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Background: Cyanoacrylate closure for the treatment of incompetent saphenous veins does not cause thermal damage and demonstrates satisfactory outcomes with rapid recovery. However, the characteristics of phlebitis-like abnormal reaction (PLAR), the most common adverse event after cyanoacrylate closure, have not been clarified. Moreover, it differs from typical phlebitis after thermal ablation. The objective of our study is to investigate the clinical features of PLAR after cyanoacrylate closure and to report its management., Methods: A total of 160 patients with 271 incompetent saphenous veins (great saphenous veins, 201; small saphenous veins, 70) underwent cyanoacrylate closure with the VenaSeal™ system. We defined PLAR as any unusual skin condition that develops suddenly, such as erythema, itching, swelling, and pain/tenderness, over the treated veins several days after cyanoacrylate closure. Oral antihistamines and intravenous dexamethasone were administered to manage PLAR., Results: Of the 271 treated veins, 69 experienced PLAR (25.4%). The mean time of occurrence was 13.6 ± 4.6 days after treatment. The rate of occurrence of erythema, itching, swelling, and pain/tenderness were 92.2%, 91.2%, 66.2%, and 48.5%, respectively. The occurrence of PLAR was significantly higher for great saphenous veins than for small saphenous veins (P < 0.001). Occurrences were more frequent in cases with a suprafascial great saphenous vein of length >10 cm than in cases with a subfascial great saphenous vein (P = 0.001). The proportion of patients who reported swelling decreased by more than half after the administration of oral antihistamine. The pain score on the 10th day also decreased significantly after the administration of antihistamine (P = 0.006)., Conclusions: PLAR must be distinguished from classic phlebitis. We believe that PLAR is a type IV hypersensitivity reaction due to a foreign body, and in our experience, antihistamines or steroids are effective for the prevention and management of PLAR., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Nexplanon® is an etonogestrel implant with a long-acting contraceptive effect. Although several studies underlined its safety profile, its implant can rarely lead to moderate or severe adverse event. Here, we presented a case of delayed-type hypersensitivity reaction against Nexplanon® that resolved after its removal., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Brown Norway (BN) rats were topically sensitized to polymeric diphenylmethane-diisocyanate (MDI) and challenged with MDI-aerosol approximately every 2 weeks over a time period of 2 months. Half of the sensitized animals were pretreated with capsaicin for partial C-fiber defunctionalization. After the fourth challenge inflammatory and pro-inflammatory factors in bronchoalveolar lavage (BAL) fluid and cells and physiological delayed-onset breathing patterns were analyzed. The latter endpoint was examined in the capsaicin pretreated group before and after each challenge. Findings were compared against naïve but repeatedly MDI-challenged BN rats. BAL-neutrophils, -protein, and -LDH as well as lung weights were significantly increased in the MDI-sensitized and challenged rats relative to the naïve, challenged control rats. With regard to these endpoints, capsaicin pretreatment did not affect the responsiveness to MDI-aerosol. In contrast, pro-inflammatory cytokines, the Th2 cell cytokine IL-4, and the CC-chemokine MCP-1 were significantly increased in BAL-cells of capsaicin pretreated and MDI-sensitized rats, whilst in the normal MDI-sensitized rats markedly less pronounced changes (if any) occurred. In the former group, IL-4 and MCP-1 were also significantly increased in the lung draining lymph nodes. Time-related increased frequencies of delayed-onset responses were observed in MDI-sensitized rats after subsequent MDI-challenges, however, differences between capsaicin pretreated and normal rats were not found. Despite the remarkable differences between normal and capsaicin pre-treated rats in the concentrations of pro-inflammatory and Th1-/Th2-cell specific cytokines, the inflammatory endpoints in BAL as well as the physiological measurements did not identify appreciable differences amongst these groups. This study included an ancillary study addressing the analysis of the modulating effect of capsaicin pre-treatment of naïve Wistar rats exposed for single 6h to MDI-aerosol. The results indicated more pronounced changes on endpoints in the BAL-fluid of capsaicin-pretreated rats as compared to rats with intact C-fibers. This complex picture appears to suggest that C-fibers may modulate the allergic inflammatory response elicited by MDI-challenge. It appears that tachykinergic sensory C-fibers modulate the protective pathways against irritant-related lung inflammation and, similarly, also pro-inflammatory immunological factors modulating allergic inflammation. Although difficult to disentangle unequivocally the mechanisms involved, neuro-immunological factors may be important in triggering and maintaining this complex disease and cytokine/chemokine patterns may not necessarily predict the functional outcome of test.

