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Delayed type hypersensitivity against semliki forest virus in mice: local transfer of delayed type hypersensitivity with thioglycollate-induced peritoneal exudate cells.

In mice, a strong delayed type hypersensitivity (DH) without detectable neutralizing antibodies in serum could be obtained after intracutaneous injection of inactivated Semliki Forest virus (SFV) mixed with the adjuvant dimethyl dioctadecyl ammonium bromide (DDA). Thioglycollate-induced peritoneal exudate cells (PEC) from these mice were highly effective in passive transfer of DH against SFV locally in footpads of naive recipient mice. DH reactions were measured with a footpad swelling test. By contrast, either immune PEC from nonstimulated peritoneal cavities or thioglycollate-induced PEC from mice which had developed neutralizing antibodies were unable to transfer DH passively.

Animals↗

L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity.

Repeated Ag exposure results in a shift in the time course of contact hypersensitivity (CH) from a typical delayed-type to an immediate-type response followed by a late phase reaction. Chronic CH responses are clinically relevant to human skin allergic diseases, such as atopic dermatitis, that are usually caused by repeated stimulation with environmental Ags. Chronic inflammatory responses result in part from infiltrating leukocytes. To determine the role of leukocyte adhesion molecules in chronic inflammation, chronic CH responses were assessed in mice lacking L-selectin, ICAM-1, or both adhesion molecules. Following repeated hapten sensitization for 24 days at 2-day intervals, wild-type littermates developed an immediate-type response at 30 min after elicitation, followed by a late phase reaction. By contrast, loss of ICAM-1, L-selectin, or both, eliminated the immediate-type response and inhibited the late phase reaction. Similar results were obtained when wild-type littermates repeatedly exposed to hapten for 22 days were treated with mAbs to L-selectin and/or ICAM-1 before the elicitation on day 24. The lack of an immediate-type response on day 24 paralleled a lack of mast cell accumulation after 30 min of elicitation and decreased serum IgE production. Repeated Ag exposure in wild-type littermates resulted in increased levels of serum L-selectin, a finding also observed in atopic dermatitis patients. The current study demonstrates that L-selectin and ICAM-1 cooperatively regulate the induction of the immediate-type response by mediating mast cell accumulation into inflammatory sites and suggests that L-selectin and ICAM-1 are potential therapeutic targets for regulating human allergic reactions.

Administration, Cutaneous↗

Multiple drug hypersensitivity--proof of multiple drug hypersensitivity by patch and lymphocyte transformation tests.

BACKGROUND: Multiple drug hypersensitivity (MDH) was first described in 1989 by Sullivan et al. as drug allergies to two or more chemically different drugs. So far, the diagnosis of MDH was associated almost exclusively with antibiotics and was defined based on history alone. AIMS OF THE STUDY: The objective of this study was to prove MDH by two independent tests, namely patch (PT) and lymphocyte transformation (LTT) tests. METHODS: Here we present 7 patients matching the definition of a MDH which were documented by positive LTT as well as PT to different drugs. RESULTS: Three of the 7 patients developed sensitization to the different compounds during the same treatment period and had one longer-lasting allergic reaction. For another 4 patients sensitization to the different drugs occurred at distinct time points. CONCLUSIONS: Our data support the concept of a MDH syndrome. The multiple sensitizations can be proven by skin and in vitro tests. We propose two subtypes of MDH: MDH, which develops against different drugs given simultaneously, and a second subtype, where the sensitizations develop sequentially. Antibiotics are often involved, but we also found sensitization to antiepileptics, hypnotics, antidepressants, local anesthetics, corticosteroids and other drug classes.

Adult↗

Delayed hypersensitivity and immune protection against herpes simplex virus: suppressor T cells that regulate the induction of delayed hypersensitivity effector T cells also regulate the induction of protective T cells.

