Ross Rocklin

Labcorp · Medical

Background: Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermat...

Background: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels. Methods: We enrolled patients with persis...

Histamine has long been recognized as a mediator of acute allergic reactions in humans and was one of the first chemical substances shown to be associated with mast cells. β-Imidazolylethylamine was first synthesized in 1907 (Shore et al., 1959) and was given the name histamine (Greek, histos) because of its ubiquitous presence in animal tissues. A...

The effect of vitamin E supplementation on the immune response of healthy older adults was studied in a double-blind, placebo-controlled trial. Subjects (n = 32) resided in a metabolic research unit and received placebo or vitamin E (800 mg dl-alpha-tocopheryl acetate) for 30 d. Alpha-tocopherol content of plasma and peripheral blood mononuclear ce...

Activation of neutrophils (PMN) within the airways results in the secretion of a number of products such as reduced oxygen metabolites that could contribute to the inflammatory response associated with asthma. However, mediators of allergy, such as histamine, prostaglandin E2 (PGE2), isoproterenol, and adenosine, may serve to mitigate this inflamma...

Allergen-specific immunotherapy has been shown to be clinically effective in patients with seasonal allergic rhinitis and/or asthma. Patients who receive this therapy undergo a number of specific immunologic changes in response to the allergen being administered. These include a "blunting" of the seasonal rise of allergen-specific IgE as well as lo...

Diagnostic nasal cytology has been advocated for use in distinguishing allergic from nonallergic rhinitis. We sought to determine prospectively the frequency of nasal eosinophilia (NE) in 100 patients in whom having allergic rhinitis (AR), nonallergic rhinitis, and other atopic conditions not involving the respiratory tract have been diagnosed. A n...

The signals required to induce purified normal human B cell subpopulations into IgE production were studied. Pokeweed mitogen (PWM)-stimulated T cell supernatant induced IgE synthesis in low-density but not high-density Percoll-gradient-separated resting B cells. The PWM supernatant also enhanced (greater than 2-fold) IgE synthesis by anti-IgM (but...

Although clinical responses to allergens have been shown to primarily involve IgE antibodies, there is often no clear correlation between the amount of allergen-specific IgE present in the serum and the nature and severity of allergic symptoms. This observation raises the question of the possible role of non-IgE mediated types of immune responses i...

We studied the ability of monocytes to metabolize [3H]arachidonic acid (AA) provided exogenously by activated T cells, and the extent to which dexamethasone suppressed eicosanoid production by normal and atopic cells. [3H]AA metabolites were identified using a reverse-phase high pressure liquid chromatography system (HPLC). Unstimulated and PHA-sti...

We investigated the ability of the human lymphokine leukocyte inhibitory factor (LIF) to modulate neutrophil-endothelial cell (EC) adherence. EC were cultured from collagenase-treated human umbilical cord veins and grown in complete medium supplemented with EC growth factor. Adherence was measured as the percent of 51Cr-labeled neutrophils remainin...

IgE synthesis by the human myeloma line U-266 was enhanced 3- to 15-fold in the presence of supernatants from cultures of mononuclear cells (MNC). The enhancing activity was concentration-dependent and was derived from cells that were cultured in the absence of serum and received no in vitro stimulation by exogenous mitogens or lymphokines. T- and...

The current studies were designed to extend our investigations on the ability of the lymphokine leukocyte inhibitory factor (LIF) to function as a neutrophil activator. Specifically, we investigated whether LIF could modulate neutrophil (PMN) aggregation. Aggregation was measured as the increase in light transmission using a Payton aggregometer. We...

Neutrophils from atopic and nonatopic donors were treated with prostaglandins D2 and E2 before stimulation of the respiratory burst. Both agents inhibited neutrophil response to formyl-methionyl-leucyl-phenylalanine, but superoxide production was inhibited much more profoundly by D2 than by E2. Inhibition was similar in atopics and nonatopics. Phor...

The lymphokine leukocyte inhibitory factor (LIF) has previously been documented to enhance several neutrophil (PMN) functions, including stimulated chemotaxis and superoxide generation, phagocytosis and adherence of opsonized targets, and antibody-dependent cellular cytotoxicity. The present studies were designed to investigate the effects of LIF o...

