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A unique type of Ag-specific hypersensitivity was induced by challenging the Ag-sensitized mice at the ear. It was elicited within 1 h after the Ag challenge, and thus was distinct from either the delayed-type hypersensitivity (DTH) which developed in 24 h or the immune complex-mediated hypersensitivity which evolved in 4 to 6 h. This hypersensitivity was referred to as early-type hypersensitivity (ETH). The time required for these types of hypersensitivity to develop after immunization was also different; DTH required 4 to 6 days, ETH 9 to 11 days, whereas plasma protein-induced immune complex-mediated hypersensitivity needed 18 to 21 days. The ETH could be induced by a smaller amount of Ag than DTH, and unlike DTH could be transferred by either immune sera or T cell-derived culture factor which was small m.w. Although the ETH developed later than DTH after sensitization, it lasted longer once developed and the pattern of response was inversely related to DTH. Furthermore, the denatured hepatitis B surface Ag induced DTH but not ETH, in contrast to native hepatitis B surface Ag that induced both, suggesting that the epitopes recognized by TETH cells were distinct from those recognized by TDTH cells. The ETH could be induced by most Ag tested including poly(Glu60Ala10Tyr10, L-lactic dehydrogenase, insulin, chicken egg white lysozyme, polymerized human serum albumin, horse gamma-globulin, transferrin, fibrinogen, and plasminogen, but not by purified protein derivative. Because poly(Glu60Ala10Tyr10, L-lactic dehydrogenase, egg white lysozyme and insulin were under the Ir gene control and the inducibility of ETH was Ag dependent and was closely correlated with that of DTH, the expression of ETH also must be regulated by Ir gene. The histopathologic changes in ETH consisted of capillary congestion and edema. The vasopermeability was increased and there was the leakage of plasma proteins into the tissue. Based on these data, we concluded that the ETH reported in this study was a novel type of Ag-specific hypersensitivity.
Exposing mice to UV radiation in the UVB range (280-320 nm) causes a selective immune suppression that contributes to the development of UVB-induced skin cancers. Among the immune responses suppressed by UVB irradiation are contact and delayed hypersensitivity reactions to haptens administered at unexposed sites. In these studies we provide evidence that delayed and contact hypersensitivity to the same hapten are not equivalent reactions and that they are suppressed in UVB-irradiated mice by 2 different mechanisms. This conclusion is based on the findings that: suppression of contact hypersensitivity could not be overcome by immunizing UVB-irradiated mice with hapten-coupled antigen-presenting cells derived from normal donors; and treatment of UVB-irradiated mice with methylprednisolone before immunization prevented the suppression of delayed hypersensitivity but had no effect on the suppression of contact hypersensitivity. The decreased ability to induce contact hypersensitivity in UVB-irradiated mice could be transferred to x-irradiated mice by reconstituting them with spleen cells from UVB-irradiated donors. The induction of hapten-specific suppressor cells, however, required both UVB irradiation and priming with hapten. Based on these results, we postulate that UVB irradiation induces a population of suppressor-inducer cells with specificity for a modified skin antigen and that this antigen serves as a carrier molecule for haptens that induce contact hypersensitivity and for tumor-specific transplantation antigens on UVB-induced tumors.
Twenty-one healthy Nigerian volunteers distributed into four groups participated in a study to determine the significance of chloroquine disposition in chloroquine-induced pruritus. It involved the administration of chloroquine with or without promethazine pre-administration to the subjects. Group I consisted of 8 chloroquine non-hypersensitive subjects receiving 2 tablets of chloroquine sulphate (300 mg base); Group II consisted of 5 chloroquine non-hypersensitive subjects receiving 2 tablets of chloroquine sulphate 30 minutes after 25 mg promethazine tablet pre-administration; Group III consisted of 5 chloroquine hypersensitive subjects treated as in Group II; Group IV consisted of 3 hypersensitive subjects treated as in Group I. Blood (5 ml) and urine samples were collected periodically for up to 6 days post-dose. The samples were analysed for chloroquine and some of its oxidation metabolites by a specific HPLC method. Probit plots of cumulative drug/metabolite ratios were done to determine if there is polymorphism in chloroquine metabolism. There was bimodality only in the distribution of chloroquine/monodesethylchloroquine ratios, suggesting polymorphism in the metabolic oxidation of chloroquine in these subjects. Higher levels of monodesethylchloroquine were obtained in Group IV subjects when compared with any of the other groups. The oral clearance rate, elimination half-life, and volume distribution at steady state of chloroquine in the study groups were not significantly different (P greater than 0.05). In the absence of promethazine there appears to be an extensive metabolism of chloroquine in hypersensitive individuals to produce monodesethylchloroquine which probably determines the degree of pruritus experienced by an individual.
