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Biomedical subjects

E L Morgan

Publications and source records attributed to E L Morgan.

At least 55 records · Page 3Linked to original sources
PubMed1984

Interaction of the novel inotropic agent, ASL-7022, with alpha and beta adrenoceptors in the cardiovascular system of the pithed rat: comparison with dobutamine and dopamine.

Three selective inotropic agents, ASL-7022, dobutamine and dopamine, were evaluated for their effects at alpha and beta adrenoceptors in the cardiovascular system of the pithed rat. ASL-7022, dobutamine and dopamine were equipotent as pressor agents in propranolol- and reserpine-pretreated pithed rats; however, the mechanisms involved in their alpha adrenoceptor-mediated pressor effects were markedly different. The pressor response of ASL-7022 was mediated entirely by postsynaptic vascular alpha-2 adrenoceptors, whereas the pressor response of dobutamine was mediated exclusively by postsynaptic vascular alpha-1 adrenoceptors. The pressor response of dopamine was mediated by both postsynaptic vascular alpha-1 and alpha-2 adrenoceptors. All three compounds elicited beta-2 adrenoceptor-mediated vasodepressor responses in pithed rats when vascular tone was elevated by a constant infusion of angiotensin II. In contrast to the equal vasopressor potencies of these compounds, the vasodepressor activities varied by more than two orders of magnitude with ASL-7022 being the most potent and dopamine the least potent. Based on ratios of relative potencies for alpha adrenoceptor-mediated vasopressor effects and beta-2 adrenoceptor-mediated vasodepressor effects, it appears that dobutamine possesses an equal balance between its vasopressor and vasodepressor potencies, such that the net effect in the vasculature is a physiological antagonism with little or no change in blood pressure, consistent with clinical observations and experiments in animals. In contrast, the vasopressor potency of dopamine exceeds its potency as a depressor agent, such that the net effect is vasoconstriction, consistent with clinical and animal studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

C3d-K, a kallikrein cleavage fragment of iC3b is a potent inhibitor of cellular proliferation.

The C3d-K fragment generated from human iC3b by plasma kallikrein is a potent suppressant of cellular proliferation. Originally characterized as inhibiting human and murine T lymphocyte function, C3d-K is shown in these studies to suppress mitogen-induced B cell growth, the spontaneous proliferation of several tumor cell lines, as well as all forms of T cell proliferation, including that induced by interleukin 2 (IL 2). In addition, synthesis of IL 2 in mixed lymphocyte cultures is blocked by C3d-K, but not IL 2 synthesis induced by Con A. The C3d-K fragment has no effect on resting cells; however, sensitivity to the inhibitory effect of C3d-K is acquired during the activation process. Because the proliferation of mitogen-activated spleen cells is not inhibited by exposure to C3d-K for the initial 24 hr of culture, only late steps in the cell activation process are C3d-K sensitive. When C3d-K is present throughout the course of the 72-hr culture, suppression was observed. Data obtained with the tumor cell lines suggest that once suppression is achieved, it is long-lasting even in the absence of C3d-K.

Animals↗
PubMed1984

Interactions of epinephrine, norepinephrine, dopamine and their corresponding alpha-methyl-substituted derivatives with alpha and beta adrenoceptors in the pithed rat.