Late allergic reactions (LAR) following allergen challenge occur in different compartments. We studied the kinetics of nasal and bronchial nitric oxide (NO) in mild asthmatics after allergen challenge. Twelve males with intermittent asthma (28 yr, FEV1 97% of predicted, PC20methacholine <8 mg/ml) and known LAR after bronchial allergen challenge underwent nasal and bronchial allergen provocation using the same allergen separated by a washout of 3 weeks. Nasal and bronchial NO were measured before challenge, during early (EAR) and late phase reactions, and 24 h after allergen. The mean (sem) maximum fall of FEV1 at EAR was 31.9+/-3.2% (P=0.001), and 17.6+/-2.2% (P=0.004) during LAR. All patients developed nasal EAR (max. fall in nasal rhinomanometric flow 64.8+/-7.6% of baseline) after nasal challenge, and 10 patients demonstrated nasal LAR with a fall in nasal flow of 65.9+/-6.6% (both P=0.002, respectively). During EAR, there was stronger reduction of nasal (-19.2+/-6.2%,P=0.039) than bronchial NO (-6.9+/-5.2% of baseline, P=ns). In contrast, bronchial NO also tended to decrease during bronchial LAR (-8.8+/-6.8%,P=ns), while nasal NO slightly increased non-significantly (+17+/-10.8%, P=ns). After 24 h, bronchial NO was significantly elevated (+78.1+/-40.1%, P=0.039), whereas nasal NO was unchanged (+6.1+/-15.1%, P=ns). The intraindividual difference between bronchial and nasal changes of NO during LAR, but not EAR or after 24 h, was significant (lung vs. nose: -35.6+/-14.1% relative difference, P=0.039). Despite similar functional responses in nose and bronchi, nasal NO kinetics following allergen challenge differ from bronchial NO. The concise mechanisms accounting for this discrepancy warrant further investigations.

Human CD99 is a small highly O-glycosylated cell-surface protein expressed on most leukocytes. It was recently found to be expressed at endothelial cell contacts and to participate in the transendothelial migration (TEM) of monocytes in vitro. In order to analyze the physiologic relevance of CD99 in vivo we searched for the mouse homolog. We cloned a mouse cDNA coding for a protein 45% identical in its sequence with human CD99. Based on the cDNA, we generated antibodies against this mouse homolog of CD99, which detected the antigen on most leukocytes, on endothelia of various tissues, and at cell contacts of cultured endothelial cells. Cell aggregation of CD99-transfected Chinese hamster ovary (CHO) cells was completely blocked by anti-CD99 antibodies. The same antibodies inhibited TEM of lymphocytes in vitro, independent of whether T cells or endothelial cells were preincubated with antibodies. In a cutaneous delayed-type hypersensitivity (DTH) reaction, anti-CD99 antibodies inhibited the recruitment of in vivo-activated T cells into inflamed skin as well as edema formation. We conclude that mouse CD99 participates in the TEM of lymphocytes and in their recruitment to inflamed skin in vivo. This establishes CD99 as a valid target for interference with cutaneous inflammatory processes.

To understand the mechanisms involved in immunological tolerance to skin-associated antigens, we have developed transgenic (Tg) mice that express a model self-antigen, membrane-bound chicken ovalbumin (OVA), under the control of a keratin 14 (K14) promoter. K14-mOVA Tg mice express OVA mRNA in the epidermis, and appear normal. K14-mOVA Tg mice failed to mount T cell and delayed type hypersensitivity reactions to OVA, suggesting that the Tg mice were tolerant to OVA. Skin dendritic cells, including Langerhans cells, may contribute to the tolerance induction because migratory skin DC derived from K14-mOVA efficiently activated CD8(+) T cells from OVA-specific T-cell receptor (Va2/Vb5) Tg (OT-I) mice. OT-I cells expanded and accumulated in skin-draining lymph nodes after intravenous injected into K14-mOVA mice and exhibited activation markers. Graft-versus-host disease-like skin lesions appeared in K14-mOVA mice by day 7 after injection of OT-I cells. These studies demonstrate that K14-mOVA Tg mice are susceptible to an autoimmunelike skin disease induced by passively transferred naïve CD8(+) OVA T-cell receptor Tg T cells, and serve as a good model for understanding self-tolerance and for the investigation of the pathogenesis, treatment and potential prevention of cell-mediated autoimmune reactions in skin.