The release and metabolism of endogenous arachidonic acid (AA) in physiologically activated platelets obtained from 11 atopic patients with allergic rhinitis and/or asthma was compared to that of sex- and age-matched nonatopic controls. Prelabeled [3H]AA platelets were stimulated with thrombin or collagen and the amount of free [3H]AA and radiolabe...

This study documents, by means of both solid and liquid phase assays, the presence of anti-idiotypic antibodies (Ab2) in the serum of one allergic individual undergoing ragweed immunotherapy. Serum from this individual was collected and F(ab')2 fragments specific for ragweed antigen E (AgE) were prepared (Ab1). These AgE-specific F(ab')2 Ab1, follo...

The present study demonstrates the cross-reactivity of a murine monoclonal antibody (MoAb) directed against purified ragweed antigen E (AgE) with human Ab1. This antiragweed AgE MoAb (clone SC7H.1G, IgM kappa) was used to detect Ab2 in the sera obtained from the three groups of subjects. Utilizing an ELISA assay, we found that immunoglobulins from...

The distinctions in physiologic functioning between atopic and non-atopic individuals are often subtle and have not been well defined. Although the neutrophil plays a supporting role in atopic disease, several differences in neutrophil function have been noted when atopic and non-atopic subjects were compared. For example, decreased enzyme release...

Activated neutrophils may play a part in atopic disorders. In these studies, neutrophils were obtained from atopic and nonatopic adults for assessment of respiratory-burst activity. Superoxide production was measured in the resting state and after stimulation with phorbol myristate acetate, formyl-methionyl-leucyl-phenylalanine (f-met-leu-phe), or...

This study documents, by means of both solid and liquid phase assays, the presence of anti-idiotypic antibodies (Ab2) in the serum of one allergic individual undergoing ragweed immunotherapy. Serum from this individual was collected and F(ab′)2 fragments specific for ragweed antigen E (AgE) were prepared (Ab1). These AgE-specific F(ab′)2 Ab1, follo...

The effect of phorbol 12-myristate 13-acetate (PMA), calcium ionophore (A23187), opsonized zymosan (OZ), and N-formylmethionyl-leucyl-phenylalanine (f-Met-Leu-Phe) on protein phosphorylation was examined in purified eosinophils (eos) isolated from human peripheral blood. Eos were prelabeled with [32P]orthophosphate, stimulated with several activati...

We prospectively studied the effect of ragweed immunotherapy on the generation of suppressor T cells that modulate total and antiragweed IgE production in five patients with seasonal allergic rhinitis. Suppressor T cell depletion was accomplished by treating mononuclear cells (MNCs) with the monoclonal antibody Leu 2b followed by the addition of co...

The human lymphokine, leukocyte inhibitory factor (LIF), was investigated for its effect on neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) for K562 targets. Highly purified LIF (0.5 to 2 U/ml) induced a significant dose-dependent potentiation of neutrophil ADCC by up to 54.9% (p less than 0.001). Higher concentrations of LIF in...

Human leukocyte inhibitory factor (LIF) is a lymphokine initially defined by its ability to inhibit the random migration of neutrophils. We have recently demonstrated that LIF also potentiates a number of f-met-leu-phe-mediated functions as well as enhancing one Fc receptor-mediated function (antibody-dependent cellular cytotoxicity). In this paper...

Glucocorticoid-induced enhancement of polyclonal immunoglobulin production of the IgG, A, and M classes by human peripheral blood mononuclear cells has been shown to be dependent on regulatory T-cells. The following in vitro investigation demonstrated an enhancing effect of glucocorticoid on IgE production by mononuclear cells from atopic patients,...

Until recently, histamine has been considered only in the context of its being the major mediator of immediate-type hypersensitivity responses. However, subsequent investigations have demonstrated an additional role for histamine as a regulator of both cellular and humoral immune responses. In this review, we will analyze critically histamine modul...

In order to study the biochemical consequences of prolonged in vitro activation of human blood eosinophils, aqeous whole cell lysates, cell-free supernatants from resting eosinophils, and cells activated with opsonized zymosan, calcium ionophore (A23187), N-formylmethionylleucylphenylalanine (fMet-Leu-Phe), and phorbol 12-myristate 13-acetate (PMA)...

