Dirk K. Greineder

Generation of Antigen-Specific Suppressor Cells during Allergy Desensitization

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 injections of ragweed extract, their mononuclear cells specifically suppressed a ragweed proliferative response six and 12 months after desensitization was begun (31 per cent and 48 per cent suppression, respectively). Suppressor mononuclear cells were not detected in 10 control subjects of in 10 patients with ragweed hayfever who were not desensitized. When mononuclear cells taken from treated patients were passed over columns containing insolubilized histamine, antigen-specific suppressor cells that could be activated by ragweed antigen were depleted. These results indicate that antigen-specific suppressor cells, probably bearing histamine receptors, are generated during desensitization to allergy and may be partly responsible for the efficacy of this therapy.

A randomized controlled trial of a pediatric asthma outreach program.

BACKGROUND Previous studies have shown that asthma education and case management may reduce asthma emergency care, hospitalizations, and expenditures. OBJECTIVE We sought to study the effect of an asthma outreach program (AOP), a team-based, case-management intervention, on emergency ward (EW) and hospital use. METHODS Fifty-seven patients aged 1 to 15 years with the diagnosis of asthma based on the usual clinical practice criteria who were continuously enrolled in a staff-model health maintenance organization for a period of at least 2 consecutive years were randomized into 2 intervention groups. The control group received a single intensive asthma education intervention, and the AOP group received the same initial education but then was followed-up by an asthma case management nurse throughout the intervention period. RESULTS EW visits, hospitalizations, and total outside-of-health-plan expenditures (consisting of EW and hospital expenses, as well as miscellaneous costs, such as ambulance, durable medical equipment, tertiary referrals, and home care) were assessed from claims filed for a year before and after enrollment. Control group patients experienced significant reductions in EW visits (39%), hospitalizations (43%), and outside-of-health-plan costs (28%), possibly as a result of the baseline educational intervention received by all enrolled patients, in conjunction with regression to the mean. AOP group patients experienced significant reductions in EW visits, (73%, P =.0002), hospitalizations (84%, P =.0012), and outside-of-health-plan use (82%, P <.0001). When compared with the control group, AOP group patients demonstrated additional significant reductions in EW visits (57%, P <.05), hospitalizations (75%, P <.05), and outside-of-health-plan use (71%, P <.001). Estimates of direct savings to the health plan ranged from

Mediators of immunity: lymphokines and monokines.

7.69 to

Modulation of cellular immune function in vitro by histamine receptor-bearing lymphocytes: Mechanism of action

11.67 for every dollar spent on the AOP nurses salary, depending on assumptions. CONCLUSIONS Asthma patients in a staff-model health maintenance organization decreased their resource use between 57% to 75% by participation in an AOP as compared with a randomized control group receiving only an educational intervention. Substantial savings were achieved compared with the cost of the AOP nurse.

Histamine-induced suppressor factor (HSF): further studies on the nature of the stimulus and the cell which produces it.

Publisher Summary 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 factors are discussed. Evidence is presented for single factors with multiple activities, a topic that has plagued investigators in this field. Cellular immune reactions are mediated by T lymphocytes, and the expression of these phenomena includes cutaneous delayed-type hypersensitivity, contact allergy, resistance to infection by facultative intracellular microorganisms, graft rejection, and tumor surveillance. These reactions result from complex interactions between T cells and B cells, T cells and other T cells, T cells and macrophages. Lymphokines are classified functionally according to their effects: inhibitory, stimulatory, or inflammatory. The chapter describes various soluble factors that are prime candidates for mediating various immunologic reactions, particularly those relating to cellular immunity. These factors can be produced by a variety of nonlymphoid sources. This implies a more general biologic role for lymphokines and monokines in host defense and other homeostatic mechanisms. The ability of cell types other than lymphocytes to produce lymphokine- and monokine-like factors provides a safeguard for the organism.