It is known that, in patients of allergic asthma and rhinitis, the late-phase reaction (LPR) occurs 6-12 h after allergen challenge, but there are few reports concerning cytokine production in the cutaneous LPR in atopic dermatitis (AD). We report here the results of our study on the relationship between the cutaneous LPR and the production of cytokines such as IL-4, IL-5, IL-2 and IFN-gamma by peripheral blood mononuclear cells (PBMC) of AD patients. We selected 29 pure AD patients with no history of atopic airway diseases who showed high serum IgE antibody against Dermatophagoides farinae and performed skin prick testing with three different antigens and observed the resultant cutaneous reactions in 23 of the AD patients. Furthermore, we measured the cytokine production by the cultured PBMC under the stimulation of the antigens and compared it with the results of the skin tests. 13 (57%) of these 23 AD patients demonstrated positive LPR in response to D. farinae, and the mean concentration of IL-5 produced by PBMC was higher in these LPR-positive AD patients compared to the LPR-negative ones. Additionally, we noticed that there was a positive correlation between the mean diameter of the erythema of LPR and the level of IL-5 production by PBMC in the LPR-positive patients. We suggest that there are at least two groups in AD patients, i.e. LPR-positive and LPR-negative ones. The observation of LPR can be an important and practical way to classify AD patients into subgroups, which may enable us to regard IL-5 or eosinophils as a target for treatment.

It is well established that ultraviolet radiation has immunomodulatory effects that may be involved in skin cancer. Recent studies have shown that ultraviolet A radiation (320-400 nm) as well as ultraviolet B (290-320 nm) is immunosuppressive. This means sunscreens that mainly absorb ultraviolet B (protection against erythema) may be less effective in preventing ultraviolet radiation-induced immunosuppression than broad-spectrum products. We have studied the effects of ultraviolet A exposure on the human delayed-type hypersensitivity response and compared the efficacy of sunscreens having different levels of ultraviolet A protection under both solar-simulated radiation and outdoor real-life solar exposure conditions. Delayed-type hypersensitivity was assessed using recall antigens. In a first study, two groups of volunteers were exposed to ultraviolet A (either full spectrum ultraviolet A or ultraviolet A1) without prior application of sunscreen and they were shown to exhibit significantly reduced delayed-type hypersensitivity responses. In order to compare the efficacy of sunscreens in preventing photoimmunosuppression, three groups of subjects received 10 cumulative exposures to solar-simulated radiation; one group was exposed unprotected and the other two were exposed after being applied either a ultraviolet B or a broad-spectrum sunscreen, each with the same sun protection factor 9, but with different ultraviolet A protection factors 9 and 2. Then, an outdoor study was conducted in which delayed-type hypersensitivity was assessed before and after six daily exposures. Two different groups of subjects were treated with one of two sunscreens having the same sun protection factor 25 but different ultraviolet A-protection factors. In unprotected volunteers, responses to delayed-type hypersensitivity tests were significantly reduced irrespective of ultraviolet exposure conditions (full spectrum ultraviolet A, ultraviolet A1, solar-simulated radiation). The ultraviolet B sunscreen failed to protect from solar- simulated radiation-induced immunosuppression. In contrast, the broad-spectrum sunscreen having the same sun protection factor but providing high protection in the ultraviolet A range significantly reduced local ultraviolet-induced immunosuppression and prevented the distal effects. In the outdoor study, as compared with delayed-type hypersensitivity responses obtained before sun exposure, no alteration of immune response was detected when the skin was protected by broad-spectrum sunscreen sun protection factor 25 and ultraviolet A-protection factor 14. Conversely, a broad-spectrum sunscreen sun protection factor 25 ultraviolet A-protection factor 6 failed to protect against the sun-impaired response. The above studies clearly demonstrate the role of ultraviolet A in the induction of photoimmunosuppression together with the need for sunscreen products providing efficient photoprotection throughout the entire ultraviolet spectrum.

The Gell and Coombs's classification divides drug allergies into four pathophysiological types, namely anaphylaxis (type I), antibody-mediated cytotoxic reactions (type II), immune complex-mediated reactions (type III), and delayed type hypersensitivity (type IV). Although this classification was proposed more than 30 years ago, it is still widely used. As only a limited number of drug allergies fit into this classification which does not include our current understanding of the immune response, its use is not recommended, particularly in the context of the preclinical safety evaluation of new therapeutic agents. In fact, three different situations can be identified, namely pseudo-allergic reactions, primarily antibody-mediated reactions and cell-mediated reactions, which could serve as a basis for modern and more adequate classifications

Delayed type hypersensitivity (DTH) reactions are antigen-specific, cell-mediated immune responses which, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, fungi, and certain tumors) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. We have shown that acute stress administered immediately before antigenic challenge results in a significant enhancement of a skin DTH response in rats. A stress-induced trafficking or redeployment of leukocytes to the skin may be one of the factors mediating this immunoenhancement. Here we investigate the effects of varying the duration, intensity, and chronicity of stress on the DTH response and on changes in blood leukocyte distribution and glucocorticoid levels. Acute stress administered for 2 h prior to antigenic challenge, significantly enhanced the DTH response. Increasing the duration of stress from 2 h to 5 h produced the same magnitude enhancement in cutaneous DTH. Moreover, increasing the intensity of acute stress produced a significantly larger enhancement of the DTH response which was accompanied by increasing magnitudes of leukocyte redeployment. In contrast, chronic stress suppressed the DTH response when it was administered for 3 weeks before sensitization and either discontinued upon sensitization, or continued an additional week until challenge, or extended for one week after challenge. The stress-induced redeployment of peripheral blood lymphocytes was attenuated with increasing exposure to chronic stress and correlated with attenuated glucocorticoid responsivity. These results suggest that stress-induced alterations in lymphocyte redeployment may play an important role in mediating the bi-directional effects of acute versus chronic stress on cell-mediated immunity in vivo.

