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T cell function is a critical determinant of immune responses as well as susceptibility to allergic diseases. Activated T cells can differentiate into effectors whose cytokine profile is limited to type 1 (IFN-gamma-dominant) or type 2 (IL-4-, IL-5-dominant) patterns. To investigate mechanisms that connect extracellular stimuli with the regulation of effector T cell function, we have measured immune responses of transgenic mice whose NF-kappa B/Rel signaling pathway is inhibited in T cells. Surprisingly, these mice developed type 2 T cell-dependent responses (IgE and eosinophil recruitment) in a model of allergic pulmonary inflammation. In contrast, type 1 T cell responses were severely impaired, as evidenced by markedly diminished delayed-type hypersensitivity responses, IFN-gamma production, and Ag-specific IgG2a levels. Taken together, these data indicate that inhibition of NF-kappa B can lead to preferential impairment of type 1 as compared with type 2 T cell-dependent responses.
Strength of T cell receptor (TCR) signaling, coreceptors, costimulation, antigen-presenting cell type, and cytokines all play crucial roles in determining the efficiency with which type 2 T lymphocytes (Th2, Tc2) develop from uncommitted precursors. To investigate in vivo regulatory mechanisms that control the population of type 2 T cells and disease susceptibility, we have created lines of transgenic mice in which expression of a chimeric cytokine receptor (the mouse interleukin 2 receptor beta chain [IL-2Rbeta] extracellular domain fused to the cytoplasmic tail of IL-4Ralpha) is targeted to the T lymphoid lineage using the proximal lck promoter. This chimera transduced IL-4-specific signals in response to IL-2 binding and dramatically enhanced type 2 responses (IL-4, IL-5, and immunoglobulin E production) upon in vitro TCR stimulation or in vivo antigen challenge. Thus, type 2 effector function was augmented by IL-4 signals transduced through a chimeric receptor expressed in a T cell-specific manner. This influence was sufficient for establishment of antigen-induced allergic airway hyperresponsiveness on a disease-resistant background (C57BL/6).
In vivo challenge procedures can be very useful in the analysis of allergic symptoms. Skin testing has a high degree of sensitivity and specificity for determining antigens that cause allergic disease. However, positive skin tests do not necessarily indicate that a specific allergen causes symptoms specific for a certain organ. Nasal and whole lung provocation testing can help define relevant allergens that cause rhinitis or asthma symptoms. These tests are safe when performed properly under close medical supervision and have predictive values that make them useful diagnostic tools.
Allogenic whole cell and lysate cancer vaccines are associated with very different clinical outcome, which could be due to different immune responses to critical tumor-associated antigens. We used a guinea pig model to evaluate the immune responses to melanoma-associated carbohydrate antigens administered in whole cell and soluble lysate vaccines produced from the same cell lines and administered with or without Bacille Calmette-Guerin (BCG). Animals immunized with whole cell vaccine developed a significantly higher delayed-type hypersensitivity (DTH) reaction. The IgG response to all tumor-associated carbohydrate antigens except GD2 was significantly higher in animals immunized with whole cell vaccine than lysate vaccine. This study indicates that whole cell vaccine is superior to soluble or lysate vaccine because it induces a better immune response against cell-surface antigens. The addition of BCG significantly increased the antibody response, suggesting that an exogenous adjuvant may immunopotentiate antigens better in the presence of an intact cell membrane.
We compared the expression of prostaglandin H synthase-2 (PGHS-2, cyclooxygenase) message and protein in alveolar macrophages (AM) and blood monocytes (BM) from 20 atopic subjects (AS) and nine control subjects (CS) at baseline and after 1 to 14 d of oral administration of therapeutic doses of prednisone. At baseline, the amounts of PGHS-2 mRNA in AM and BM varied within a similar range among subjects from each group. PGHS-2 protein was present in AM and BM from most AS, but it was also present in CS. In AS, PGHS-2 mRNA and protein significantly increased after prednisone administration, whereas in CS PGHS-2 message and protein remained undetectable or, if present at baseline, was decreased after prednisone. Ex vivo both atopic and normal monocytes and macrophages exhibited the expected decrease in stimulated PGHS-2 mRNA with glucocorticoids. PGHS-1 expression was not altered by prednisone in either group. The differential regulation of the inducible PGHS isoform by prednisone may be mediated by effects on cytokine production in AS.
