activated" T cells, even though IL-2 synthesis of treated cells is diminished. The effect of C3d-K is long lasting, non-reversible and requires only a short exposure to the target cell.

Animals↗
PubMed1985

Synthetic Fc peptide-mediated regulation of the immune response. II. Analysis of secreted immunoglobulin classes, accessory cell contribution, and lymphocyte proliferation in p23-stimulated spleen cell cultures.

The synthetic peptide p23 representing residues 335 to 357 in the CH3 domain of human IgG1 was able to increase levels of secreted Ig in murine spleen cell cultures. This in vitro response was optimal in the presence of between 10(-4) and 10(-3) micron p23/ml and the levels of secreted Ig reached a maximum on day 4 or day 5 of culture. Supernatants from p23-treated cell cultures generally contained more IgM than IgG and undetectable levels of IgA. Induction of Ig secretion by p23 was macrophage-independent but T cell-dependent and, with respect to the latter case, removal of T cells from spleen cells reduced the levels of both IgM and IgG. Although maintaining the B cell differentiation-inducing quality of its progenitor molecule, the Fc gamma fragment, p23 appeared to have lost the ability to induce B cell proliferation. Evidence is presented that a sequence functionally similar to p23 is extant in mouse IgG by showing that murine Fc gamma fragments were also able to induce increases in Ig-secreting cells in murine spleen cell cultures.

Animals↗
PubMed1985

Human C3a-mediated suppression of the immune response. I. Suppression of murine in vitro antibody responses occurs through the generation of nonspecific Lyt-2+ suppressor T cell.

C3a derived from the third component of human complement was found to suppress in vitro murine anti-SRBC responses. C3a-mediated suppression occurs through the generation of nonspecific Lyt-2+ suppressor T cells. The generation of suppressor cells occurs at an early phase in the response because incubation of naive T cells with C3a for as little as 30 min results in suppression of the anti-SRBC response. The generation of suppressor T cells requires the interaction of T cells, C3a, and a Sephadex G-10-adherent cell, presumably a macrophage. Although the mechanism of action of these suppressor cells has not been elucidated, several possibilities have been eliminated. C3a-suppressor T cells do not apparently release inhibitory lymphokines, nor is helper cell activity inhibited by a 2-day co-culture with these suppressor cells. The observation that interleukin 2 (IL 2)-containing lymphokine preparations could overcome C3a-induced suppression led us to investigate the interaction of the suppressors with IL 2 producer cells. However, neither C3a nor C3a-generated suppressor T cells can block the synthesis of IL 2.

Animals↗
PubMed1985

Lymphocyte activation by the Fc region of immunoglobulin. I. Role of prostaglandins in the down regulation of Fc fragment-induced polyclonal antibody production.

Fc fragment-, subfragment-, and p23-induced polyclonal antibody production are regulated by endogenous and exogenous PGE. Addition of the PG synthetase inhibitor indomethacin (IM) to murine spleen cell cultures resulted in a significant increase in the amount of Ig secreted. Moreover, addition of exogenous PGE to culture resulted in a marked suppression of IgM and IgG secretion. Splenic adherent macrophages and P388D1 cells release PGE upon stimulation with Fc fragments, subfragments, and p23. The inclusion of IM or aspirin in culture was found to abrogate the ability of Fc fragments to induce PGE release from adherent cells. These results suggest a role for PG in immune complex mediated regulation of immune responses.

Adjuvants, Immunologic↗
PubMed1985

Regulation of antibody responses by rheumatoid factor. I. Polyclonal activation of human B cells by rheumatoid factor-containing preparations from seropositive plasma.

Rheumatoid factor (RF)-containing IgM preparations isolated from the plasma of two seropositive patients were able to increase the number of Ig-secreting cells in normal human peripheral blood lymphocyte cultures. This polyclonal B cell activation was optimal in the presence of both T cells and monocytes. A relationship was established between the activator and RF in these preparations based on the ability of both to bind to insolubilized human IgG. The presence of the activator also coincided with the presence of large, RF-containing Ig complexes. These data suggest that RF contributes to the formation of B cell-stimulating immune complexes--a phenomenon with possible negative consequences in disease states characterized by these complexes.

Adult↗
PubMed1985

Salivary gland lymphocytes in primary Sjogren's syndrome lack lymphocyte subsets defined by Leu-7 and Leu-11 antigens.

