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A "second generation" antibody to a highly purified lymphocyte product was raised in a goat against material eluted from a rabbit anti-guinea pig lymphokine immunoadsorbent column. This anti-lymphokine serum, in constrast to anti-lymphocyte serum (ALS) did not appear to contain cytotoxic antibodies directed against membrane antigens on guinea pig lymph node lymphocytes. Furthermore, the anti-lymphokine serum did not inhibit the formation of spontaneous T rosettes nor significantly depress lymphocyte response to mitogens. The anti-lymphokine serum totally suppressed the delayed skin reactivity to PPD and contact sensitivity to DNCB when injected intradermally around the site of antigen challenge. By contrast, intradermally injected ALS did not appear to suppress the PPD response in sensitized guinea pigs. Intravenously and i.p. administered anti-lymphokine serum was somewhat less effective in suppressing the delayed skin response to PPD. The intradermal injection of the antiserum had no effect on nonspecific inflammation evoked by turpentine-olive oil or on the extravasation of circulating Evans blue evoked by intradermally injected histamine. Histologic examination of 24-hr DNCB-induced skin lesions from sensitized guinea pigs treated with intradermally injected anti-lymphokine serum showed marked reduction of mononuclear infiltration of the dermis and of epidermal lesions, as compared with skin sites taken from sensitized animals pretreated with normal goat serum. The anti-lymphokine serum injected i.v. also markedly reduced the perivascular infiltration of the dermis and subcutis in skin reaction sites from sensitized animals challenged with PPD. Intravenous treatment with ALS for 3 consecutive days caused extensive depletion of the paracortical areas of peripheral lymph nodes whereas treatment with normal serum and anti-lymphokine serum caused no such depletion. It is proposed that the anti-lymphokine serum is directed against activated lymphocyte products, one of them being MIF. These products are involved in the mediation of delayed hypersensitivity reactions. This is in marked contrast to ALS, the suppressive action of which appears to be central rather than peripheral.
BACKGROUND: When capsaicin is injected intradermally, hyperalgesia develops around the injection site. The authors observed that volunteers report painful sensations in the skin remote from the injection site during tourniquet constriction of the affected extremity. METHODS: Each volunteer received an intradermal injection of capsaicin on the volar forearm, followed by intermittent tourniquet constriction of the extremity. In some participants, the tourniquet position was rotated between different sites on the upper extremities. Laser Doppler measurements were made in the skin to measure capillary blood flow during pain magnification. RESULTS: Hyperalgesia developed in the volunteers who were tested after the capsaicin injection. Blood flow increased three times in the dermal capillaries remote from the injection site after capsaicin injection. The tourniquet-induced pain reached peak intensity soon after tourniquet inflation. Tourniquet constriction of the arm on the affected side reliably induced painful exacerbation in each person tested. The quality of the sensation was described as burning and extended across the arm in most volunteers. Only when pinprick hyperalgesia was detectable did the volunteers experience the diffuse, immediate pain sensation. The pain initiated by the tourniquet constriction likely is related to changes in skin capillary blood flow. CONCLUSIONS: Low cutaneous blood perfusion is related to the intensity of ongoing, spontaneous pain when secondary hyperalgesia is present. The specific trigger(s) have yet to be identified.
In four groups of six rats a random dorsal flap was raised, and 5, 20, or 200 mg/ml lignocaine or 0.9% sodium chloride, were injected intradermally. Cutaneous laser Doppler blood cell flux was measured at 12 time points over 130 minutes. In six other groups 5, 20, 100, 200, or 400 mg/ml lignocaine concentrations, or sodium chloride were tested. Blood cell flux was measured at the time that the flap was raised and 30 minutes after the injections. The area of the flap that survived was measured on day 10. Raising of the flaps resulted in a significant reduction in blood cell flux, which was followed by a significant increase at 10 minutes (p < 0.05) after the injections with all lignocaine concentrations tested. Injections of 5, 20 and 100 mg/ml lignocaine elicited a significant increase (p < 0.05) in blood cell flux compared with baseline values. There was no reduction in blood cell flux values at any concentration of lignocaine tested. Compared with sodium chloride, injections of lignocaine had no significant effect on flap survival. We conclude that, despite an increase in blood cell flux, lignocaine had no effect on flap survival in this model.