We have been studying delayed hypersensitivity (DH) to herpes simplex virus (HSV) in order to examine the role of this response in host defense against acute and recurrent HSV infections. In previous reports the basic parameters of DH to HSV have been characterized by using a murine ear swelling model, and also the regulation of DH to HSV induced by i.v. injection of the virus. In this paper, we describe a murine protection system and our use of the ability to specifically regulate DH to HSV to examine the correlation between T cells that transfer DH (TDH) and cells that transfer protection from acute HSV infection. Both DH and protection can be transferred with lymph node cells from mice immunized subcutaneously 4 days previously. The effector cell appears to be a T cell, because serum from these donors confers no protection and treatment of immune cells with anti-Thy-1.2 plus complement reduced their ability to protect. Tolerance of DH to HSV was induced by i.v. injection 7 days before subcutaneous immunization. Tolerized mice were unable to generate protective cells. Furthermore, tolerized mice contained suppressor T cells that suppressed not only DH but also the development of protective cells. Regulation of protective cells was shown to be virus specific, because mice tolerized with vesicular stomatitis virus (VSV) were not impaired in their ability to generate T cells that protected from HSV infection. The correlation between the TDH cell and cells that transfer protection from acute HSV infection is discussed.

Acute Disease↗

Delayed hypersensitivity in mice induced by intravenous sensitization with sheep erythrocytes: evidence for tuberculin type delayed hypersensitivity of the reaction.

Delayed hypersensitivity (DH) reaction can be induced in mice by intravenous sensitization with sheep erythrocytes (SRBC). However, as the sensitizing procedure is quite different from a usual mode of sensitization for DH using complete Freund's adjuvant (FCA), the nature of this reaction has been a matter of controversy. In an attempt to characterize this reaction, we placed special interest on two possibilities regarding the nature of this reaction; Jones-Mote reaction or tuberculin type DH. From the kinetics study on the DH after challenge, the DH reaction to SRBC in mice by intravenous sensitization was clearly distinguished from the Arthus reaction. The dose-response pattern of this reaction also suggested that the contribution of Arthus reactivity to delayed reactivity was negligible. Cell reconstitution experiments revealed this DH to be quantitatively thymus cell dependent. Furthermore, this DH required macrophages at its manifestation stage, and appearance of basophil infiltration at the lesion was absent. In addition, strain difference and ageing of host mice influenced the DH reaction in exactly the same fashion in which these factors influence the tuberculin type-DH induced by subcutaneous sensitization with methylated human serum albumin (MHSA) in FCA. Taken collectively, it was concluded that this DH reaction can be categorized as the tuberculin type.

Aging↗

Regulation of delayed-type hypersensitivity. VI. Antigen-specific suppressor T cells and suppressor factor for delayed-type hypersensitivity to histocompatibility antigens.

Mice develop highly significant levels of delayed-type hypersensitivity (DTH) to major and minor histocompatibility antigens when injected s.c. with lymphoid cells from X-irradiated allogeneic donors. However, when mice are inoculated i.v. with a high dose of X-irradiated allogeneic lymphoid cells, they not only fail to develop DTH to the allogeneic cells, but their ability to respond to an immunogenic challenge of the alloantigens is also significantly depressed. This suppression is adoptively transferable by antigen-specific suppressor T cells and not by immune serum. Cell surface phenotypic analysis shows that the primary suppressor cells for alloantigens are Thy-1+, Lyt-1+2-, and Ia-, whereas the secondary suppressor cells appearing after boosting injection are Thy-1+, Lyt-1+2+, and Ia-. These suppressor T (Ts) cells localize in the lymphoid organs shortly after their induction and are largely absent from the spleen or lymph node 1 month later. However, "suppressor memory" can be recalled by an immunogenic dose of alloantigens which would normally induce DTH effector cells rather than suppressor cells in naive mice. When the suppressor cells were cultured in vitro for 48 hr, the supernatant contained suppressive activity. It appears likely that the manifestation of the suppressor cells is via soluble, antigen-specific suppressor factor(s), the production of which is dependent on viable T cells.

Animals↗

[Post anthrax vaccine delayed hypersensitivity. II--delayed hypersensitivity in humans vaccinated against anthrax].

