Proanthocyanidins inhibit UV-induced immunosuppression through IL-12-dependent stimulation of CD8+ effector T cells and inactivation of CD4+ T cells.

The inhibition of UVB-induced immunosuppression by dietary grape seed proanthocyanidins (GSP) has been associated with the induction of interleukin (IL)-12 in mice, and we now confirm that GSPs do not inhibit UVB-induced immunosuppression in IL-12p40 knockout (IL-12 KO) mice and that treatment of these mice with recombinant IL-12 restores the inhibitory effect. To characterize the cell population responsible for the GSP-mediated inhibition of UVB-induced immunosuppression and the role of IL-12 in this process, we used an adoptive transfer approach. Splenocytes and draining lymph nodes were harvested from mice that had been administered dietary GSPs (0.5%-1.0%, w/w), exposed to UVB, and sensitized by the application of 2,4-dinitrofluorobenzene (DNFB) onto the UVB-exposed skin. CD8(+) and CD4(+) T cells were positively selected and transferred into naive mice that were subsequently challenged by application of DNFB on the ear skin. Naive recipients that received CD8(+) T cells from GSP-treated, UVB-irradiated donors exhibited full contact hypersensitivity (CHS) response. Naive mice that received CD4(+) suppressor T cells from GSP-treated, UVB-exposed mice could mount a CHS response after sensitization and subsequent challenge with DNFB. On culture, the CD8(+) T cells from GSP-treated, UVB-exposed mice secreted higher levels (5- to 8-fold) of Th1 cytokines than CD8(+) T cells from UVB-irradiated mice not treated with GSPs. CD4(+) T cells from GSP-treated, UVB-exposed mice secreted significantly lower levels (80%-100%) of Th2 cytokines than CD4(+) T cells from UVB-exposed mice not treated with GSPs. These data suggest that GSPs inhibit UVB-induced immunosuppression by stimulating CD8(+) effector T cells and diminishing regulatory CD4(+) T cells.

Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation.

Tim-3 is a cell surface molecule preferentially expressed in Th1 and Th17 cells. Galectin-9 is a ligand for Tim-3 and the binding of galectin-9 to Tim-3 induces apoptosis. We recently developed a stable form of galectin-9 (sGal-9) by partial deletion of the linker peptide. In this study, we characterized the therapeutic effects of sGal-9 on inflammatory reactions in contact hypersensitivity and IL-23-induced psoriatic mouse models. In contact hypersensitivity in mice, the ear swelling response was suppressed by sGal-9. In vitro treatment with sGal-9 resulted in cell apoptosis of CD4, CD8, and hepatic NK cells. sGal-9-treated mice had decreased IFN-gamma- and IL-17-producing T cells. Similarly, sGal-9 reduced epidermal thickness and dermal cellular infiltrate levels in IL-23-induced psoriasis-like skin inflammation. This was accompanied by decreased skin lesion levels of IL-17 and IL-22. sGal-9 may be a unique and useful therapeutic tool for the treatment of Th1- and/or Th17-mediated skin inflammation.

Sesquiterpene lactone mix patch testing supplemented with dandelion extract in patients with allergic contact dermatitis, atopic dermatitis and non-allergic chronic inflammatory skin diseases.