The ability of purified (80,000-fold) human leukocyte inhibitory factor (LIF) to modulate several formyl-methionyl-leucyl-phenylalanine (f-met-leu-phe)-induced neutrophil functions was evaluated. Although not affecting directed migration itself, at low concentrations (1/2 to 2 U/ml), LIF was demonstrated to potentiate chemotaxis induced by f-met-le...

We have recently demonstrated that atopic T lymphocytes have decreased sensitivity to prostaglandin E2 (PGE2). In order to determine whether this decreased sensitivity was reflected at the receptor level, we have employed a radioligand binding assay utilizing [3H]PGE2. We have demonstrated a single specific reversible binding site for [3H]PGE2 on n...

We have documented a single, specific binding site for [3H]pyrilamine on normal human T helper, T suppressor, B cells, and monocytes. The binding of the radioligand to its receptor is reversible with cold H1 antagonist, saturates at 40 to 60 nM, and binding equilibrium is achieved in 2 to 4 min. Using a computer program (Ligand), we calculated the...

To evaluate the potential role of immunoregulatory cells modulating the maternal immunologic response during pregnancy, we carried out phenotypic and functional studies in patients with normal obstetrical histories during each trimester and in patients with chronic idiopathic spontaneous abortions. Using monoclonal antibodies (Ortho), total numbers...

We previously have found that monocytes from patients with allergic rhinitis and/or asthma produce less PGE2 than cells from normal subjects in response to a histamine-induced lymphokine. In order to investigate this observation further, we measured the fatty acid content in the total phospholipids derived from the plasma, red cells, buffy coat cel...

Suppressor cell function was studied in 31 patients with primary biliary cirrhosis. Blood mononuclear cells were activated in vitro with suboptimal or optimal concentrations of concanavalin A and suppression of mitogen-induced proliferation or synthesis of anti-mitochondrial antibodies was measured. At suboptimal concentrations of concanavalin A, m...

The effect of PGE2 and PGD2 on several lymphocyte functions in vitro was evaluated in nonatopic and atopic subjects. Both PGE2 and PGD2 inhibited phytohemagglutinin-induced protein synthesis ([3H] leucine uptake) by nonatopic mononuclear cells and T cells in a dose-dependent manner (10(-6) to 10(-12) M). Protein synthesis by atopic mononuclear cell...

The effects on neutrophil function of the new immunomodulatory agent fanetizole mesylate were studied. Fanetizole did not affect random or stimulated migration, phagocytosis, or degranulation by normal human neutrophils. Production of superoxide in response to the chemotactic factor formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe) was markedly...

Do eosinophils modulate lymphocyte function? This question was studied by examining the effect of purified eosinophils (eos) on lectin-induced human lymphocyte proliferation. Intact resting or zymosan-stimulated eos or their extracts were cocultured with phytohemagglutinin-stimulated mononuclear cells in vitro and [3H]thymidine uptake was measured...

The regulatory influence of atopic eczema and non-atopic T cells on spontaneous IgE synthesis by eczema B cells was examined. Eczema B cells were cocultured with either autologous or allogeneic T cells in RPMI 1640 with 10% fetal calf serum at 0.75 X 10(6) cells/ml (B/T = 0.5) and supernatant IgE was measured by a modified PRIST assay. Net IgE synt...

The effect of dexamethasone (DM) on de novo in vitro total IgE synthesis by blood mononuclear cells (MNC) was studied in atopic patients with eczema and in nonatopic control subjects. Unfractionated blood MNC were cultured at 1 X 10(6) cells per milliliter for 7 days in RPMI 1640 with 10% fetal calf serum with or without decreasing concentrations o...

The fact that histamine can influence the immune process at different stages and that it can influence different subpopulations of cells at concentrations that probably exist in vivo during physiologic and pathologic events indicates that it can be seriously considered as a significant modulator of inflammatory and immune processes. Once histamine...

The effect of Fanetizole mesylate or CP-48,810, a new immunostimulating drug, on suppressor cell function and IgE synthesis in vitro was evaluated in atopic patients with allergic rhinitis and/or asthma and eczema. In the absence of the drug, histamine (10(-3)M) stimulated blood mononuclear cells from 23 atopic patients suppressed concanavalin A-in...