The effects of alpha-methyl substitution of epinephrine, norepinephrine and dopamine were investigated at alpha-1, alpha-2, beta-1 and beta-2 adrenoceptors in the pithed rat. alpha-Methyl substitution of these three phenethylamines variably altered their capacity to elicit alpha adrenoceptor-mediated vasoconstriction, with slightly enhanced potency being observed for alpha-methyl substitution of norepinephrine and dopamine and a marked reduction in potency for alpha-methyl substitution of epinephrine. However, in all instances, alpha-methyl substitution resulted in a higher selectivity for alpha-2 adrenoceptors (over alpha-1 adrenoceptors). Thus, while epinephrine, norepinephrine and dopamine all produced vasoconstriction that was mediated equally by postsynaptic vascular alpha-1 and alpha-2 adrenoceptors, their corresponding alpha-methyl-substituted derivatives produced vasoconstriction exclusively by activation of postsynaptic vascular alpha-2 adrenoceptors. The beta-1 adrenoceptor-mediated chronotropic effects of these phenethylamines were inconsistently affected by alpha-methyl substitution, with an increase in potency being observed for alpha-methyl substitution of norepinephrine and decreases in potency being observed for alpha-methyl substitution of epinephrine and dopamine. In marked contrast, alpha-methyl substitution of epinephrine, norepinephrine and dopamine was associated with consistent and dramatic increases in potency for beta-2 adrenoceptor-mediated vasodepressor activity. These results indicate that alpha-2 and beta-2 adrenoceptors possess the unique ability to recognize and/or accept alpha-methyl substituents on phenethylamines and that this ability is not shared by their respective receptor subtypes, the alpha-1 and beta-1 adrenoceptors. Furthermore, the results show that alpha-methylepinephrine is a potent beta adrenoceptor agonist, with an apparent 500-fold selectivity for beta-2 adrenoceptors over beta-1 adrenoceptors.

Animals↗
PubMed1984

Anaphylatoxin-mediated regulation of human and murine immune responses.

C3a and C5a derived from the human complement components C3 and C5, respectively, were found to possess immunoregulatory activities. C3a was found to be capable of suppressing both antigen-specific and polyclonal antibody responses. In contrast, C3a was unable to suppress antigen- or mitogen-induced B or T cell proliferative responses. Helper T cells were found to be the target of C3a-mediated immunosuppression. Suppression occurred via the generation of suppressor T cells. In contrast to the results obtained with C3a, C5a was found to augment both antigen-specific and non-specific in vitro humoral immune responses. Moreover, C5a potentiated antigen- and alloantigen-induced T cell proliferative responses. As opposed to C3ades Arg-77, C5ades Arg retained all of the immunoregulatory activity associated with the intact molecule. Helper T cells are required for C5a-mediated potentiation of the Fc fragment-mediated polyclonal antibody response. Substitution for T cells by a soluble T cell-replacing factor rendered lymphocytes refractory to the enhancing properties of C5a.

Anaphylatoxins↗
PubMed1983

Synthetic Fc peptide-mediated regulation of the immune response. I. Characterization of the immunomodulating properties of a synthetic 23-amino acid peptide derived from the sequence of the CH3 domain of human IgG1.

A synthetic 23-amino acid peptide derived from the CH3 domain of human IgG1 was found to be a potent adjuvant as well as a polyclonal activator. The Fc peptide was found to enhance human and murine humoral, and T cell-mediated immune responses. Moreover, in vivo administration of Fc peptide enhanced murine natural killer cell activity. The synthetic Fc peptide was found to be more potent, on a molar basis, than native Fc fragments in inducing polyclonal antibody production and potentiating immune responses.

Adjuvants, Immunologic↗
PubMed1983

Lymphocyte phenotype and function in pseudolymphoma associated with Sjögren's syndrome.

Lymph node (LNL) and salivary gland lymphocytes (SGL) from three patients with pseudolymphoma and primary Sjögren's syndrome (1(0)SS) were characterized with monoclonal antibodies to demonstrate (a) a predominance of T cells (greater than 80%) reactive with anti-T cell antibodies OKT4 (greater than 70%) and OKT8 (less than 20%); (b) a high prevalence of activation antigens (greater than 50% of cells reactive with antibody OKT10 and anti-Ia antibody); (c) polyclonal B cells (8-15% of all cells expressing kappa or lambda); and (d) a specific B cell subset defined by reactivity with antibody B532 that was not present in their peripheral blood. In vitro functional studies showed that both SGL and LNL provided T helper activity for immunoglobulin synthesis and that this activity could be abolished by treatment with antibody OKT4 plus complement. The SGL and LNL exhibited little natural killer, antibody-dependent cellular cytotoxicity, or cytotoxic T cell activity. Normal karyotype was observed in SGL, LNL, and peripheral blood lymphocytes (PBL) from these patients. These findings indicate that pseudolymphoma in 1(0)SS results from the infiltration of salivary glands and extraglandular tissues by nonneoplastic T helper cells. Monoclonal antibodies provide an important tool to distinguish pseudolymphoma from non-Hodgkins (B cell) lymphomas that have a markedly elevated incidence in 1(0)SS patients. Our finding of T helper cells in pseudolymphoma tissues supports the hypothesis that chronic stimulation of B cells by helper T cells leads to eventual escape of a malignant B cell clone.