We investigated the value of patch testing with dandelion (Compositae) extract in addition to sesquiterpene lactone (SL) mix in selected patients. After we detected a case of contact erythema multiforme after patch testing with dandelion and common chickweed (Caryophyllaceae), additional testing with common chickweed extract was performed. A total of 235 adults with a mean age of 52.3 years were tested. There were 66 men and 169 women: 53 consecutive patients with allergic contact dermatitis (ACD); 43 with atopic dermatitis (AD); 90 non-atopics suffering from non-allergic chronic inflammatory skin diseases; 49 healthy volunteers. All were tested with SL mix 0.1% petrolatum (pet.) and diethyl ether extracts from Taraxacum officinale (dandelion) 0.1 and 3.0% pet. and from Stellaria media (common chickweed) 0.1 and 3% pet. A total of 14 individuals (5.9%) showed allergic reaction (AR) to at least 1 of the plant allergens, 4 (28.6%) to common chickweed extract, and 11 (78.6%) to Compositae allergens. These 11 persons made the overall prevalence of 4.7%: 8 (3.4%) were SL-positive and 3 (1.3%) reacted to dandelion extract. 5 persons (45.5%) had AD, 2 had ACD, 2 had psoriasis and 2 were healthy controls. The Compositae allergy was relevant in 8 cases (72.7%). The highest frequency of SL mix sensitivity (9.3%) was among those with AD. Half the SL mix-sensitive individuals had AD. ARs to dandelion extract were obtained only among patients with eczema. A total of 9 irritant reactions (IRs) in 9 individuals (3.8%) were recorded, 8 to SL mix and 1 to common chickweed extract 3.0% pet. No IR was recorded to dandelion extract (P = 0.007). Among those with relevant Compositae allergy, 50.0% had AR to fragrance mix and balsam of Peru (Myroxylon pereirae resin) and colophonium. SLs were detected in dandelion but not in common chickweed. Our study confirmed the importance of 1 positive reaction for emerging, not fully established, Compositae allergy. In conclusion, the overall prevalence of 4.7% in our study represents a basal SL mix detection rate of 3.4% reinforced and safely supplemented by testing with the dandelion extract.

Effects of acute stress, relaxation, and a neurogenic inflammatory stimulus on interleukin-6 in humans.

Effects of three experimental manipulations: mental stress, relaxation, and a nociceptive inflammatory stimulus, capsaicin, on levels of interleukin-6 (IL-6) were examined. Fifty subjects were pre-trained in relaxation and then randomized to a stress (Stroop test), relaxation (tape), or control (video) manipulation. Subjects participated in an evening reactivity session including 20 min of stress, relaxation, or control followed by a capsaicin injection in the forearm. Cardiovascular variables and levels of IL-6 were measured before and after the manipulation, and at regular intervals up to 60 min post-capsaicin. Group assignment did not differentially affect change in IL-6 over time, either before or after capsaicin. Small but significant increases in IL-6 were seen at 60 min post-capsaicin. These findings suggest that an acute stress manipulation does not modulate IL-6 within this time frame. Although IL-6 did increase following a neurogenic inflammatory stimulus, it did so subsequent to the maximum flare, suggesting that flare mechanisms are independent of IL-6.

Modulation of cutaneous inflammation by angiotensin-converting enzyme.

Cutaneous neurogenic inflammation is a complex biological response of the host immune system to noxious stimuli. Present evidence suggests that zinc metalloproteases may play an important role in the regulation of neurogenic inflammation by controlling the local availability of neuropeptides, such as substance P (SP), that are capable of initiating or amplifying cutaneous inflammation after release from sensory nerves. To address the hypothesis that the dipeptidyl carboxypeptidase angiotensin-converting enzyme (ACE) is capable of modulating skin inflammation, we have analyzed murine allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD) using wild-type C57BL/6J (ACE(+/+)) or genetically engineered mice with a heterozygous deletion of somatic ACE (ACE(+/-)). In 2,4-dinitro-1-fluorobenzene-sensitized ACE(+/-) mice, ACD was significantly augmented in comparison to ACE(+/+) controls as determined by the degree of ear swelling after exposure to hapten. Likewise, systemic treatment of ACE(+/+) mice with the ACE inhibitor captopril before sensitization or elicitation of ACD significantly augmented the ACD response. In contrast, local damage and neuropeptide depletion of sensory nerves following capsaicin, injection of a bradykinin B(2), or a SP receptor antagonist before sensitization significantly inhibited the augmented effector phase of ACD in mice with functionally absent ACE. However, in contrast to ACD, the response to the irritant croton oil was not significantly altered in ACE(+/-) compared with ACE(+/+) mice. Thus, ACE by degrading bradykinin and SP significantly controls cutaneous inflammatory responses to allergens but not to irritants, which may explain the frequently observed exacerbation of inflammatory skin disease in patients under medication with ACE inhibitors.

Restraint-induced modulation of allergic and irritant contact dermatitis in male and female B6.129 mice.