Washed, [3H]serotonin-labeled platelets from rats and guinea pigs were stimulated in vitro with a novel protein extracted from rat submandibular salivary glands (RS-PAP) and with the phospholipid platelet- activating factor 1-0-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine (AGEPC). Rat platelets, which are refractory to AGEPC stimulation, underwent shape-change, aggregation and secretion of [3H]serotonin in response to graded doses of RS-PAP and AGEPC. Intradermal injections of histamine, RS-PAP and AGEPC caused a dose-related increase in local microvascular permeability in rats, as measured by the extravasation of plasma containing Evans blue dye. Similarly, histamine, RS-PAP and AGEPC increased cutaneous vascular permeability when injected intradermally in guinea pigs. The vascular permeability induced by histamine and RS-PAP, but not by AGEPC, was partially inhibited by pretreatment with an antihistamine (diphenhydramine HCl). Pretreatment of guinea pigs with captopril, an inhibitor of angiotensin-converting enzyme (ACE), partially inhibited cutaneous responses to subsequent intradermal injections of histamine, RS-PAP and AGEPC. Regardless of pretreatment with diphenhydramine or captopril, skin test sites injected with large amounts of RS-PAP became hemorrhagic within minutes and necrotic within 12 hours.
BACKGROUND: Although the roles of histamine H3 receptors have been studied in several tissues such as the brain, lung, spleen, colon and peripheral sensory nerve endings, the involvement of H3 receptors in skin responses particularly in relation to scratching behaviour are not well documented. OBJECTIVES: This work was performed to study the effects of histamine H3 antagonists on scratching behaviour in mast cell-deficient mice. METHODS: Histamine H3 antagonists iodophenpropit and clobenpropit, histamine and substance P were injected intradermally into the rostral part of the back of mast cell-deficient (WBB6F1 W/Wv) and wild-type (WBB6F1+/+) mice and scratching behaviour was measured for 60 min. The effects of H1 antagonists on scratching behaviour induced by H3 antagonists were also investigated. RESULTS: Intradermal injection of iodophenpropit and clobenpropit at doses of 10 and 100 nmol per site caused significant increases in scratching behaviour in both mast cell-deficient and wild-type mice. Histamine also caused a dose-related increase in the incidence of scratching behaviour, and a significant effect was observed at a dose of 100 nmol per site in both mast cell-deficient and wild-type mice. Substance P was also effective in causing scratching behaviour in both mast cell-deficient and wild-type mice. However, histamine H1 antagonists diphenhydramine and chlorphenamine failed to inhibit H3 antagonist-induced scratching behaviour in both types of mice. CONCLUSIONS: Our results indicated that intradermal injection of H3 antagonists induces scratching behaviour and that chemical mediators other than histamine seem to be involved in the response.
An intradermal jet injector was used to administer combined diphtheria, tetanus, and pertussis (D.T.P.) vaccines to infants aged 2 to 12 months. A second dose was given one month after the first and a third six months after the second. Each dose was considerably smaller than the standard intramuscular dose. Blood samples taken one month after the third dose showed a satisfactory diphtheria and tetanus antitoxin response in all but a few cases. The antibody response to the pertussis component was not examined. Reactions were insignificant. Intradermal jet injection is proposed as a cheap, extremely rapid, and effective technique for D.T.P. immunization, especially suitable for use in remote areas where trained staff and facilities are few and many children require immunization.
A search was made for in vivo release of factor(s) that may be responsible for prominent eosinophil accumulations in human allergic skin reactions. Using a specially designed skin chamber appended to the base of unroofed skin blisters, we have found at ragweed-challenged sites in sensitive subjects the release of significantly greater histamine (15 +/- 3 ng/ml) than at control sites (3 +/- 0.5 ng/ml). Eosinophil accumulation after 2 hr was also significantly greater on membrane filters appended to ragweed-challenged sites than control sites (55 +/- 15 vs 4 +/- 0.5). Intradermal injection of ultrafiltrates of the chamber fluids from antigen-challenged sites, but not of fluids from control sites, induced prominent eosinophil accumulation (mean = 25/mm2) when injected intradermally in autologous uninvolved skin. Neither ultrafiltered antigen solution nor histamine (employed in concentrations similar to those released in the chambers) evoked such in vivo responses when injected intradermally in the same subjects (mean = less than 1/mm2). The eosinophil responses to injected ultrafiltered chamber fluid from antigen-challenged sites peaked at 30 min, whereas even greater eosinophil responses to unaltered antigen started after 60 min. These findings suggest that in vivo release of a low m.w. factor or factors other than histamine is very likely responsible for at least part of the in vivo eosinophil accumulation in human allergic reaction sites. Additional findings suggest that a significant portion of the time lag between intradermal antigen and dermal eosinophil accumulation is encompassed by local mediator release.