Aged↗
PubMed1983

Suppression of humoral immune responses by synthetic C3a peptides.

Synthetic oligopeptides based on the COOH-terminal sequence of native human C3a were examined for the ability to suppress antigen-specific and polyclonal antibody responses. The synthetic peptides were found to qualitatively mimic the suppressive actions of human C3a, but proved to be less active on a molar basis. Comparison of the activity of the peptides with native C3a indicates that the most potent peptide is C3a 57-77 with C3a 65-77, C3a 70-77, C3a[Ala 71,72]70-77, and C3a 73-77 being less active, respectively. These results indicate that the region of the C3a molecule responsible for immunosuppression is located in the COOH region.

Anaphylatoxins↗
PubMed1983

Polyclonal activation of murine B lymphocytes by immune complexes.

Murine splenic B lymphocytes are stimulated by homologous immune complexes to proliferate and secrete polyclonal antibody. The use of antibody from whole serum or monoclonal antibodies to form complexes resulted in the stimulation of mouse B lymphocytes. The ratio of antibody to antigen appears to be critical for the generation of the polyclonal antibody response. Because antigen and antibody are added independently at culture initiation, the exact nature of the complex is unknown, but optimal polyclonal antibody formation occurs in slight antigen excess. Immune complex-induced polyclonal antibody production requires the presence of both macrophages and T cells, whereas B cell proliferation requires only macrophages. The role of the macrophage appears to be to cleave a low m.w. (17,000) fragment from the complex, which is responsible for lymphocyte activation.

Animals↗
PubMed1983

Anaphylatoxin-mediated regulation of the immune response. II. C5a-mediated enhancement of human humoral and T cell-mediated immune responses.

C5a derived from the fifth component of human complement was found to potentiate both specific and non-specific human in vitro humoral immune responses. In addition, C5a is capable of potentiating antigen- and alloantigen-induced T cell proliferative responses. In contrast to these results, C5a was unable to modulate mitogen-induced B and T cell proliferative responses. The carboxyterminal arginine of C5a is not essential in order for C5a to enhance immune responses. C5ades Arg was found to augment the immune response to the level of C5a-mediated enhancement. The serum carboxypeptidase inhibitor, 2-mercaptomethyl-5-quanodinopentanoic acid, which prevents cleavage of the terminal arginine, allowed us to assay the effects of C5a on in vitro immune responses in the presence of serum. Helper T cells are involved in C5a-mediated immuno-potentiation. Substitution of T cells by soluble T cell-replacing factors, (Fc)TRF, rendered lymphocyte cultures refractory to the enhancing properties of C5a.

Adult↗
PubMed1983

Suppression of T lymphocyte functions by human C3 fragments. I. Inhibition of human T cell proliferative responses by a kallikrein cleavage fragment of human iC3b.