Various metabolic inhibitors and agents which increase intracellular cyclic nucleotide levels were investigated for their effects on the generation of suppressor cells in a co-culture system. Human blood mononuclear cells (MNC) were stimulated with histamine (10(-3) - 10(-5)M) for 24 h in the absence or presence of other agents, washed, co-cultured...

T lymphocytes mediate a number of cellular-immune reactions including cutaneous delayed hypersensitivity of the tuberculin or contact types, resistance to infection by intracellular facultative microorganisms, host versus graft and graft versus host rejection phenomena, and tumor surveillance. These reactions result from complex cellular interactio...

Tlymphocytes mediate a number of cellular-immune reactions including cutaneous delayed hypersensitivity of the tuberculin or contact types, resistance to infection by intracellular facultative micro-organisms, host vs. graft and graft vs. host rejection phenomena, and tumour surveillance. These reactions result from complex cellular interactions be...

In vitro IgE synthesis by blood mononuelear cells obtained from atopic patients and non-atopic subjects was investigated using a sensitive double antibody radioimmunoassay. De novo total IgE synthesis was detected in the culture supernatants of 6/6 eczema patients and 22/33 atopic patients without eczema but not in non-atopic subjects. Further, IgE...

To characterize the defect responsible for abnormal histamine-induced suppressor cell function observed in atopic subjects, we studied histamine-induced suppressor factor (HSF) production and augmented prostaglandin E2 production. In addition, we exogenously provided interleukin 1 to determine whether abnormal histamine-induced suppressor cell func...

The effects of the lymphokine, leukocyte inhibitory factor (LIF), on human neutrophil function were studied. This soluble mediator, which is defined by its specific inhibition of neutrophil locomotion, does not interfere with chemotactic factor binding and does not affect basal or stimulated superoxide generation by neutrophils. In contrast, phagoc...

A possible mechanism to explain the suppression of mitogen-induced lymphocyte proliferation in vitro by histamine-stimulated mononuclear cells was investigated. In initial experiments, the inhibitory action of histamine-induced suppressor factor (HSF) on lymphocyte proliferation was documented to be reduced by the addition of indomethacin (1 microg...

In vitro IgE synthesis by blood mononuclear cells from atopic patients and nonatopic subjects was examined. A total of 1 X 10(6) mononuclear cells cultured in RPMI-1640 and 10% fetal calf serum with or without cycloheximide was found to be optimal to detect de novo synthesis. A modified Phadebas IgE paper radioimmunosorbent test was employed for th...

A product of histamine-stimulated human lymphocytes, histamine-induced suppressor factor or HSF, was characterized by enzyme treatment, sensitivity to reduction and alkylation, by molecular sieve chromatography, and by polyacrylamide gel electrophoresis. HSF was found to have a wide pH stability (pH 3-10), sensitivity to temperatures greater than 8...

The effect of histamine-induced suppressor factor (HSF) on the humoral immune response was examined with the model of polyclonal B cell activation induced during a primary mixed lymphocyte culture (MLC). The number of plaque-forming cells (PFC) generated during MLC was measured by a protein A plaque assay. HSF was produced by incubating lymphocytes...

We have analyzed the cellular interactions required for the generation of histamine- and concanavalin A (Con A)-induced suppressor T cells by employing a co-culture assay and techniques for fractionation of human blood mononuclear cells (PBMC). PBMC cultured in the presence of histamine (0.1 mM-1 mM) or Con A (20 micrograms/ml) for 24 h, mitomycin...

The interaction of leukocyte inhibitory factor (LIF), a lymphokine that acts as a cell-directed inhibitor of neutrophil locomotion, with the plasma membrane of its target cell was studied. LIF bound specifically to intact neutrophils and to neutrophil plasma membrane vesicles but not to intact macrophages, erythrocytes, or plasma membrane vesicles...

A case of Pneumocystis carinii pneumonia and cytomegalovirus infection occurring in a previously healthy adult male homosexual who was not receiving known immunosuppressive therapy is described. This 35-year-old man had been treated with metronidazole and tetracycline for an intermittent diarrheal illness of 5 months' duration. He was then admitted...