To detect cell immunity characterized by delayed postvaccination hypersensitivity to anthrax in man and assess its dynamics, vaccination using unencapsulated live anthrax vaccine was performed in 668 healthy volunteers. Vaccination was performed either by scarification (n = 172), subcutaneous injection (n = 202), or low-dose (n = 202) or high-dose (n = 83) inhalation. The anthraxin intradermal tests were performed in each patient at various times during the year following vaccination (D7, D15, D90, D180, D365). This study confirm that, regardless of the mode of administration, the vaccine induces cell-mediated immunity in man, as determined by positive anthraxine skin test. The incidence of positive tests decreases with time regardless of the mode of vaccination. After one year, the test remained positive in 34.8% of subjects vaccinated by subcutaneous injection, 37.5% vaccinated by low-dose inhalation, 34.2% vaccinated by high-dose inhalation, and 22.4% vaccinated by scarification. These findings are in agreement with those obtained in clinical epidemiological studies documenting the effectiveness of encapsulated live anthrax vaccine in man.

Administration, Inhalation↗

[Evaluation of immediate hypersensitivity and environmental factors by intracutaneous skin tests and specific IgE antibodies in allergic children. Part 1. The annual change of immediate hypersensitivity measured by intracutaneous skin tests and radioallergosorbent test].

To evaluate the relation between immediate hypersensitivity and environmental factors, a total of 2,187 allergic children were given the intracutaneous skin tests (IC test) and specific IgE antibodies (RAST) at Kudanzaka Hospital over a period of 21 years (1967-1987). The incidence of positive IC test to house dust (HD) and Japanese cedar pollen (sugi) increased, and that to molds increased transiently in the period 1965-1975. There was no sex difference in the incidence. Asthmatic children with allergic rhinitis scored higher both in IC test and RAST than those with asthma only. The more severely asthmatic children had a higher incidence of positive IC test to HD, molds, sugi, ragweed, cat dander, silk and buckwheat (sobagara). The recent rise of in the number of allergic diseases was partly proved by higher positive IC tests to HD and sugi. The number of positive test to HD mites also increased because twice as many non-wooden houses as wooden houses, have been built since 1969, and there were 3 times as many, high-rise building in 1975 as in 1965. Pollution and the increasing area of sugi forests were also responsible for increased allergic problems.

Animals↗

[Evaluation of the relationship between immediate hypersensitivity and environmental factors by intracutaneous skin tests and specific IgE antibodies in allergic children. Part 2. The age distribution of immediate hypersensitivity by intracutaneous skin test and radioallergosorbent test].

To evaluate immediate hypersensitivity and environmental factors, 2,187 allergic children were given intradermal skin tests (ID test) and specific IgE antibodies (RAST) at Kudanzaka Hospital for 21 years (1967-1987). The incidence of positive ID test to house dust (HD) was 23% at 1 year, 50% at 2 years, 63% at 3 years and 84% at 8 years of age. The results of average positive test obtained at an earlier age in 1975 and 1985 than in 1965. Children born recently begin to have positive test scores earlier than those born between 1965 and 1969. This could be related to the recent increase in the number of HD mites. The incidence of positive ID test to Japanese cedar pollen (sugi) was 5% at 1 year, 10% at 4 years, 16% at 8 years and 30% at 15 years of age. The positive test scores were again obtained at an earlier age in 1975 and 1985 than in 1965, in the same way as for HD mites. Children born between 1965 and 1969 showed 30-60% positive rate after 13 years of age; this level was seen after 10 years of age in children born in 1975 and 1979, and after 6 years in those born between 1980-1984. This could be due to the recent increase in the amount of sugi pollen. Only Candida showed any significant rises in positive rate 27% at 1 year of age; slow increase was observed in the case of ragweed, molds, epidermals and others. No remarkable change was seen in ragweed and Alternaria at the years of examination and the years of birth.

Adolescent↗

Definition of a Trichophyton protein associated with delayed hypersensitivity in humans. Evidence for immediate (IgE and IgG4) and delayed hypersensitivity to a single protein.

