Partial characterization of a prostaglandin-induced suppressor factor.
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Biomedical subjects
Publications and source records attributed to D R Webb.
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We examined the differences between allergic and nonallergic rhinitis. One hundred forty-two patients were evaluated. Forty-eight patients were diagnosed as having allergic rhinitis (AR) on the basis of histories correlating with skin tests and markedly elevated total serum IgE levels. Forty-two percent of these patients had nasal eosinophilia (greater than or equal to 25%) and 58% had histories or findings consistent with asthma. Fifty-two individuals had no evidence for immunologic nasal disease, incriminated physical agents as precipitants, and demonstrated no associated respiratory pathology. These patients were classified as having vasomotor rhinitis (VMR). Twenty-one patients had symptoms similar to those of patients with VMR but they demonstrated nasal eosinophilia and were classified as having eosinophilic nonallergic rhinitis (ENR). These patients had a high prevalence of nasal polyps and were significantly more responsive to medical therapy than any group studied. It is concluded that nasal eosinophilia is of little value in the evaluation of AR but provides significant information regarding the therapy and prognosis in nonallergic rhinitis.
Antigen stimulated changes in cyclic AMP levels which are the result of increases in prostaglandin levels, were measured by immunofluorescence in frozen spleen sections. The results provide direct visual confirmation of previous reports in that an increase in the number of cells staining positively for cyclic AMP were detected. The increase in cyclic AMP levels occurs in approximately 40% of the cells in the cortical region of the spleen. No staining was observed in deeper regions. Using sRBC as a particulate antigen and DNP-BGG as a soluble antigen, it was possible to show that a slightly smaller increase in the number of cyclic AMP positive cells occurs using DNP-BGG compared to sRBC. These data mean that antigen stimulated changes in splenic AMP levels occurs in a much larger population than could be accounted for on the basis of antigenic specificity. Such a result is consistent with previous data showing the increase in cAMP is a result of a prior increase in prostaglandin. Thus, any cell bearing a prostaglandin receptor could respond by showing an elevated cAMP level.
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Having previously established, that prostaglandins play a role in the regulation of the immune response to polyvinyl pyrollidone, a T-independent antigen, further investigations of the role of prostaglandins and cyclic nucleotides in the control of the immune response to polyvinyl pyrollidone were initiated. Strongly immunogenic (PVP 360,000) and weakly immunogenic (PVP 10,000) molecular sizes of polyvinyl pyrollidone were examined for their effects on splenic PGF2 alpha, PGE and cyclic nucleotide levels. The results show, that PVP 360,000 induces marked changes in PGF2 levels. There is an early marked depression at 2 hours after injection followed by an increase which peaks at 2 hour. At subsequent time intervals (9-10, 13-14 and 16-18 hour) high values were observed, especially in the latter case. cAMP levels undergo significant fluctuations, exhibiting very big rise at 12 and 13 hour post-immunization, cGMP levels are elevated at 2 hour declining thereafter. PGE level in C57Bl mice exhibits very substantial increase at 4-6 hour after immunization, in athymic mice, however, the increase was not significant and was preceded by a profound drop in PGE concentration. PGE level in the splenocytes from athymic mice shows a constant increase till 4 hour after PVP addition, followed by a little decrease at 6-7 hour. cAMP concentration in athymic mice exhibits a drop at 3-4 hour after immunization, followed by an increase at 5-6 hour post-immunization. Indomethacin, an inhibitor of prostaglandin synthetase, blocks the changes in PGF2 and cGMP level but has little effect on cAMP. In contrast, the weakly immunogenic form PVP 10,000 induces a large bimodal increase in cAMP levels peaking at 2 hour and again increasing between 6-8 hour; cGMP levels also rise, but more slowly. The increase in cAMP is blocked by indomethacin even though no comparable increases in PGF2 levels are observed. The changes induced by PVP 10,000 appear to be dependent on T cells since comparable changes are not observed in athymic mice. Although PVP 10,000 is non-immunogenic in normal mice or whole spleen cultures, it is immunogenic in athymic mice and purified B cell cultures. This difference has been traced to an apparent difference in the activation of T cells vs. B cells by PVP 10,000. Lastly, although inhibition of PG synthesis results in an enhancement of the immune response to PVP 360,000, no such enhancement is observed with PVP 10,000. The relevance of prostaglandin and cyclic nucleotide changes to the development of the immune response is discussed.