Employing a coculture assay and techniques for fractionation of human peripheral blood mononuclear cells (PBMC), we have analyzed the cellular interactions required for the generation and expression of histamine-induced suppressor activity. PBMC cultured in the presence of histamine (10−4 to 10−3M) for 24 hr could function as suppressor cells. In o...

An IgG blocking factor previously described to be present in the serum of normal multigravid women inhibits the production of macrophage migration inhibitory factor (MIF) by maternal lymphocytes responding to paternal antigens. In the present study, this blocking factor was detected in primigravid women during 12–26 weeks of gestation. The factor w...

To detect a potential defect in immunoregulatory function in atopic subjects, we studied histamine-induced suppressor-T-cell activity and histamine Type 1 and Type 2 receptors on T cells. Peripheral-blood mononuclear cells from 16 atopic subjects generated less histamine-induced suppressor activity than did those from 20 nonatopic normal controls (...

An IgG blocking factor previously described to be present in the serum of normal multigravid women inhibits the production of macrophage migration inhibitory factor (MIF) by maternal lymphocytes responding to paternal antigens. In the present study, this blocking factor was detected in primigravid women during 12–26 weeks of gestation. The factor w...

Leukocyte inhibitory factor (LIF), a lymphokine that inhibits the random and directed migration of polymorphonuclear (PMN) leukocytes, was purified from a human non-T, non-B leukemia cell line (Reh). From 10 liters of serum-free supernatant, 1.3 microgram of protein with LIF activity was obtained by the sequential use of affinity chromatography wit...

The modulatory role of histamine was investigated in an in vitro model involving immunoglobulin production by human blood mononuclear cells. The addition of histamine in vitro had little effect on the spontaneous production of IgG (measured by double-antibody radioimmunoassay). However, the addition of histamine (10−4–10−9M) to mononuclear cells st...

The nature of the mononuclear suppressor cell and the fraction of crude soluble egg antigen (SEA) capable of activating antigen-specific suppressor cells were studied in 32 Egyptian children infected with schistosomiasis mansoni. Crude SEA was fractionated on Con A Sepharose, and the unbound and bound material (eluted with alpha-methyl-D-mannoside)...

An LIF-like activity spontaneously produced by a 'non-T, non-B leukemia' cell line (Reh) was partially characterized. Reh cells were grown in RPMI 1640 in 10% fetal calf serum to a density of 1.6x106 cells/ml. The cells were then transferred to serum-free medium (RPMI 1640) and cultured for varying periods of time up to 48 hr. The cellfree supernat...

Once considered only mediators of inflammation, autacoids, (histamine, prostaglandins and beta-mimetic catecholamines) have been found to be generated during specific early and late phases of immunity. They need sufficient concentrations to affect immunocytes and can modulate immunity usually by inhibiting it. Receptors for the autacoids on the imm...

The release of leukocyte migration inhibitory factor (LIF) by human lymphocytes stimulated by pulse exposure to phytohemagglutinin (PHA) was investigated. The activation by PHA occurred very rapidly, since measurable amounts of LIF was produced by cells exposed to PHA for only 15 min at 37°C, and maximum stimulation was reached after 1 hr. Once ini...

Pharmacological agents known to modify intracellular levels of adenosine and guanosine 3′,5′-cyclic monophosphate (cAMP and cGMP) were tested for their ability to influence the formation of leukocyte migration inhibitory factor (LIF) by human lymphocytes stimulated by phytohemagglutinin (PHA). The cAMP-elevating agents, papaverine (3 × 10−5M) and d...

Aliquots of human blood mononuclear cells were cultured in vitro in the absence or presence of varying concentrations of histamine (10(-3)-10(-8) M) for 24 hr, mitomycin treated, washed, and cocultured with autologous indicator cells that were then stimulated by PHA. The degree of suppression of thymidine uptake was measured in the presence of hist...

This chapter discusses a broad array of lymphokines and monokines that have marked biological effects on a variety of cell types, including B and T lymphocytes, macrophages, and other cells. The migration inhibitory factors, the chemotactic factors, the mitogenic factors, the helper and suppressor factors, the lymphotoxins, and growth-promoting fac...