Dermatophytes of the genus Trichophyton cause infections of human skin, nails, and hair. Unlike most Ags, Trichophyton can elicit either immediate (IH) or delayed (DH) hypersensitivity skin reactions. Previous studies isolated a 30-kDa Ag (Tri t 1) that caused IH skin tests. The study presented here used skin testing and in vitro T cell proliferation assays to monitor purification of an Ag, designated Protein IV, associated with DH reactions. Protein IV was purified by cation exchange HPLC; amino acid sequence analysis of the N-terminus and nine internal peptides (143 residues) revealed no homologies to Tri t 1 or to any other known proteins. A mAb-based ELISA was developed to measure Protein IV. Protein IV elicited DH skin reactions in subjects with a history of athlete's foot but also caused IH skin reactions. Serologic responses to Protein IV were studied in 59 adults who had been skin tested with Trichophyton extract. IH skin reactions were associated with a positive RAST (14/23) as well as with specific IgE (13/23) and IgG4 (14/23) Abs to Protein IV. DH skin tests were not associated with IgE or IgG4 Abs. IgE anti-Protein IV Abs were quantitatively correlated with IgG4 Abs (r = 0.57, p < 0.001). Specific IgG Abs to Protein IV were highest in IH subjects (gm = 230 U/ml), and lowest in those with DH (gm = 91 U/ml) or negative (gm = 81 U/ml) skin tests; furthermore, the prevalence of IgG Abs increased significantly with age. Protein IV is the first defined protein associated with both DH and IH skin reactions; these reactions are characterized by distinct serologic responses. The results establish that diverse immune responses in humans can be directed against the same protein.

Adult↗

The hypersensitivity pneumonitis diagnostic index: use of non-invasive testing to diagnose hypersensitivity pneumonitis in metalworkers.

BACKGROUND: Since 1993, several outbreaks of hypersensitivity pneumonitis (HP) have been reported in metalworkers. We report the largest outbreak of HP in metalworkers yet known. It occurred in a Connecticut factory that produces precision parts for the aerospace industry. The workers typically presented with systemic and respiratory problems ("sick fatigue," myalgias, cough, dyspnea, wheezing, and chest tightness). They had variable findings on clinical tests, which complicated diagnosis. An HP diagnostic index was developed to help reduce the uncertainties in case identification. METHODS: Data from 16 biopsy-confirmed cases and 14 non-HP patients were compared, and the HP diagnostic index was derived using variables that best discriminated between the two groups. The index is based on (a) work-related symptoms, (b) dry crackles on auscultation, (c) restrictive spirometry, (d) decreased diffusion capacity and/or increased A-a oxygen gradient, (e) elevated erythrocyte sedimentation rate, (f) abnormal radiographic images, and (g) abnormal gallium scans. We then applied the HP diagnostic index and, for comparison, the "Kenosha epidemiological case criteria" (developed during a recent HP outbreak in an automobile factory) to our data set. RESULTS: The HP diagnostic index and the Kenosha criteria confirmed HP in overlapping sets of 36 and 34 patients, respectively, that were both in good agreement with the clinical diagnoses. CONCLUSIONS: The HP diagnostic index relies less heavily on symptoms, subjective evaluations, and invasive tests than the Kenosha criteria, but both identified similar subsets of the 61 patients as having HP. The HP diagnostic index could provide a useful tool in future HP outbreaks, which are increasingly being recognized in metalworking facilities.

Alveolitis, Extrinsic Allergic↗

Divergence of contact hypersensitivity in vivo compared with hapten-specific lymphocyte proliferation and interferon-gamma production in vitro following ultraviolet B irradiation: the possibility that UVB does not affect the sensitizing phase of contact hypersensitivity.

A hapten-specific lymphocyte proliferation assay, which measures the in vitro stimulation of DNA synthesis (as assessed by [3H]thymidine incorporation), was used to determine systemic immunization induced by an epicutaneously applied hapten in addition to the more commonly used method which measures ear (or footpad) swelling. 2,4-Dinitrofluorobenzene (DNFB) was painted on the shaved backs of C57BL/6 mice for two consecutive days after ultraviolet B (UVB) irradiation (at 1000 J/m2), and DNFB-sensitized lymph node cells (LNC) were obtained from the regional lymph nodes 4 days later. Although the ear swelling response (ESR) was suppressed by UVB radiation, as previously reported, analysis of LNC culture supernatants showed that the production of interferon-gamma, a Tc1-type cytokine, was not inhibited by the UVB irradiation. In addition, contact dermatitis was induced (at levels similar to those of non-irradiated mice) by painting DNFB on the abdomen as a secondary response. We then examined the effect of UVB exposure alone on the ESR by injecting a mast cell degranulator, compound 48/80, 7 days after irradiation. Both the ESR and the percentage of degranulated mast cells were significantly reduced in UVB-irradiated mice. These results demonstrate that UVB irradiation does not affect the sensitizing phase of contact hypersensitivity, but modulates the elicitation phase and reduces the ESR primarily by suppressing the degranulation of mast cells. Therefore, suppression of the ESR alone cannot always be considered as hapten-specific immunotolerance.