When purified human C'1 esterase is injected intradermally in man, increased vascular permeability results. This effect is not blocked by soybean trypsin inhibitor and is not abolished by pretreatment with the antihistamine, pyribenzamine, or by compound 48/80. Thus, the effect is not due to the release of endogenous histamine. The decreased permeability response of individuals with a specific hereditary deficiency of C'2 is evidence for the complement-dependent nature of this reaction. The apparently normal response to intradermal C'1 esterase developed by individuals with an acquired specific deficiency of C'3 suggests that the vasoactive substance may be derived from one of the early reacting complement components. Characteristic attacks of angioedema have been provoked by the intradermal injection of human C'1 esterase in two individuals with hereditary angioneurotic edema. Patients with hereditary angioneurotic edema are unresponsive to intradermal injections of C'1 esterase immediately after attacks.
The parasitic helminth Onchocerca volvulus causes ocular onchocerciasis (river blindness) and onchocercal skin disease. To understand the immunologic basis for early stage skin disease, we developed a model in which C57B1/6 mice were immunized subcutaneously and injected intradermally (in the ear) with soluble O. volvulus antigens (OvAg). We found that ear thickness increased significantly after intradermal injection of OvAg and remained elevated for at least 7 days. Dermatitis was dependent on prior immunization, and was associated with an intense cellular infiltrate in the dermis. Neutrophils were the predominant inflammatory cells in the dermis 12 hr after intradermal injection, with only occasional eosinophils present. Conversely, increased ear thickness at later time points was associated with eosinophils, and neutrophils were only rarely detected. Both cell types were present at intermediate time points. These data indicate that recruitment of neutrophils and eosinophils to the skin is temporally regulated.
BACKGROUND: The feasibility and accuracy of sentinel lymph node (SLN) biopsy examination for breast cancer patients with clinically node-negative breast cancer after neoadjuvant chemotherapy (NAC) have been investigated under the administration of a radiocolloid imaging agent injected intradermally over a tumor. In addition, conditions that may affect SLN biopsy detection and false-negative rates with respect to clinical tumor response and clinical nodal status before NAC were analyzed. METHODS: Seventy-seven patients with stages II and III breast cancer previously treated with NAC were enrolled in the study. All patients were clinically node negative after NAC. The patients then underwent SLN biopsy examination, which involved a combination of intradermal injection over the tumor of radiocolloid and a subareolar injection of blue dye. This was followed by standard level I/II axillary lymph node dissection. RESULTS: The SLN could be identified in 72 of 77 patients (identification rate, 93.5%). In 69 of 72 patients (95.8%) the SLN accurately predicted the axillary status. Three patients had a false-negative SLN biopsy examination result, resulting in a false-negative rate of 11.1% (3 of 27). The SLN identification rate tended to be higher, although not statistically significantly, among patients who had clinically negative axillary lymph nodes before NAC (97.6%; 41 of 42). This is in comparison with patients who had a positive axillary lymph node before NAC (88.6%; 31 of 35). CONCLUSIONS: The SLN identification rate and false-negative rate were similar to those in nonneoadjuvant studies. The SLN biopsy examination accurately predicted metastatic disease in the axilla of patients with tumor response after NAC and clinical nodal status before NAC. This diagnostic technique, using an intradermal injection of radiocolloid, may provide treatment guidance for patients after NAC.
BACKGROUND: Intradermal injection of platelet-activating factor (PAF) causes wheal and flare reactions, which are inhibited by antihistamines. However, PAF does not release histamine from human dispersed skin mast cells in vitro. The purpose of this study was to investigate the extent and possible mechanisms of PAF-induced histamine release in human skin in vivo with the use of dermal microdialysis. METHODS: Hollow dialysis fibers were inserted into the upper dermis in forearm skin and each fiber was perfused with Krebs-Ringer bicarbonate solution at a rate of 3.0 microliters/min. PAF (4.5 to 36 mumol/L), lyso-PAF (36 mumol/L), vehicle (negative control), and codeine 750 or 250 mumol/L (positive control) were injected intradermally above separate fibers. Dialysate was collected in 2-minute fractions for 20 minutes and histamine analyzed spectrofluorometrically. RESULTS: PAF, but not lyso-PAF, caused statistically significant dose-related histamine release and wheal and flare reactions. Intradermal mepivacaine administration significantly abrogated flare reactions by PAF and codeine and inhibited histamine release and wheal reactions by PAF but not by codeine. Long-term topical capsaicin administration inhibited histamine release and wheal reactions by PAF but not by codeine. It inhibited flare reactions induced by both compounds. PAF did not release histamine from blood basophils. CONCLUSIONS: These data suggest that PAF induced histamine release from mast cells in intact human skin indirectly via neurogenic activation. Further, on the intradermal injection of PAF histamine release and the skin responses, the wheal and the flare, are differentially regulated by neurogenic components.