Cell-mediated immunity (CMI) to soluble egg antigen (SEA) and tuberculin purified protein derivative (PPD) was evaluated by means of in vitro lymphocyte proliferation and quantitation of in vivo granuloma size in 31 Kenyan children (ages 7 to 16) with Schistosoma mansoni infection. Although antigen-induced proliferative responses varied from patien...

Human leukocyte migration inhibitory factor (LIF) appears to be a serine esterase and protease exhibiting specific affinity towards arginine esters and amides. On the basis of indirect evidence that an amide of the oligopeptide benzoyl-phenylalanyl-valyl-arginine might have high and selective affinity for LIF, we prepared an ester of this oligopept...

The effects of human lymphokines on the surface charge density of human polymorphonuclear (PMN) leukocytes have been determined using the laser Doppler technique of electrophoretic light scattering. Unfractionated antigen (streptokinase-streptodornase or candida)-stimulated lymphocyte supernatants were found to decrease the mode electrophoretic mob...

The cells which elaborate a soluble suppressor factor in vitro in response to histamine (histamine-induced suppressor factor or HSF) were partially characterized in the present studies. Human blood T- and B-cell populations were purified by affinity chromatography with rabbit anti-human F(Ab′)2 and examined for their ability to make HSF. Highly pur...

We used a suppressor-cell assay to study a possible mechanism of allergy desensitization. Before specific immunotherapy, blood mononuclear cells from 20 patients with ragweed hayfever failed to exhibit suppressor activity in vitro after stimulation by ragweed antigen E. However, when the 10 patients with allergic rhinitis had been desensitized by i...

The hypothesis that hormones produced by the placenta contribute to immunosuppression during pregnancy is an attractive one. In order partially to evaluate this hypothesis, we utilized the Migration Inhibition Factor (MIF) Assay, which is an in vitro model of delayed hypersensitivity in that presensitized lymphocytes stimulated by antigen release a...

Electrophoretic light scattering (laser Doppler electrophoresis) has been employed to study the surface charge density of macrophages treated with several lymphokine preparations. Guinea pig peritoneal exudate macrophages were exposed to 1) unfractioned supernatants from antigen-stimulated human and guinea pig lymphocyte cultures, 2) fractionated g...

Treatment of human mononuclear cells with sodium metaperiodate (NaIO4) or neuraminidase and galactose oxidase (NGO) results in lymphocyte activation and subsequent generation of supernatants rich in migration inhibitory factor (MIF) and leukocyte inhibitory factor (LIF). Preliminary characterization of these mediators by Sephadex G-100 gel filtrati...

Guinea pig lymphocytes are stimulated by histamine to produce a soluble factor with immunosuppressive properties. This factor, termed histamine-induced suppressor factor or HSF, abrogates the production of migration inhibitory factor (MIF) and proliferative response to specific antigen. In the present study we have determined the lymphocyte subpopu...

Human leukocyte inhibitory factor or LIF was generated in vitro by stimulating blood lymphocytes with concanavalin A (Con A). The control and Con A active supernatants were partially purified by gel filtration on Sephadex G-100. The fraction containing LIF (68,000 daltons) activity was then subjected to isoelectric focusing (pH 3 to 10 ampholines)...

Sensitized human or guinea pig lymphocytes stimulated by specific antigen or nonspecifically by mitogens elaborate a soluble leukocyte inhibitory factor (LIF) that selectively inhibits the random migration of polymorphonuclear (PMN) leukocytes. LIF has the properties of a protein and is unique among lymphocyte mediators because of its esterase natu...

Leukocyte inhibitory factor (LIF), which was derived from human peripheral blood lymphocytes by stimulation with concanavalin A ad partially purified by Sephadex G-100 gel filtration, inhibited the in vitro spontaneous migration and chemotaxis of human PMN leukocytes as assessed in a Boyden chamber micropore filter assay. The inhibitory activity wa...

When soluble histamine is added to guinea pig lymphocytes in vitro, antigen-induced cellular proliferation and the production of migration inhibitory factor is suppressed. The inhibitory effects that are produced by histamine have been shown to be mediated by the histamine-type 2 receptors of the involved cells, but the exact nature of this suppres...