Animals↗

Both hypersensitive and non-hypersensitive responses are associated with resistance in Salix viminalis against the gall midge Dasineura marginemtorquens.

Hypersensitivity responses (HR) play a major role in plant resistance to pathogens. It is often claimed that HR is also important in plant resistance to insects, although there is little unambiguous documentation. Large genotypic variation in resistance against the gall midge Dasineura marginemtorquens is found in Salix viminalis. Variation in larval performance and induced responses within a full-sib S. viminalis family is reported here; 36 sibling plants were completely resistant (larvae died within 48 h after egg hatch, no gall induction), 11 plants were totally susceptible, 25 plants were variable (living and dead larvae present on the same plant). Resistance was associated with HR, but to different degrees; 21 totally resistant genotypes showed typical HR symptoms (many distinct necrotic spots) whereas the remaining 15 genotypes showed no, or very few, such symptoms. Hydrogen peroxide, used as a marker for HR, was induced in genotypes expressing HR symptoms but not in resistant genotypes without symptoms, or in susceptible genotypes. These data suggest that production of hydrogen peroxide, and accompanying cell death, cannot explain larval mortality in the symptomless reaction. Another, as yet unknown, mechanism of resistance may be present. If so, then it is possible that this unknown mechanism also contributes to resistance in plants displaying HR. The apparent complexity observed in this interaction, with both visible and invisible plant responses associated with resistance against an adapted insect species, may have implications for the study of resistance factors in other plant-insect interactions.

Adaptation, Physiological↗

Rsv1-mediated resistance against soybean mosaic virus-N is hypersensitive response-independent at inoculation site, but has the potential to initiate a hypersensitive response-like mechanism.

Rsv1, a single dominant gene in soybean PI 96983, confers resistance to most strains of Soybean mosaic virus (SMV), including strain G2. The phenotypic response includes the lack of symptoms and virus recovery from mechanically inoculated leaves. To study the resistance mechanism, SMV-N (an isolate of strain G2) was introduced into PI 96983 by grafting. Hypersensitive response (HR)-like lesions occurred on the stems, petioles, and leaf veins, and virus was recovered from these lesions. The response demonstrated the cytological and histological characteristics of HR as well as elevated transcription of a soybean salicylic acid-inducible, pathogenesis-related (PR-1) protein gene. Mechanical inoculation of PI 96983 primary leaves with a high level of SMV-N virions caused no symptoms or up regulation of the PR-1 protein gene transcript. Furthermore, inoculation with infectious viral RNA did not alter the resistance phenotype. The data suggest that interaction of SMV-N with Rsv1 has the potential to induce an HR-like defense reaction. Rsv1-mediated resistance in the inoculated leaf, however, is HR-independent and operates after virion disassembly.

Genes, Dominant↗

Expression of the Pseudomonas syringae avirulence protein AvrB in plant cells alleviates its dependence on the hypersensitive response and pathogenicity (Hrp) secretion system in eliciting genotype-specific hypersensitive cell death.