Bone marrow-derived blood basophils are recruited into the tissues by immuno mechanisms in a variety of delayed time-course hypersensitivity responses. In the skin these are called cutaneous basophil hypersensitivity (CBH) reactions. In guinea pigs, it is now established that the elicitation of CBH is dependent on T cell- and/or (antibody)-triggered mechanisms. Both are subject to modulation. T cell-mediated CBH seems to be suppressed in basophil-poor tuberculin-type reactions. B cells mediate CBH via antibody of IgG1 isotype through mechanisms that involve Fc receptors, which can be competitively blocked. After basophils arrive at a CBH reaction they can be triggered by antigen to immediately release mediators such as histamine. Thus, one consequence of the arrival and accumulation of basophils at delayed hypersensitivity reactions is to augment the anaphylactic potential of a given tissue site. In reactions to parasites, release of mediators by tissue basophils seems to aid in the expulsion of these multicellular organisms, In addition, histamine released by recruited basophils, or by locally resident mast cells, may modulate some delayed reactions through stimulation of histamine-2 receptors on cells such as T lymphocytes. In mice, mast cell release of serotonin and subsequent stimulation of the local vasculature seems to be required to allow diapedesis and tissue accumulation of various bone marrow-derived accessory leukocytes in delayed-type hypersensitivity responses. Thus, basophils and mast cells, and their release of mediators such as vasoactive amines, are involved in the onset, development, and function of various tissue hypersensitivity responses.
The effect of the IgE-mediated reaction on the passive cutaneous anaphylaxis (PCA) reaction was studied at local skin sites of monkeys, and we found that the IgE-mediated reaction appeared to enhance the PCA reaction. Interactions among IgE-mediated reaction, PCA reaction and delayed hypersensitivity reaction were also determined. Contact dermatitis induced with DNCB was utilized as the delayed hypersensitivity reaction. The IgE-mediated reactior or PCA reaction, as well as simple serum irritation, enhanced the delayed hypersensitivity reaction. It is thus assumed that the IgE-mediated reaction enhances the PCA reaction and that this in turn accelerates the delayed hypersensitivity reaction.
Administration of cyclosporin A (CsA; 25 mg/kg) orally to guinea pigs from the time of immunization with ovalbumin (OVA) in complete Freund's adjuvant, followed by drug withdrawal 4 days later, resulted in marked potentiation of classical, tuberculin-like delayed-hypersensitivity skin responses to OVA. However, no such augmentation of delayed-type hypersensitivity (DTH) to purified protein derivative (PPD) was demonstrated. The enhancing effect of CsA was also dependent on the dose of OVA used for both immunization and skin testing and on the interval between drug withdrawal and the elicitation of DTH. A single intraperitoneal injection of CsA (200 mg/kg) given 2 days before immunization also had an augmentary effect on 14-day responses to OVA. Similar treatment protocols, however, did not enhance Jones-Mote (cutaneous basophil) hypersensitivity to OVA or contact sensitivity reactions to dinitrofluorobenzene. Longer courses of CsA (25 mg/kg per os) between sensitization and skin testing severely depressed all three categories of type IV hypersensitivity reactions. Our observations may have important cautionary implications for the prospective management of immunologically mediated diseases of intermittent activity, including certain autoimmune disorders, where short courses of CsA might be contemplated.