Primary Sjogren's Syndrome (SS) is an autoimmune disease characterized by dry eyes and dry mouth due to lymphocytic infiltration of lacrimal and salivary glands. Biopsies of their salivary glands provided an opportunity to characterize the phenotypic and functional properties of inflammatory site lymphocytes. We found that the salivary gland lymphocytes (SGL) of SS patients differed from the peripheral blood lymphocytes of the same patients because: a) SGL lacked lymphocytes reactive with anti-Leu-7 and anti-Leu-11 monoclonal antibodies; b) SGL lacked natural killer (NK) activity; and c) SGL lacked the ability to suppress polyclonal B cell responses in the presence of complement fragment C3a, a function that requires the presence of Leu-7+ cells. These studies also showed that the SGL of SS patients differed from tonsillar lymph node (LN) lymphocytes of immunologically normal individuals because tonsillar LN contained Leu-7+ T cells, and tonsillar LN could suppress polyclonal B cell responses in the presence of the complement fragment C3a. The absence of this regulatory subset in the salivary glands of SS patients may contribute to pathogenesis, because these cells may be important in the suppression of polyclonal antibody synthesis and in the elimination of neoplastic or viral infected cells.

Adolescent↗
PubMed1984

Mechanisms of leukocyte regulation by complement-derived factors.

Progress over the past five years has drawn attention to the fact that the anaplylatoxins are important factors in both leukocyte activation and regulation events. The C5 anaphylatoxin has been proposed to play major role in leukocyte aggregation and adherence phenomenon. Influences of C5a on the leukocyte may lead to clinical manifestations such as respiratory distress syndrome after trauma or postpump syndrome after cardiopulmonary bypass, both effects derived from leukocyte sequestration. Many other clinical conditions involving repeated transient sequestration of leukocytes, particularly in the pulmonary vasculature, may eventually be recognized as a complication of systemic complement activation. Dramatic pathologic changes observed in the lungs of animals exposed to either C3a or C5a emphasizes the potential damage that these factors may exert via cellular activation mechanisms (Huey et al., 1983). More recent evidence that the anaphylatoxins are potent immunoregulatory factors under in vitro conditions suggests a physiologic role for these humoral factors in nonspecific modulation of the immune response. It is an attractive hypothesis to suggest that once activated, complement is capable of relaying information to the cellular immune system via the anaphylatoxins. Other components of the complement system have long been known to exert regulatory influences on the immune system, and perhaps molecular description of such entities as the C3d-K fragment will serve to unravel this seemingly more complex effector system. In any case, as our understanding of both the chemical and biologic nature of factors derived from blood complement components advances, it has become apparent that a major function of complement may be to modulate the immune response. We have already demonstrated that these factors are selective both for cell type and for eliciting a variety of cellular responses. From this, one can infer that manipulation of the cellular events will eventually be possible. Hence a therapeutic value may be realized once involvement of these complement factors under in vivo conditions is better characterized.

Anaphylatoxins↗
PubMed1984

Potentiation of the rat delayed-type hypersensitivity reaction by the Fc portion of human IgG1.

Fc fragments derived from a human IgG1 myeloma protein potentiate the rat delayed-type hypersensitivity (DTH) reaction to antigen challenge. Lewis rats immunized with heat-killed tubercle bacilli give augmented DTH reactions to the purified protein derivative of tuberculin when Fc fragments are included in the challenge dose. Similar potentiation of DTH by pFc' fragments indicates that the active site is located in the CH3 domain of IgG1. Histologic evaluation of the augmented reaction sites revealed predominantly mononuclear cell infiltrates characteristic of DTH reactions. Skin tests of tubercle bacilli-sensitized rats with an unrelated antigen and/or Fc fragments fail to elicit significant reactions. Augmentation of the DTH reaction to purified protein derivative is restricted to the Fc or pFc' region fragments since intact monomeric IgG1, Fab fragments, and bovine serum albumin were all shown not to be active potentiators. The DTH reaction of ovalbumin-sensitized rats was similarly augmented when Fc fragments were included with a challenge dose of ovalbumin, thus supporting the general nature of the phenomenon. These results support the concept of Ig molecules as multifunctional proteins that can not only serve effector functions but also participate in the regulation of immune responses.