One thousand 5-wk-old male turkeys from each of two commercial strains (A and B) were grouped into low, medium, and high responders based on the cutaneous basophil hypersensitivity (CBH) response obtained 24 h after toe-web inoculation with 100 micrograms of phytohemagglutinin-P (PHA-P). The CBH response for Strain A was higher than strain B (P = 0.00001) and ranged from 0 to 1.95 mm, with a mean of 0.66, whereas the CBH response for Strain B ranged from 0 to 1.67 mm with a mean of 0.38. At 6 wk of age, 36 birds from each of the six response groups were inoculated into the left thoracic air sac with 1.5 x 10(7) cfu of an early log phase broth culture of Escherichia coli. Samples of 5 or 10 birds were necropsied from each of the six groups at 7, 14, 28, and 42 d postinfection (PI). Birds were scored for air-sacculitis/pericarditis (AS) and turkey osteomyelitis complex (TOC). Overall mortality of birds inoculated with E. coli was 31%. There were no mortalities in unchallenged controls. Strain A had significantly higher Week 1 mortality, marginally higher overall mortality (P = 0.1), and higher AS scores than Strain B. There were no TOC lesions detected until 7 d PI, after which all mortalities had TOC lesions in multiple sites. The differences in CBH response within each strain were not clearly correlated to E. coli susceptibility. However, these data suggest that air sac inoculation of E. coli can provide a useful model for the study of TOC. The greater incidence of disease in Strain A indicates that an enhanced inflammatory response may increase susceptibility to E. coli septicemia.

Leukocyte rolling and emigration in response to inflammatory stimuli appears to involve both E-selectin- and P-selectin-dependent adhesion, which suggests that these molecules have overlapping functions. To clarify their relative contributions in chronic inflammation, we examined delayed-type contact hypersensitivity (DTH) responses in P-selectin, E-selectin, and E-/P-selectin-deficient mice. Oxazolone-induced increases in ear thickness and ear weight were equivalent in wild-type mice and in P-selectin and E-selectin mutants, but were significantly reduced in E-/P-selectin mutants. The number and area of microabscesses on the ears of E-/P-deficient mice were decreased by 72% and 93%, and the number of leukocytes invading the subdermal ear tissue was reduced. T cells from E-/P-deficient mice transferred oxazolone reactivity into naive wild-type mice. However, when donor T cells from wild-type mice were transferred into E-/P-selectin-deficient mice, the DTH response was significantly impaired. These results show that leukocyte recruitment into a subacute inflammatory reaction can occur when either P-selectin or E-selectin is present, but is significantly reduced when both selectins are absent. Both P- and E-selectin are likely to play important roles in the development and maintenance of inflammatory diseases.

Delayed-type hypersensitivity (DTH) reactions are initiated by sensitized T cells. Their progression is dependent upon the local release of various autacoids, including cytokines and eicosanoids, by T cells, infiltrating inflammatory cells, and resident tissue cells. 12(R)-hydroxy-5,8,14-eicosatrienoic acid [12(R)-HETrE], an eicosanoid produced by skin and cornea, possesses potent proinflammatory properties at picomolar concentrations including vasodilation, increase in membrane permeability, neutrophil chemotaxis, and angiogenesis. Because DTH reactions are associated with many of these same phenomena, we examined the effect of 12(R)-HETrE and related 12-hydroxyeicosanoids on the expression of DTH to purified protein derivative of tuberculin in sensitized guinea pigs. In the absence of purified protein derivative of tuberculin, none of the eicosanoids evoked erythema or edema after intradermal injection at doses up to 100 pmol. When injected together with purified protein derivative of tuberculin, 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid [12(R)-HETE], but not its enantiomer 12(S)-HETE, significantly inhibited macroscopic expression of delayed reactivity (erythema) only at the highest dose tested, 10 pmol. In contrast, 12(R)-HETrE significantly enhanced expression of DTH at doses between 1 fmol and 1 pmol (50% and 30% increases above control, respectively). Its stereoisomer, 12(S)-HETrE, did not enhance DTH at any tested dose, but was able to block the activity of 12(R)-HETrE when injected simultaneously. Enhancement or inhibition of visible skin responses was not associated with qualitative or quantitative changes in cellular infiltrates at the reaction site. 12(R)-HETrE had no effect on the nonimmunologic inflammatory skin reaction induced by phorbol myristate acetate, suggesting selectivity toward DTH. We conclude that 12(R)-HETrE enhances DTH via a yet to be determined mechanism and that its stereoisomer, 12(S)-HETrE, may be a useful antagonist for studying the inflammatory actions of this eicosanoid.