Utilization and cost of immunotherapy for allergic asthma and rhinitis

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 suppression has not been fully explored. The present studies have evaluated, following immunization, the effect of histamine on macrophage function in vitro, and affinity chromatography to delete a subpopulation of cells bearing histamine receptors. When we treated monolayers of peritoneal exudate cells with histamine (up to 10−3 M) we found that histamine did not interfere with antigen binding by macrophages, macro phage presentation of antigen to lymphocytes, nor the antigen-independent or antigen-dependent lymphocyte-macrophage rosetting. Columns containing insolubilized conjugates of histamine and rabbit serum albumin depleted a subpopulation of cells responsive to histamine i.e., the non-adherent cells made migration inhibitory factor and proliferated in the presence of histamine. The latter finding suggested that the retained cells might have suppressor function and if so, might mediate their effect through the release of a soluble factor. Preliminary data obtained in these studies supports this hypothesis. We conclude that cells bearing histamine receptors may serve a regulatory role in cellular immunity after their activation by histamine by producing a non-dialyzable factor with immunosuppressive properties.

Terfenadine-associated ventricular arrhythmias and QTc interval prolongation: A retrospective cohort comparison with other antihistamines among members of a health maintenance organization☆

Abstract 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 subpopulation which elaborates HSF, the lymphoid tissue source, the kinetics of its generation in relation to immunization, and the nature of the histamine receptor involved in modification of the release of HSF. HSF activity could be detected in populations of cells from spleen and lymph nodes prior to active immunization of the donor, but not in cells from the donors blood or thymus. Following immunization with ortho -chloro benzoyl-bovine γ-globulin in complete Freunds adjuvant (CFA), more HSF activity was detected in cells from the donors spleen and lymph nodes. The peak response was seen 2 weeks postimmunization when significant amounts of HSF also were made by cells from the blood and thymus. Concentrations of T-cell-enriched and B-cell-enriched populations were tested for their ability to make HSF. We found that T-cell-enriched, but not B-cell-enriched populations, made significant amounts of HSF. Cells from the lymph nodes of immunized donors were chromatographed over affinity columns made of insolubilized conjugates of histamine with albumin. The nonretained cells were unable to generate HSF, whereas HSF activity was detected in the cells that were retained by the columns. This finding strongly suggests that the HSF-producing cells have receptors for histamine. Cells from CFA-immune lymph nodes were incubated with H 1 (2-methyl histamine) and H 2 (4-methyl histamine) agonists to determine their relative potency and, therefore, the nature of the histamine receptors on these cells that were modifying HSF release. Although both agonists could induce generation of HSF when high concentrations (10 −3 M ) were used, only the H 2 agonist stimulated production or release of HSF at lower concentrations (10 −5 M ). These HSF-producing cells appear to be selectively sensitive to H 2 agonists and likely have a predominance of H 2 receptors. Allergic mediators other than histamine were studied to determine their ability to allow elaboration of HSF-like activity from CFA-immune lymph node cells. Serotonin (10 −3 M ), slow-reacting substance of anaphylaxis (100 units/ml), eosinophil chemotactic factor (tetrapeptide; 10 −5 M ), and prostaglandin E 1 (10 −4 M ) were unable to induce HSF-like activity in lymph node cells from donors immunized with CFA. Furthermore, other agents which raise intracellular levels of cyclic adenosine 3′,5′-monophosphate (cyclic AMP) such as isoproterenol and cholera toxin, as well as the dibutyryl form of cyclic AMP itself, were also unable to generate HSF-like activity. Thus, histamine is unique among the allergic mediators in stimulating elaboration of the suppressive substance. These findings also suggest that the ability of histamine to stimulate HSF may not reside in the conventional pathway linked to cAMP accumulation, but rather to an as yet undefined pathway of cell activation. A model is presented which further implicates histamine as a modulator of cellular immune reactions.

Systemic reactions to immunotherapy.