Serotonin (5-HT) is pruritogenic in humans and suggested to be involved in some pruritic diseases. Our experiments were carried out to determine whether an intradermal injection of 5-HT would elicit itch-associated response in mice and to elucidate the 5-HT receptor subtypes involved in this 5-HT action. 5-HT (14.1-235 nmol site(-1)) injected intradermally into the rostral back elicited scratching of the injected site, with bell-shaped dose-response relationship. The scratching induced by 5-HT (100 nmol site(-1), peak effective dose) was suppressed by capsaicin (repeated administration) and the opioid antagonist naloxone, features being similar to human itching. Scratching was also elicited by the 5-HT2 receptor agonist alpha-methylserotonin, but not by the 5-HT1A receptor agonist R(+)-8-hydroxy-N,N-dipropyl-2-aminotetralin nor the 5-HT3 receptor agonists 2-methylserotonin and 1-phenylbiganide. Scratching induced by 5-HT and alpha-methylserotonin was inhibited by peroral pretreatment with 5-HT1/2 receptor antagonists methysergide and cyproheptadine. 5-HT-induced scratching was also inhibited by intradermal injection of methysergide. Peroral pretreatment with 5-HT3 receptor antagonists ondansetron and 3-tropanyl-3, 5-dichrobenzoate did not significantly suppress 5-HT-induced scratching. The results suggest that scratching induced by intradermal injection of 5-HT is itch-associated response. The 5-HT action may be mediated at least partly by cutaneous 5-HT2 receptors.
Intradermal injection of endothelin-1 (ET-1) causes vasoconstriction (pallor) at the injection site, surrounded by a larger area of vasodilation (flare) in humans. Some of the vasomotor responses to ET-1 are thought to be mediated by prostaglandins. In the present study, we investigated the involvement of cyclooxygenase-derived products of arachidonic acid metabolism on the cutaneous vasomotor responses to ET-1. Ten normal subjects (25-44 years) were studied after treatment with either indomethacin (50 mg t.i.d.) or placebo according to a double blind cross-over design. Five doses of ET-1 (5 x 10(-5) to 5 x 10(-1) pmol) were injected intradermally 2 h after the last dose of indomethacin or placebo. Pallor and flare areas measured by planimetry 15 min after the injection were analyzed to evaluate cutaneous vasomotor responses to ET-1. ET-1 induced dose-dependent pallor and flare responses that were significant at the dose of 5 x 10(-3) pmol or greater. Indomethacin did not affect the ET-1-induced pallor but significantly shifted to the right the flare dose-response curve to ET-1. The inhibition of the flare response to 5 x 10(-1) pmol ET-1 was 58.9 +/- 8.5%. These results indicate that the cutaneous vasodilation induced by intradermal injection of ET-1 is mediated by the release of vasodilating cyclooxygenase products.
Intradermal injection of capsaicin induces a region of visual flare (neurogenic inflammation) and regions with modality specific hyperalgesia. Their temporal and spatial profiles have been studied to elucidate the mechanism behind neurogenic inflammation and hyperalgesia. Until today, the flare response has mainly been quantified by visual inspection. However, recent developments of thermography and laser-Doppler flowmetry have facilitated quantitative measurement of the neurogenic inflammation. The purpose of the present study was (1). to measure the temporal and spatial profiles of neurogenic inflammation and hyperalgesia induced by capsaicin by using thermography/laser-Doppler flowmetry and various sensory tests, and (2). to correlate the parameters related to neurogenic inflammation with the areas of secondary hyperalgesia. Eight healthy volunteers were injected intradermally with 250 microg of capsaicin. Five minutes after the injection, temperature and blood flow were measured by thermography and a laser-Doppler flowmetry, and followed by assessment of visual flare and hyperalgesia. Punctate hyperalgesia, stroking hyperalgesia, and heat hyperalgesia were assessed by von Frey hair, cotton swab, and radiant heat stimulator, respectively. This procedure was repeated 30 and 60 min after the injection. A significant increase in blood flow and temperature was detected by laser-Doppler flowmetry and thermography (F=102.08, P<0.001, and F=8.46, P=0.002, respectively). Throughout the experiment, the areas of visual flare, stroking hyperalgesia, and punctate hyperalgesia were covered by the area of significantly increased blood flow detected 5 min after the injection. The intensity of pain to heat stimuli significantly increased over time at the distal site and the proximal site (P<0.05). However, there was no significant difference between the pain intensity to radiant heat stimuli inside/outside the area of punctate hyperalgesia. These results seem to indicate that a possible contribution of neurogenic inflammation to secondary hyperalgesia (especially to radiant heat stimuli) must be reconsidered.