Oral and intrathymic exposure to antigen can each induce systemic antigen-specific immune tolerance, but the mechanisms have not been well defined. We studied the effects that the route of exposure to antigen has on the mechanisms of tolerance in vivo using synthetic polymorphic class II major histocompatibility complex (MHC) peptides in a skin delayed-type hypersensitivity (DTH) response model. Lewis rats were immunized by injection in the footpad with synthetic peptides (RT1.Bu and/or RT1.Du) derived from the hypervariable domain of MHC class II beta chain of the Wistar-Furth rat in complete Freund's adjuvant and challenged 2 weeks later by injection in the ear with the MHC peptides. An "oral" group received the peptide mixture by gavage (100 micrograms/day for 5 days) 3 days before immunization, and an "intrathymic" group received a single intrathymic injection of 100 micrograms of peptides 48 hours before immunization. Oral therapy reduced the DTH response to 23 +/- 7%, and intrathymic exposure reduced the DTH response to 26 +/- 6% (P < 0.001) as compared with control DTH responses of unmodified Lewis animals. Immunohistological evaluation of DTH skin lesions showed that oral and intrathymic therapy each decreased mononuclear cell infiltration, fibrin deposition, and endothelial activation when compared with that seen in control rats. In contrast, while both protocols markedly reduced interleukin (IL-2) and interferon-gamma expression, they had differing effects on local expression of IL-4, transforming growth factor-beta, IL-2R, and CD45RC (a possible discriminant between Th1 and Th2 cells in rats). Oral therapy was associated with increased expression of IL-4 and preservation of transforming growth factor-beta expression by residual IL-2R+, CD45RC- mononuclear and endothelial cells, whereas thymic exposure suppressed essentially all features of immune activation including IL-2R induction and cytokine expression. Our data a) document the detailed pattern of cytokine expression and mononuclear and endothelial cell activation markers during DTH responses and b) confirm that oral tolerance is associated with immune deviation to a predominance of Th2 cell function, whereas intrathymic tolerance may be mediated by T-cell anergy or clonal deletion.

The guinea pig complement factor H(FH) and the plasma precursor(PMCFS-1) of the major monocyte-chemotactic factor(MCFS-1) found in the skin site of delayed hypersensitivity reaction(DHR) induced in the guinea pigs were compared in the antigenicity and the function. Both anti-FH-IgG and anti-MCFS-1-IgG formed a single precipitation line against FH, PMCFS-1, MCFS-1 and guinea pig plasma, and these lines fused one another without any spur formation. The inhibition activity of FH for C3bBb was absorbed by anti-MCFS-1-F(ab')2 in a dose-dependent manner. PMCFS-1 inhibited C3bBb activity dose-dependently as FH. These results show that FH is identical to PMCFS-1 and imply that FH, converted to MCFS-1 plays as a monocyte-chemotactic factor in the site of DHR.

The mechanisms involved in behavioral modulation of immunity by Pavlovian conditioning have not been delineated, although an elevation in adrenocortical steroids has been invoked as an explanation. Therefore, we investigated whether or not a 4-day, murine delayed type hypersensitivity (DTH) response could be modified by a taste aversion conditioning paradigm. Mice were conditioned by the pairing of their saccharin (0.1%) drinking water (SAC) with a cyclophosphamide (CY) injection (50 mg/kg) on Day 0. Conditioned mice that were exposed on Day 3 to SAC + CY, SAC + normal saline, or water + CY exhibited significant suppression of DTH induced paw swelling when compared to nonconditioned controls. Conditioned immunosuppression was demonstrated, since the DTH response was suppressed by SAC without a concomitant reexposure to the immunosuppressant, CY. However, when dexamethasone (3 mg/kg) was used as the conditioning agent, the SAC + vehicle group showed no reduction in paw swelling. A serum corticosterone time course study was performed to examine possible involvement of glucocorticoids in conditioned immunosuppression. On Day 3, mice were sacrificed 30, 60, 90, 120 min and 24 h after reexposure to SAC or water. No significant differences in serum corticosterone levels were detected between nonconditioned controls and any conditioned group at any time point. These results demonstrate conditioned immunosuppression of a cell-mediated immune response that is not linked to a rise in glucocorticoid levels.