The nonpathogenic bacteria Pseudomonas fluorescens and Escherichia coli can elicit a genotype-specific hypersensitive response (HR) in plants if they express both the HR and pathogenesis (Hrp) protein secretion system and the HrpZ harpin from P. syringae pv syringae 61 and a P. syringae avirulence (avr) gene whose presence is recognized by a corresponding disease resistance gene in the plant. We have found that the recognition event appears to require transfer of the Avr protein into the plant cell. Elicitation of a genotype-specific HR was observed with avrB+ P. fluorescens in soybean and Arabidopsis plants carrying resistance genes RPG1 and RPM1, respectively, and with avrPto+ E. coll in tomato plants carrying resistance gene PTO, but only if the Hrp secretion system, HrpZ, and the appropriate Avr proteins were produced in the same bacterial cell. The failure of avrB hyperexpression and exogenous AvrB or HrpZ to alleviate these requirements in soybean and Arabidopsis suggests that the site of AvrB action is not in the bacterial cell or plant apoplast. An Arabidopsis rps3 (rpm1) glabrous1 mutant was transformed with constructs expressing avrB and was crossed with an Arabidopsis ecotype Columbia (RPM1 GLABROUS1) plant. F1 seedlings (identified by their kanamycin-resistant, pubescent phenotype) exhibited extensive necrosis on cotyledon leaves 10 days postgermination. Ecotype Columbia and rps3-1 leaves biolistically cobombarded with plasmids expressing the beta-glucuronidase (GUS) gene and avrB failed to produce GUS activity (indicative of cell death) only when RPM1 and avrB were present in the leaf. Thus, both stable and transient expression of avrB in Arabidopsis resulted in RPM1-dependent necrosis, and the only demonstrable site of action for AvrB was inside plant cells.

Arabidopsis↗

Non-IgG1 nature of cutaneous basophil hypersensitivity factor in contact sensitivity. III. Cutaneous basophil hypersensitivity factor promotes histamine release from guinea pig bone marrow basophils after antigenic stimulation.

Cutaneous basophil hypersensitivity factor (CBH-F) from the sera of 1-fluoro-2,4-dinitrobenzene contact-sensitized guinea pigs promoted histamine release from bone marrow basophils in the presence of the antigen, dinitrophenylated epidermal microsomes as well as in vivo activity to induce CBH reaction in naive recipients and in vitro activity to mediate antigen-dependent basophil chemotaxis. The amount of histamine released was around 20% of the total release when compared to that of concanavalin A-induced basophil degranulation (50-60%). Divalent cations were required in this reaction because addition of EDTA completely suppressed histamine release from passively sensitized basophils with CBH-F. Though it is not known at present whether the same molecule is involved in basophil chemotaxis and histamine release, this histamine-releasing activity was recovered in the same preparations with basophil chemotactic activity after several purification steps.

Animals↗

Loss of cutaneous delayed hypersensitivity reactions in nevus anemicus. Evidence for close concordance of cutaneous delayed hypersensitivity and endothelial E-selectin expression.

BACKGROUND: The relationship of adhesion molecules in the dermis to immunologically mediated cutaneous inflammation can be understood by focusing on a serendipitous phenomenon: a lack of dermatitis within the margins of a nevus anemicus (NA) in generalized contact dermatitis. The expression and induction of endothelial and epithelial adhesion molecules with intradermally injected cytokines were investigated. OBSERVATIONS: Nevus anemicus without dermatitis lacked histopathological changes consistent with inflammatory cellular infiltration. The surrounding skin of the dermatitic lesion expressed HLA-DR, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1, and E-selectin on endothelial cells, and HLA-DR and ICAM-1 in the epidermis. However, the skin of the NA lacked endothelial E-selectin and epidermal HLA-DR and ICAM-1 expression. Interferon gamma, injected intradermally, induced endothelial and epidermal HLA-DR and ICAM-1 expression in the NA and surrounding normal skin. While interferon gamma strongly induced E-selectin expression on endothelial cells in normal skin, it failed to induce endothelial E-selectin expression in the NA. CONCLUSIONS: This study suggests that vessels in the NA do not respond normally to proinflammatory cytokines, at least at the level of E-selectin expression. The absence of keratinocyte ICAM-1 and HLA-DR expression in the NA lesion in contact dermatitis is likely caused by the absence of infiltrating lymphocytes, rather than by the intrinsic unresponsiveness of keratinocytes to interferon gamma. Among the endothelial cell adhesion molecules in delayed hypersensitivity, E-selectin appears to be indispensable in recruiting circulating T lymphocytes to the skin.

Antigens, CD↗