Animals↗
PubMed1984

Interaction of the enantiomers of 3-0-methyldobutamine, a metabolite of dobutamine, with alpha- and beta-adrenoreceptors in the cardiovascular system of the pithed rat.

The pharmacological activities of the enantiomers of 3-0-methyldobutamine, a metabolite of dobutamine, were investigated at alpha- and beta-adrenoreceptors in the cardiovascular system of pithed rats. Neither enantiomer of 3-0-methyldobutamine produced vasoconstriction in pithed rats, indicating a lack of alpha 1- or alpha 2-adrenoreceptor agonist activity. However, both enantiomers of 3-0-methyldobutamine were found to be alpha 1-adrenoreceptor antagonists. The alpha 1-adrenoreceptor antagonist activity of the enantiomers of 3-0-methyldobutamine was selective, since neither enantiomer antagonized alpha 2-adrenoreceptors at doses up to 10 mg/kg, i.v. The alpha 1-adrenoreceptor antagonist activity of (+)- and (-)-3-0-methyldobutamine was studied in detail in pithed rats. Based on a Schild analysis of the antagonism of the alpha 1-adrenoreceptor mediated pressor effects of cirazoline, (+)-3-0-methyldobutamine had a DR2 value (i.e., dose required to produce a two-fold rightward shift in the dose-response curve of cirazoline) of 0.16 mg/kg, i.v., whereas the DR2 value for (-)-3-0-methyldobutamine was 10.3 mg/kg, i.v. Thus, the potent alpha 1-adrenoreceptor antagonist activity of 3-0-methyldobutamine resides predominantly in the (+)-enantiomer, the latter being approximately 64-fold more potent than the (-)-enantiomer. Both enantiomers of 3-0-methyldobutamine were weak beta 1-adrenoreceptor antagonists that, at high doses, inhibited the chronotropic effect of isoprenaline. In addition, both enantiomers were weak beta 2-adrenoreceptor agonists that produced modest decreases in diastolic blood pressure at high doses. The beta 1-adrenoreceptor antagonist and the beta 2-adrenoreceptor agonist effects of the enantiomers of 3-0-methyldobutamine occurred at doses in excess of 3 mg/kg, i.v. attesting to their weak activity, and neither effect was stereoselective. It is hypothesized that of the potent alpha 1-adrenoreceptor blocking activity of 3-0-methyldobutamine, which resides predominantly in the (+)-enantiomer, may contribute, in part, to the reduction in total peripheral vascular resistance observed following infusion of dobutamine.

Animals↗
PubMed1984

Possible relationship between receptor reserve and the differential antagonism of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses by calcium channel antagonists in the pithed rat.

The effect of the calcium channel antagonist diltiazem was investigated on the alpha-1 and alpha-2 adrenoceptor-mediated pressor responses elicited by cirazoline and B-HT 933, respectively, in pithed rat. Diltiazem (3 mg/kg i.v.) selectively inhibited the alpha-2 adrenoceptor-mediated pressor effect of B-HT 933 but did not affect the alpha-1 adrenoceptor-mediated pressor effect of cirazoline. However, after removal of spare postsynaptic vascular alpha-1 adrenoceptors by treatment with the irreversible alpha adrenoceptor antagonist phenoxybenzamine, the alpha-1 adrenoceptor-mediated pressor response of cirazoline became highly sensitive to antagonism by diltiazem and resembled in this regard alpha-2 adrenoceptor-mediated vasoconstriction for which no receptor reserve exists. In addition, as the alpha-1 adrenoceptor reserve was progressively reduced by treatment with increasing doses of phenoxybenzamine, the alpha-1 adrenoceptor-mediated pressor response of cirazoline became progressively more sensitive to inhibition by diltiazem, such that there was a high inverse correlation between the magnitude of the alpha-1 adrenoceptor reserve and the degree to which this response was antagonized by diltiazem. There was also a high inverse correlation between the intrinsic activity of alpha-1 adrenoceptor selective agonists and the degree to which their pressor responses were inhibited by diltiazem. Thus, pressor responses of agonists with high intrinsic activities (large receptor reserve) were resistant to antagonism by diltiazem, whereas the alpha-1 adrenoceptor-mediated pressor responses of partial agonists with low intrinsic activities (no receptor reserve) were highly sensitive to antagonism by diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