The delayed-type hypersensitivity reaction (DHR) in human skin is prototypic for many inflammatory dermatoses. However the cellular events that precede gross lesion formation are unknown. In this study, inflammatory cell populations and adhesion molecule expression in early phases of DHR elicited by 2,4-dinitrochlorobenzene were evaluated. The first discernible event (at 1 hour) was mast cell degranulation, followed by induction of endothelial leukocyte adhesion molecule (ELAM-1) expression on dermal postcapillary venules at 2 hours. Endothelial leukocyte adhesion molecule expression peaked at 24 hours and declined by 48 hours. In contrast, endothelial expression of intercellular adhesion molecule-1 (ICAM-1) remained at constitutive levels. Intrafollicular T-cell migration occurred independent of ICAM-1 expression and commenced as early as 4 hours after challenge. Mature, activated CD4-positive lymphocytes that expressed a helper-inducer/memory phenotype predominated in early lesions. These results demonstrate in vivo that mast cell degranulation, ELAM-1 expression, and memory T-cell-follicular interactions are key events in subclinical evolutionary stages of cutaneous DHR.

Two hundred twenty-one consecutive adult cardiac surgical patients were examined prospectively for nutritional protein state, acute phase protein response, and delayed hypersensitivity reaction in an attempt to identify patients at high risk for the development of sternal wound infection, which occurred in 6 patients (2.7%). There was no significant correlation between preoperative nutritional protein concentrations (retinol-binding protein, prealbumin, and transferrin) and acute phase protein levels (C-reactive protein, alpha 1-acid glycoprotein, and complements B and C3), nor a statistically significant relationship between nutritional state or acute phase protein response and the development of sternal infection. Preoperative complement C3 levels were elevated, however, in 80.0% of those in whom sternal infections developed compared with 30.6% of those with well-healed wounds. Similarly, postoperative concentrations of alpha 1-acid glycoprotein were elevated in 80.0% of those in whom sternal infections developed compared with 28.6% of those with well-healed wounds. There was no correlation between delayed hypersensitivity and the risk of sternal infection, nor between preoperative nutritional protein and acute phase protein values. Seventy-three percent of patients were anergic on postoperative day 2. Stepwise logistic regression showed that age, body weight, preoperative intensive care unit stay, repeat median sternotomy, internal mammary artery grafting, postoperative hemorrhage, and postoperative cardiac arrest correlated with the development of sternal infection, whereas transfusion requirement, reexploration for bleeding, and the operation performed did not. We conclude that routine delayed hypersensitivity testing is of no value in predicting high-risk cardiac surgical patients when the anergy battery is placed on the preoperative day. Although statistically insignificant, possibly due to the small number of patients in whom sternal infection developed in this study (type II error), a larger study might find preoperative complement C3 and post-operative alpha 1-acid glycoprotein levels to be predictive of patients at risk for the development of sternal wound infection. The final logistic model for the predicted risk 2%) of sternal wound infection is: PREDSWC = exp(EQ)/1 + exp(EQ) where EQ = (0.38 x age) + (0.24 x weight) + (5.42 x preop ICU) + (4.39 x redo) + (7.14 x IMA) + (4.49 x hemorrhage) + (8.81 x arrest) - 62.72, and where preop ICU, redo, hemorrhage, and arrest are defined as yes (1) or no (0), IMA-is defined as 0, 1, or 2, age is in years, and weight is in kilograms.

A simple and standardized new technic for evaluation of delayed hypersensitivity reactions with recall antigens, the Multitest, was applied on 186 cancer patients. The present results are: 1) Cancer patients with local disease present less important hypersensitivity skin reactions than the control subjects. The hypoergie of cancer patients is associated with the presence of distant metastases but not with the presence of regional lymph node involvement. 2) The immune depression is, at equal stages, the same in the case of breast neoplasma as in lung neoplasma. 3) Chemotherapy for breast cancer as applied in our service does not provoke depression of immune reactions. 4) Radiotherapy for breast cancer increases the anamnestic reactions. We have observed a reduction of the total number of lymphocytes as described in the literature.

Some sesquiterpene lactones and related compounds were tested for anti-inflammatory activity in rodents. In the edema-induced carrageenan inflammation screen, the alpha-methylene-gamma-lactone moiety of the sesquiterpene lactones was required for inhibitory activity. The 6-hydroxy group of helenalin also was required for potency. In the tenulin series, the 2,3-epoxy derivatives were marginally active. The same structure was required for inhibition of the writhing reflex. In the chronic adjuvant arthritic screen, compounds containing the alpha-methylene-gamma-lactone moiety, the beta-unsubstituted cyclopentenone ring, and the alpha-epoxy cyclopentenone system afforded significant inhibition at 2.5 mg/kg/day. The sesquiterpene lactones were marginally effective against induced pleurisy. The delayed hypersensitivity was suppressed by these agents whereas immunoglobulin synthesis was slightly stimulated. No delerious side effects were observed with these agents from the limited tests performed.