AIM: To establish the optimal dose of the mitogen phytohaemagglutinin (PHA) and the optimal time for measuring increased skin-fold thickness in red deer following intradermal injection, as an indicator of cell-mediated immune response. METHODS: Three doses (10, 50 and 250 microg) of PHA were injected intradermally in the right side of the neck, and phosphate buffered saline (PBS) was injected at a fourth site as a control, in 20 captive Iberian red deer (Cervus elaphus hispanicus) hinds. Skin-fold thicknesses were measured at 0, 12, 24, 36, 48, 60, 72, 84 and 96 h following injection. RESULTS: The highest dose of PHA tested (250 microg) resulted in a clear and long-lasting cellular response; increases in skin-fold thickness between 48 and 84 h post-injection varied minimally and response correlated positively with liveweight. No correlations with liveweight and no clear increases in skin-fold thickness occurred at the lower doses of PHA or the PBS. CONCLUSIONS AND CLINICAL RELEVANCE: This technique could be applied with minimal training and without specialised equipment in deer, for immunological and ecological research.
Intradermal injection of mice with ribonuclease antibody, followed by intravenous injection with ribonuclease, resulted in permeability increase, demonstrable by "blueing." The size of the blued area depends on the quantity of antibody injected and on the interval between the two injections. If antigen was injected first and antibody was injected subsequently, a similar increase in permeability was observed in animals having a complete complement system (MuB1-positive) and in animals which have a deficient complement system (MuB1-negative). Marked differences in response were observed between these two types of mice if antigen was injected some hours after the antibody. In MuB1-negative mice, a blueing reaction was not observed at intervals between injections (2(1/2) hours if 3 microg N antibody and 15 hours if 25 microg N antibody were injected intradermally) at which MuB1-positive animals showed a marked permeability increase. At these intervals, blueing did occur in MuB1-negative animals if they were injected with the serum of MuB1-positive mice or with fresh guinea pig serum. Blueing was not induced if the serum of MuB1-negative mice or heated guinea pig serum was injected. The occurrence of two distinct phases of the cutaneous reaction, of which only one involves the complete hemolytic complement system, was deduced from these observations.
Nocifensive behaviors induced by the intradermal injection of three different P2X receptor agonists, ATP, BzATP or alpha,beta-meATP, into a hindpaw were measured in rats that were injected intrathecally with either an NMDA (MK-801) or an NK-1 (L-703,606) receptor antagonist or were pretreated systemically with the VR1 agonist resiniferatoxin (RTX). The same procedures were performed in animals injected intradermally with either capsaicin or formalin. Spinal infusion of MK-801 (10-50 nmol/10 micro l) similarly reduced the number of nociceptive events triggered by each of the P2X agonists and was also effective against capsaicin and formalin induced behaviors. Intrathecal administration of L-703,606 (50-100 nmol/10 micro l) had its greatest antinociceptive effect against capsaicin-induced behaviors followed by ATP and BzATP. L-703,606 was completely ineffective against behaviors induced by formalin or the other P2X agonist, alpha,beta-meATP. Pretreatment with RTX 2 days prior to testing significantly decreased the number of nociceptive events caused by each of the P2X agonists as well as capsaicin and formalin (capsaicin>BzATP>ATP>formalin>alpha,beta-meATP). The remaining nociceptive events in RTX animals injected with alpha,beta-meATP were significantly higher than in animals injected with either ATP or BzATP. Intradermal administration of different P2X receptor agonists induced similar levels of nocifensive behaviors and activity at spinal NMDA receptors. Capsaicin-sensitive fibers were likely activated following injection of BzATP and ATP, but not alpha,beta-meATP, and appeared to trigger the spinal release of substance P. The differences in mechanisms employed by the different P2X agonists may be a function of respective selectivity for P2X receptor subtypes.