BACKGROUND - Angioedema is a potentially life-threatening side effect of angiotensin-converting enzyme (ACE) inhibitors. Although the mechanism of angioedema is not certain, bradykinin has been implicated in its pathogenesis. Compared with Caucasians, African Americans are at an increased risk of ACE inhibitor-associated angioedema, independent of ACE inhibitor dose or concurrent medications. Because urinary kallikrein levels are decreased in African Americans with hypertension, we hypothesized that endogenous bradykinin levels may be decreased in African Americans and that they therefore may be more sensitive to ACE inhibitor-induced increases in bradykinin or to exogenous bradykinin.
OBJECTIVE - To test this hypothesis, we measured the wheal response to intradermal injection of bradykinin in salt-replete hypertensive and normotensive African Americans and Caucasians.
METHODS - Two doses of bradykinin, 1 microgram and 10 micrograms, were administered on separate days in a randomized, double-blind fashion.
RESULTS - Higher bradykinin dose (analysis of variance: F = 38.33, p < 0.001), African American race (analysis of variance: F = 17.90, p < 0.001), and hypertension (analysis of variance: F = 4.37, p = 0.05) were all associated with an increased wheal response to bradykinin.
CONCLUSION - These data provide additional support for racial differences in the kallikrein-kinin system and also implicate abnormalities of the tissue kallikrein-kinin system in essential hypertension.
Lactose digestion and tolerance were evaluated in 164 African Americans ranging in age from 12 to 40 y who claimed intolerance to one cup (240 mL) or less of milk. With use of a breath-hydrogen test with 25 g lactose as test dose and the presence or absence of symptoms, 50% of the subjects were classified as lactose maldigesters and intolerant, 8% were maldigesters but tolerant, 15% were digesters but intolerant, and 27% were digesters and tolerant. Forty-five subjects from the lactose maldigesting and intolerant group were further tested for milk intolerance in a double-blind study. Sixty-seven percent of the subjects reacted appropriately to the presence or absence of lactose in ingested milk whereas 33% reported symptoms to both low-lactose milk and milk containing lactose. The results suggest that the cause of milk intolerance in as many as one-third of African Americans claiming symptoms after ingestion of a moderate amount of milk cannot be its lactose content.
PURPOSE/OBJECTIVES - To determine if adverse reactions to IV immunoglobulin G (IVIG) were being detected by nurses and frequent vital sign monitoring.
DESIGN - Retrospective chart review.
SETTING - Bone marrow transplant (BMT), medical oncology, and pediatric units and the outpatient clinic of a 720-bed hospital in middle Tennessee.
SAMPLE - 62 charts of patients undergoing BMT who had received IVIG. METHODS/MAIN RESEARCH VARIABLES: Charts were reviewed for patient demographics, number and type of IVIG infusion, incidence of adverse reactions, and related information.
FINDINGS - Nine reactions were documented out of 731 separate infusions. Only three reactions could be linked directly to IVIG infusion. Of the nine reactions, only four were detected by nursing personnel during vital sign monitoring.
CONCLUSIONS - Nursing time devoted to frequent vital sign assessment does not seem to be warranted. Protocol for administration and monitoring of IVIG at this institution was changed to reflect these findings.
IMPLICATIONS FOR NURSING PRACTICE - Frequent vital sign monitoring is advised for the initial IVIG dose. If no adverse reactions occur, only baseline vital sign monitoring is advised for subsequent infusions. Patients are taught to recognize and report symptoms of adverse reactions.