The involvement of mast cells in the elicitation of contact photosensitivity (CPS) was examined in mice treated with pharmacologic agents and in genetically mast cell-deficient W/Wv mice. Contact photosensitivity responses were diminished by pretreatment with reserpine, which may have been due to depletion of vasoactive amines in mast cells. This inhibition was almost reversed by the monoamine oxidase inhibitor, pargyline-HCl, which prevented reserpine-induced depletion of vasoactive amines such as serotonin. Defective CPS was also found in W/Wv mice, but not in their congenic littermates (+/+). Abnormal CPS in mast cell-deficient mice was due to a defect in the elicitation of CPS rather than a defect in the induction of effector T cells, since the ability to elicit CPS could be transferred to normal +/+ mice by photosensitized cells from mast cell-deficient mice. These findings favor the view that mast cells are involved in the elicitation of CPS.

Intercellular adhesion molecule-1 (ICAM-1), putatively expressed by antigen-presenting or target skin cells, is a ligand for the lymphocyte function-associated antigen (LFA-1) present on circulating lymphocytes. Immunohistochemistry of normal adult human skin using monoclonal antiserum to ICAM-1 demonstrated focal reactivity restricted to endothelium lining the dermal microvasculature. Delayed hypersensitivity responses elicited with dinitrochlorobenzene in the skin of the same subject were evaluated sequentially over a 96 h period using immunohistochemical and ultrastructural techniques. The first alteration observed consisted of mast cell degranulation within perivenular foci in the superficial dermis at 4 h after antigen challenge. Sparse superficial perivascular T-cell infiltrates were present by 24 h. Progressive staining for ICAM-1 was observed in microvascular endothelium and in dermal dendritic cells between 24 and 48 h. ICAM-1 expression was documented focally within the lower epidermis at 48 h and diffusely within the lower and upper epidermal layers at 96 h. ICAM-1 expression by keratinocytes was consistently associated with T-cell migration into the epidermis, whereas migration was never observed in the absence of ICAM-1 reactivity. Immunoelectron microscopy confirmed ICAM-1 to be exclusively present on endothelial cells, dermal dendritic cells, mononuclear cells, and keratinocytes, and permitted characterization of the patterns of membrane reactivity. ICAM-1 expression by epidermal cells appears to be closely linked to the progressive migration of T cells from the dermis into the epidermis that characterizes cutaneous delayed hypersensitivity.

The effects of both malnutrition and malarial infection on cell mediated hypersensitivity (CMH) to tuberculin, varidase and phytohemagglutinin (PHA) has been evaluated in a group of children from a rural area of Upper Volta, aged lower than 3 years. Only the response to PHA was decreased during the course of malnutrition. In plasmodium infection associated with a low degree of parasitemia, it appeared that there was no effect on the frequency of positive responses to either these antigens or mitogen at any nutritional conditions. The high prevalence of tuberculin positive test allows to support the interest of a precocious anti tuberculin vaccination.

We developed a reliable method for reconstituting thymectomized, lethally irradiated guinea pigs. Injection of 2.5-10 X 10(7) syngeneic bone marrow cells into adult thymectomized, lethally irradiated guinea pigs produced survival of 46-100% of treated animals. Gentamycin sulfate (5 mg/kg of body weight) for 10 days was required for optimal results. Acidified drinking water (pH 2.5) appeared to be required for optimal results. Thymectomized, lethally irradiated, bone marrow reconstituted ('B') guinea pigs had impaired ability to develop delayed cutaneous hypersensitivity to mycobacterial antigens and cutaneous basophil hypersensitivity to keyhole limpet hemocyanin; proliferative responses to phytohemagglutinin were impaired.

Various kinds of lipopolysaccharides (LPS) isolated from different bacterial strains exhibited more or less an adjuvant action in induction of delayed-type footpad response to ovalbumin (OA) in mice when antigen was injected subcutaneously together with LPS. There was a wide diversity in strength of the adjuvant action of LPS, and the action of the 03 antigen isolated from the culture supernatant fluid of Klebsiella was the most potent of eleven kinds of LPS tested. Besides this substance, LPS extracted from Escherichia coli 08, 09 and 0128, and Salmonella typhosa exhibited relatively strong action. The difference in strength of the action of the high and low active LPS in induction of delayed-type hypersensitivity could be observed at any doses of OA and LPS. The strength of the adjuvant activity of LPS in induction of delayed-type hypersensitivity roughly correlated with that of their adjuvant activity in augmenting immunological memory for the secondary antibody response to OA and also their ability to enlarge the regional lymph node, whereas it did not apparently correlate with that of their activity to stimulate B cells polyclonally and their ability to enlarge the spleen.