Major adverse reactions to radiographic contrast media will occur more often as contrast material is now also administered during computerized tomographic (CT) scanning. Differentiation of the two major contrast reactions, the vagus reaction and the anaphylactoid reaction, is essential. Bradycardia is the key finding for identifying the vagus reaction. The vagus reaction involving hypotension and bradycardia requires treatment with large doses of atropine given intravenously. The immediate generalized reaction or anaphylactoid reaction should be treated as anaphylaxis with administration of vasopressors, fluids, steroids and antihistamines. Steroids and antihistamines given before the examination may offer protection to those high-risk patients who have had previous anaphylactoid reactions to contrast material.
Mice treated with inhibitors of prostaglandin synthetase showed an alteration in the number of spontaneous, anti-autologous erythrocyte antigen (Hb)-antibody-forming cells in the spleens. The number of anti-Hb plaque-forming cells and rosette-forming cells in the peritoneum of mice treated with inhibitors of prostaglandin synthesis was regulated depending on a magniture of the response in the individual experiments. Depletion of T cells after the antithymocyte treatment of animals resulted in a significant diminution of the regulatory action of the prostaglandin synthetase inhibitor. The results indicate that prostaglandins are involved in the regulation of the in vivo anti-Hb autoimmune response mediating the regulatory cell action.
Adverse reactions to pharmacologic agents are becoming more and more common as more drugs are administered to sicker patients. Allergic (immunologic) reactions are difficult to distinguish from idiosyncratic (nonimmunologic) reactions, and reactions that appear to be similar may have entirely different etiologies. Diagnosis of an adverse reaction and identification of its cause require an index of suspicion, familiarity with the drugs being used, knowledge of common reactions to these drugs, and occasionally, challenge with the suspected drug. Specific diagnosis often obviates unnecessary discontinuance of an effective drug.
Prostaglandins serve an important regulatory role in immune responses. Much of their activity seems to involve regulating the early stages of lymphocyte or macrophage activation. Besides the capacity of prostaglandins to control lymphocyte activation directly by blocking transformation, at least one type, PGE2 can induce a class of glass-adherent T-cells to produce a suppressive peptide in vitro. The data we have obtained suggest the existence of a feedback loop in which PG production by an activated T-cell serves as the signal that induces a second T-cell to release a suppressor peptide. This peptide can then regulate the ability of the activated T-cell to pass through the cell cycle. Other examples of feedback loops have recently been postulated or shown to exist among immunocompetent cells. It remains to be shown how these various regulatory loops combine to form the integrated network that modulates immunoresponsiveness.
Sixteen steroid dependent and 13 steroid independent patients with bronchial asthma were treated for three months with flunisolide by aerosol. Asthma improved in these patients, other medication usage decreased and adverse side effects were minimal. A significant increase in morning plasma cortisol levels occurred in steroid dependent patients, whereas cortisol levels in steroid independent patients remained normal. An unexpected decline in response to metyrapone occurred in both groups of patients and suggests that this test is affected by flunisolide usage.
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The effects of prostaglandin E2 (PGE2) on cyclic AMP levels in various mouse lymphocyte populations were studied. It was found that spleen cells and thymocytes respond comparably to PGE2. Cortisone treatment abolished the responsiveness in thymocytes. Fractionation of splenic lymphocytes on glass wool columns into subpopulations of bone-marrow derived (B) cells or thymus-derived (T) cells showed that both B and T splenic lymphocytes can respond to PGE2. Lymphocytes or spleen cells cultured for varying periods (24--96 hrs) lose their sensitivity to PGE2 stimulation of cAMP. This "refractoriness" to PGE2 is only partially reversed by incubating lymphocytes with phosphodiesterase inhibitors.
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Beclomethasone dipropionate was administered by aerosol to 30 patients whose chronic bronchial asthma required oral corticosteroid therapy. During the initial 12 weeks of the trial, beclomethasone therapy could be discontinued in 12 of 16 patients in contrast to only one of 14 patients receiving the inert aerosol placebo. Patients receiving the placebo were then given beclomethasone, and prednisone therapy was discontinued in five more. During six months of observation, adrenal function improved and steroid toxic reactions decreased in patients in whom oral corticosteroid therapy had been discontinued. Beclomethasone aerosol was generally well-tolerated. Asymptomatic thrush developed in four patients and rhinitis developed in ten patients as prednisone therapy was discontinued.
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