Recent studies in rats have indicated that acute restraint enhances cutaneous hypersensitivity. We hypothesized that acute restraint would also modulate the development of allergic and irritant dermatitis in mice and that these restraint-induced changes would be reflected in the cutaneous cytokine profile and be gender-specific. For these studies, male and female B6.129 mice were sensitized and challenged with the contact sensitizer dinitrofluorobenzene or challenged with the irritant croton oil. Two-hour restraint was applied prior to chemical challenge. Restraint combined with chemical increased ear swelling in both genders in ACD, a change that was blocked by administration of RU-486 prior to restraint. Neither restraint nor RU-486 administration modulated development of ICD; however, IL-1beta was decreased by restraint in females only. TNF-alpha and IFN-gamma production were modified in ACD; TNF-alpha in both genders and IFN-gamma in female mice only. Our data demonstrate that acute restraint increases serum corticosterone in B6.129 male and female mice to comparable levels. Restraint modulated the murine ear swelling in ACD, but not ICD, in both genders, and the change in the ear swelling response and cytokine production were, at least in part, corticosterone-dependent.

Enhancement of the contact hypersensitivity reaction by acute morphine administration at the elicitation phase.

The present study investigated the effects of morphine on the irritant contact sensitivity (ICS) and contact hypersensitivity (CHS) reaction. ICS was induced by croton oil application on the pinnae of naïve rats. Morphine injected prior to croton oil application did not affect the ICS response when assessed by measurements of pinnae thickness. CHS was induced by applying the antigen 2,4-dinitro-1-fluorobenzene (DNFB) to the pinnae of rats sensitized to DNFB. Rats received an injection of morphine prior to either initial antigen exposure (sensitization) or antigen reexposure (challenge). Morphine prior to challenge, but not sensitization, resulted in a pronounced enhancement of the CHS response as measured by pinna thickness. Quantitative PCR also showed increased IFN-gamma mRNA levels in the inflamed tissue of morphine-treated rats. Naltrexone blocked the morphine-induced enhancement of the CHS response. The differential effects of morphine suggest that opioids have a more pronounced effect on in vivo immune responses that involve immunological memory.

The sensitizing capacity of ginkgolic acids in guinea pigs.

BACKGROUND: Ginkgo biloba possesses fruits that have caused numerous cases of allergic contact dermatitis. Low amounts of the ginkgolic acids occur in the leaves as well. OBJECTIVE: Leaf extracts are used to treat cerebrovascular and peripheral vascular disorders. The question arises whether skin hypersensitivity reactions may be adverse effects because the pharmaceutical preparations contain low amounts of ginkgolic acids. METHODS: Guinea pigs were sensitized experimentally with pure ginkgolic acids as well as with leaf extracts containing approximately 1,000 ppm of ginkgolic acids. RESULTS: The guinea pigs could be sensitized successfully with the pure ginkgolic acids. The animals could not be sensitized with the leaf extract. CONCLUSION: Leaf extracts of Ginkgo biloba taken orally or given by infusion to treat diffuse cerebral disturbances can be considered safe, even when they might contain up to 1,000 ppm of the sensitizing ginkgolic acids.

The efficacy of a moisturizer (Locobase) among cleaners and kitchen assistants during everyday exposure to water and detergents.

Workers exposed to various irritants are widely advised to use moisturizers. To evaluate the efficacy of a moisturizer (Locobase), we studied 111 cleaners and kitchen workers during everyday exposure to water and detergents. All took part in a standardized interview. After randomization, 1/2 the workers (n = 56) used Locobase during a period of 2 weeks (period L), followed by a period without any emollient (period C), or vice versa (n = 55). Clinical assessment and measurements of the skin surface temperature, electrical capacitance and transepidermal water loss (TEWL) were performed on the fingers, hands and arms on entry to the study, after 2 weeks and 4 weeks, or at drop out. The final evaluation showed that 70 (63%) were able to complete the study; 23 (21%) completed period L, but withdrew from period C after a mean of 6 days because of progressive dryness of the skin and eczema; and 12 (11%) were excluded because they used topical corticosteroids or emollients. The remaining 6 (5%) participants were lost to follow-up. Clinically, we observed a significant increase in dryness (p < 0.001) during periods of no treatment (period C), and normalization of the skin texture during use of Locobase. Clinical observations were confirmed by statistically significant differences (p < 0.001) in the electrical capacitance (epidermal hydration), which decreased during period C and increased to pre-study values during period L. No significant differences were found in skin temperatures and TEWL rates.(ABSTRACT TRUNCATED AT 250 WORDS)