The destruction of vascular smooth muscle cells (VSMCs) in autoimmune arteritis is a poorly understood phenomenon. For evaluation of the cellular interactions that may contribute to vasculitis, the immunobiology of VSMCs and lymphocytes was explored in vitro. Primary VSMC cultures were established, and the interaction of these cells (from normal or autoimmune mice) with lymphocytes was then assessed. Specifically, splenocytes from MRL/lpr or C3H mice were cocultivated with MRL/lpr or C3H VSMCs. Massive mononuclear cell clusters from normal and autoimmune mice enveloped MRL/lpr VSMCs, which culminated in the detachment of MRL/lpr VSMCs from the culture plate. In contrast, the interaction of SPs from either normal or autoimmune mice did not encompass or destroy normal VSMCs. Further investigation indicated that MRL/lpr, but not C3H, VSMCs spontaneously expressed Ia and released Il-1 like factor(s), which may be at least two mechanisms by which MRL/lpr VSMCs stimulate the in vitro mononuclear cell influx. As a result of these studies, a novel mechanism for the induction of mononuclear cell autoimmune vasculitis is proposed. VSMCs derived from autoimmune mice may stimulate a mononuclear inflammatory cell phlogistic response which culminates in VSMC autodestruction.

The blood flow velocity in the skin of the flanks of guinea pigs can be measured precisely by laser Doppler velocimetry, provided the animal is mildly sedated. The probe holder can be attached to the shaved skin with cyanoacrylate glue and can be detached after completion of blood flow velocity measurements by application of acetone without harming the animal. The technique is pain-free and non-invasive: it can be used to make serial measurements on the same animal. The system has demonstrated hyperaemia in delayed-type responses to tuberculin PPD, ovalbumin and Keyhole Limpet Haemocyanin with immunological specificity. The time course of evolution and resolution of the vasomotor response accords with previous experience. The method can detect hyperaemia-inducing mediators in the supernatant of antigen or mitogen stimulated lymphocyte cultures and could be used for their bioassay.

Many drugs and other chemicals can alter cell-mediated immunity (CMI), a response that often correlates with delayed-type hypersensitivity (DTH). Several DTH assays were evaluated to determine a method best suited for assessing chemically induced modulation of CMI in rats. The effects of various antigens, adjuvants, doses, routes, and immunosuppressants were investigated. The DTH method which produced optimum results in rats uses a footpad swelling reaction elicited by specific preparations of bovine serum albumin (BSA) and Freund's complete adjuvant (FCA). The rats were sensitized with 100 micrograms BSA in FCA injected subcutaneously at the base of the tail, and were challenged 7 days later with 75 microliter of 2% heat-aggregated BSA suspension injected into the left rear footpad. Footpad swelling was measured with pressure calipers 24 h later and compared to the contralateral footpad which was sham-injected with 75 microliters of physiological saline. Antigen-injected footpads were nearly double the thickness (7-8 mm) of the control footpads (3-4 mm), and variation between animals was small (CV = 5%). Dexamethasone and cyclophosphamide significantly suppressed the DTH reaction. Histopathological examination of the DTH reaction sites revealed a mononuclear cell infiltrate which is characteristic of type IV hypersensitivity. In addition to being highly quantitative and sensitive, this method provides a simple and reproducible assessment of CMI responses in the rat.

The properties of an epoxide metabolite of alclofenac have been investigated in a number of in vitro and in vivo tests. Alclofenac epoxide was shown to inhibit the activity of yeast alcohol dehydrogenase and form a conjugate with cysteine. The epoxide, but not alclofenac itself, showed mutagenic effects on strains of Salmonella typhimurium sensitive to alkylating agents, but had no effect on strains sensitive to intercalating agents. In addition the epoxide was active in a cell transformation assay using as a target Syrian hamster cells. No acute toxic reactions were observed in mice treated with alclofenac epoxide and the compound was devoid of analgesic and acute antiinflammatory activity. Alclofenac epoxide was found to be a sensitising agent in the guinea-pig when administered either by injection with complete Freud's adjuvant or topically as an ethanolic solution. It is postulated that the formation of the epoxide may explain some of the therapeutic and toxicological properties of alclofenac in man.

Three tests, footpad thickness, footpad weight and footpad dye accumulation have been compared for measuring the local inflammatory reaction developed in the hind footpads of the mouse after injection of increasing doses of heat killed Candida albicans yeasts. The 3 tests showed high correlation indicating that any one of them may be used to evaluate such inflammatory reactions.

Basophilic leukocytes constitute a significant proportion of the cellular infiltrates in many forms of delayed-in-onset hypersensitivity reactions in human beings, guinea pigs, and other animals. In this paper, I review current information on the role of basophils in the reactions, and present similarities and differences between Jones-Mote and classic delayed hypersensitivities.