Cleavage of human iC3b by kallikrein isolated from human plasma generates a fragment, C3d-K, which is capable of inhibiting mitogen-, antigen-, and alloantigen-induced T lymphocyte proliferation. Native C3, C3a, C3b, and C3c-K had no effect on lymphocyte proliferative responses. In addition to being a potent suppressor of mitogen- and antigen-induced proliferation, C3d-K is capable of inducing leukocytosis in both mice and rabbits. Intravenous injection of C3d-K, but not C3, C3a, C3b, or C3c-K, results in a twofold to threefold increase in the number of circulating leukocytes. Thus, C3d-K exhibits two apparently independent functions, namely suppression of T cell proliferation and leukocytosis. Cleavage of iC3b by kallikrein results in the production of only two fragments. The larger fragment, C3c-K, is 144,000 m.w. and has a chemical structure analogous to that of C3c obtained from the cleavage of C3 by trypsin or elastase. The smaller fragment, C3d-K, is 41,000 m.w. and contains the metastable binding site of C3. It is through this site located in the C3d region of the molecule that C3 attaches covalently to target cells. Analysis of the amino terminal region of C3d-K provided a sequence that fails to overlap with any sequence yet reported for other characterized C3 fragments, including C3d originally obtained from elastase digestion. A revised model of the C3 molecule is proposed, with locations of the C3e and C3d fragments assigned on the basis of chemical analyses.

Adult↗
PubMed1983

Potentiation of specific human in vitro immune responses by the Fc portion of human immunoglobulin.

Fc fragments derived from a human IgG1 myeloma protein were found to be a potent adjuvant for in vitro human immune responses. The addition of Fc to cultures of human PBL along with SRBC resulted in a pronounced enhancement of the primary in vitro anti-SRBC response. In addition to potentiating the humoral immune response, Fc was also found to augment the tetanus toxoid-induced T cell proliferative response. Augmentation of the immune response is mediated by Fc and not the result of an artifact due to the addition of extraneous protein to culture because neither intact IgG1 nor Fab fragments derived from this myeloma protein possessed any adjuvant properties. The temporal relationship of the administration of antigen and Fc to culture is critical for the potentiation of the immune response. The maximal Fc adjuvant effect was observed when Fc was added with antigen at the beginning of culture.

Adult↗
PubMed1982

Anaphylatoxin-mediated regulation of the immune response. I. C3a-mediated suppression of human and murine humoral immune responses.

The C3a fragment of the third component of complement was found to have immunosuppressive properties. C3a is capable of suppressing both specific and polyclonal antibody responses. In contrast, C3a had no effect on antigen- or mitogen-induced B or T cell proliferative responses. The carboxy-terminal arginine is essential for C3a to exhibit its immunosuppressive properties. The serum carboxypeptidase inhibitor 2-mercaptomethyl-5-guanodinopentanoic acid, which prevents cleavage of the terminal arginine that would produce C3ades Arg-77, allowed us to assay the effects of C3a on in vitro immune response systems where serum is required. When the terminal arginine is removed from C3a, the resulting C3ades Arg-77 molecule is nonsuppressive. Helper T lymphocytes are the target of C3a-mediated suppression of the immune response. Substitution of T cells by soluble T cell factors was found to abrogate the C3a suppressive activity.

Anaphylatoxins↗
PubMed1982

Role of Fc receptors in lymphocyte activation: deficiency in T- and B-lymphocytes from aged animals.

Fc fragments derived from human immunoglobulin possess the ability to induce B-cell proliferation, polyclonal antibody responses, and augment cell-mediated and T-dependent humoral responses. However, aged animals display much lower responses to Fc fragment stimulation. Proliferation and polyclonal antibody synthesis are reduced two-five-fold in aged animals compared to the young-adult responses. Furthermore, Fc fragments are unable to potentiate plaque-forming cell (PFC) development in aged animals. Aged B-lymphocytes are deficient in responding to Fc fragments, as their admixture with young-adult T-cells does not restore polyclonal antibody formation. T-cells from aged animals are also ineffective in promoting the polyclonal response when mixed with young-adult B-cells. The T-cell lesion has been further defined as a deficiency in production of an Fc fragment induced T-cell-replacing factor [(Fc)TRF]. The inability of Fc fragments to potentiate anti-SRBC responses in aged animals is also due to a T-cell defect which can be corrected by supplementation with interleukin-2 (IL-2).

Aging↗
PubMed1982

Isolation and identification of a biologically active peptide derived from the CH3 domain of human IgG1.