BACKGROUND Allergic rhinitis and asthma are important sources of morbidity among adults and children. Although immunotherapy is sometimes used to treat these conditions, there is little information on its use, adherence, or cost in the general population. OBJECTIVE We sought to characterize the recipients of immunotherapy for allergic rhinitis and/or asthma with respect to their immunotherapy and utilization of health care services. METHODS A combination of automated and manually extracted data was used to identify HMO members with diagnoses of allergic rhinitis or asthma who were treated with immunotherapy. Costs associated with immunotherapy and related care were examined by linear regression. Proportional hazards and Kaplan-Meier plots were used to evaluate duration of therapy. RESULTS Of the 122,196 persons with a diagnosis of asthma or rhinitis, 2,667 were also treated with immunotherapy. Eligibility criteria were satisfied by 603 individuals who had 28,266 encounters for immunotherapy (median 48). Most patients (>80) were treated with multiple allergens; ragweed was the most common single allergen administered. Thirty-three percent of patients with sufficient observation time completed the intended course of 61 immunotherapy treatments. Females and younger patients had shorter durations of immunotherapy. The most common reason for discontinuation of therapy was patients decision (54%). Immunotherapy costs were related most strongly to costs for care of rhinitis and asthma. Prescription drugs accounted for more than 50% of the non-immunotherapy costs; hospitalizations accounted for less than 20%. CONCLUSIONS Approximately 2% of HMO members with an asthma or rhinitis diagnosis received immunotherapy. Although screened to optimize compliance, most patients did not complete immunotherapy. Costs of non-immunotherapy care were higher for individuals who completed immunotherapy which is consistent with more severe disease in this group.

Risk management in allergen immunotherapy

This study compared the occurrence of syncope, ventricular arrhythmias, and corrected QT interval (QTc) prolongation over a 2 1/2-year period in persons prescribed terfenadine versus other prescription antihistamines among 265,000 members of the Harvard Community Health Plan (HCHP), the largest staff-model health maintenance organization in New England. HCHP maintains an automated medical record system with coded diagnoses for each ambulatory and hospital visit, and a similar automated pharmacy system with information for each member on all prescriptions filled at its pharmacies. Among 0.86 million exposure days of terfenadine and 1.04 million exposure days of other antihistamines, we found no excess risk of either clinical/arrhythmia events (odds ratio (OR), 0.86; 95% confidence interval (CI), 0.52 to 1.44) or QTc prolongation (OR, 1.00; 95% CI, 0.64 to 1.57) during courses of terfenadine versus those of other antihistamines. Joint courses of antihistamines and oral erythromycin were associated with an increased risk of QTc prolongation (OR, 2.33; 95% CI, 1.31 to 4.15), and there was a trend for this to be observed more frequently with terfenadine (OR, 2.37; 95% CI, 0.73 to 7.51; P = 0.14).

Trimethoprim/Sulfamethoxazole Incremental Dose Regimen in Human Immunodeficiency Virus-Infected Persons

Systemic anaphylactic reactions occur in a small percentage of patients receiving allergen immunotherapy. A 1 year study was performed in a large health maintenance organization to determine the incidence of systemic reactions (SR) to allergen immunotherapy. We measured the number of SR that occurred during a 12 months period. A SR data sheet was completed for each reaction, documenting the time of onset, symptoms, treatment, history of asthma or previous reaction, and concentration and type of extract. Twenty-seven thousand eight hundred six injection visits resulted in 143 SR (0.51%). Forty-five percent of the patients (pts) with SR had a history of prior SR, 50% had a history of asthma, and 36% developed reactions in season. Seventy-two percent of SR started within 30 minutes, although 8% appeared after 2 hours. Fifty-seven percent of SR occurred at concentrations of 1,000-10,000 PNU/cc, 25% at 10-100 PNU/cc, and 17% when both concentrations were given at the same visit. Eighty-three percent of SR were judged to be mild, nonlife threatening reactions, requiring no treatment or antihistamine therapy only. Seventeen percent were judged to be more severe, requiring treatment with epinephrine, with or without other agents. SR are a small but definite risk of immunotherapy. Most SR are mild, but some may be life threatening. The majority of reactions occur within 30 minutes, but significant reactions may occur after 2 hours. A large percentage of SR occurred in patients with a history of asthma, previous SR, or both.