A 24-amino acid residue peptide has been isolated from the Fc region of a human IgG1 myeloma protein. The peptide has associated with it the same ability to induce murine B cells to polyclonally secrete antibody as does the intact Fc fragment. Amino acid composition of the peptide indicates that on a mole/mole basis the isolated peptide is identical to that published for residues 335-358 in the Eu IgG1 sequence. This peptide corresponds roughly to the first 24 amino acids of the CH3 domain. It is believed that the immunoregulatory properties that have been ascribed to the Fc fragment are associated with this peptide.

Amino Acid Sequence↗
PubMed1982

Immunological tolerance in the chicken. III. Partial physiochemical characterization of two suppressive fractions from serum of chickens tolerant to bovine serum albumin.

Two soluble non-specific suppressive factors were isolated by gel chromatography from the serum of chickens tolerant to bovine serum albumin (BSA). Fraction I was found by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) to contain five proteins with mol. wts from 200,000 to 900,000 unreduced and six proteins that ranged from 70,000 to 180,000 when reduced. The composition was primarily protein, with a small amount of carbohydrate and lipid. One component was identified as IgM, one as a lipoprotein. The others remain unidentified. No evidence of the tolerogen, BSA, was found. The second factor, fraction III of both tolerant and normal serum, was found by SDS-PAGE to have two proteins with mol. wts of 54,000 and 78,000 in the unreduced form and contained a very small amount of protein, a large amount of carbohydrate, and no detectable lipid. Normal fraction III had two proteins with mol wts of 54,000 and 65,000 when reduced, whereas reduction did not affect tolerant fraction III. A soluble suppressive factor, secreted by cultured adherent cells of tolerant chickens, was found to be comparable to fraction III in molecular weight. Comparison of these results with those of other reported suppressive factors is made and possible identities of the suppressive components of fractions I and II are discussed.

Animals↗
PubMed1982

Modulation of the immune response by anaphylatoxin in the microenvironment of the interacting cells.

It was shown that the anaphylatoxins C3a and C5a can modulate in vitro immunological reactivities. C3a suppresses both the in vitro polyclonal antibody response and the specific antibody response to sheep red blood cells (SRBC) of both mouse spleen cells and human peripheral blood cells. The target cell in the mouse for C3a appears to be an Lyt-1+2- suppressor-inducer cell and macrophages appear not to be required. In contrast to C3a, C5a enhances in vitro responses of mice. Both the response to SRBC and the mixed lymphocyte reaction are enhanced by C5a. This enhancement appears to be through an Ia- macrophage that contains receptors for C5a. It appears that enhancement may be brought about by interleukin 1, which is released when Ia- macrophages are pulsed with C5a. It is suggested that these anaphylatoxins, when present in high concentrations in the microenvironment of the interacting cells of the immune system, play a dynamic role in the regulation of the immune response. Peptide fragments cleaved from the Fc portion of antibody, complexed with antigen in this microenvironment, may have a similar regulating role.

Animals↗
PubMed1982

The immune response in aged C57BL/6 mice. II. Characterization and reversal of a defect in the ability of aged spleen cells to respond to the adjuvant properties of Fc fragments.

Fc fragments derived from papain cleavage of human Ig were found to be unable to enhance the in vitro anti-SRBC response of aged mice. The inability of aged spleen cells to respond to the adjuvant properties of Fc fragments is localized to the aged T cell population. The addition of Fc fragments to cultures of aged B cells and young adult T cells, but not young adult B cells and aged T cells, resulted in an enhanced anti-SRBC response. The Fc fragment adjuvant defect in spleen cells from aged mice can be reversed by the addition of IL 2 to culture. The addition of either Fc fragments alone or IL 2 alone with antigen to intact aged spleen cell populations did not result in an enhanced anti-SRBC response. When aged spleen cell cultures receive both Fc and IL 2, however, a marked enhancement is observed. These data indicate that IL 2 action on aged spleen cells results in the acquisition of reactivity to Fc adjuvant action by aged mice.

Adjuvants, Immunologic↗