A 21-year-old woman with Crohn's disease of the colon developed a skin rash after 3 weeks of treatment with sulfasalazine. Administration of sulfasalazine was discontinued. When mesalazine was instituted 1 week later, she developed a severe hypersensitivity reaction characterized by fever, diarrhea, skin rash with subsequent desquamation, marked atypical lymphocytosis, and severe hepatotoxicity. Recovery was complete. The clinical and biological features as well as liver pathology of this case bear a striking resemblance to earlier reports of hypersensitivity reaction with severe hepatotoxicity to sulfasalazine. The authors urge caution when mesalazine is given to a patient with known hypersensitivity to sulfasalazine.
The transfer of delayed hypersensitivity to Coccidioides immitis and Candida albicans antigens with immunogenic RNA extracts was studied in a mouse model. Sensitivity was measured by skin tests and footpad swelling responses. Immunogenic RNA converted normal spleen cells in vitro so that they produced antigen-specific delayed hypersensitivity in mice that were given injections of the cells. RNase reduced the rate of, but did not abolish, in vitro interaction of immunogenic RNA extracts with lymphocytes. Immunogenic RNA transferred sensitivity on direct intraperitoneal inoculation into mice. The transfer ability was resistant to RNase preparations active against both single- and double-stranded RNA. Sedimentation gradient fractions of the immunogenic RNA were assayed by intraperitoneal injection, and converting activity was found in two fractions, greater than 33S and 6S-13S. After treatment with RNase, all activity was shifted to the less than 6S fraction. Two fractions of the immunogenic RNA in its native state (greater than 33S and 6S-13S) were also able to convert spleen cells. The data indicate that the transfer of delayed hypersensitivity by immunogenic RNA preparations is associated with RNA but may not require the intact RNA molecule.
Precise time-course studies on delayed skin reaction, lymphocyte transformation and macrophage migration inhibition were carried out from day 3 to 270 and from day 3 to 120, respectively, in guinea pigs immunized with bovine gamma-globulin (BGG) in complete Freund's adjuvant (CFA) and those immunized with BGG in incomplete Freund's adjuvant (IFA). a) Delayed skin reactions could be elicited for a long period of time after immunization with BGG in CFA in the presence of prominent antibody production and were accompanied by induration. b) Delayed reactions could be elicited transiently after immunization with BGG in IFA and were not accompanied by induration. c) At the peak of hypersensitivity, infiltrating cells at the reaction sites were composed largely of mononuclear cells and basophils, respectively, in the animals immunized with BGG and CFA and those immunized with BGG in IFA. d) Uptake of 3H-thymidine by lymphocytes was increased remarkably in the presence of BGG when cells were obtained at early stages after immunization by both methods. e) Macrophage migration inhibition was strongly positive in animals immunized with BGG in CFA but weakly positive in those immunized with BGG in IFA. Increased lymphocyte transformation preceded the appearance of positive migration inhibition. f) After immunization with BGG in CFA, Jones-Mote hypersensitivity appeared to precede the development of tuberculin-type hypersensitivity.
Radioactive tracers and immunofluorescence were employed to detect and quantitate fibrinogen/fibrin deposition in two types of cell-mediated hypersensitivity reactions in the guinea pig. Classic delayed hypersensitivity (DH) reactions to Old Tuberculin and to the azobenzenearsonate hapten were characterized by a progressive increase in the fibrinogen (125-I-HF) content which exceeded that of the albumin tracer (131-I-HSA) and paralleled the development of induration and erythema. Accumulation of 125-I-HF could be related both to increased vascular permeability to 125-I-HF and, more specifically, to retarded efflux of extra vascular 125-I-HF from tuberculin reaction sites. Warfarin inhibited 125-I-HF accumulation and the formation of urea-insoluble 125-I-HF (cross-linked fibrin) as well as induration in tuberculin reactions. Immunofluorescence studies revealed the site of Fib deposition to be extravascular, among the connective tissue fibers of the dermis, similar to that in DH reactions in man. In contrast, little 125-I-HF accumulated in cell-mediated reactions rich in basophils--cutaneous basophil hypersensitivity (CBH) reactions to keyhole limpet hemocyanin, ovalbumin, and dinitrochlorobenzene--due in part to less vascular leakage of macromolecules and to decreased formation of urea-insoluble fibrin. By immunofluorescence Fib deposits were found in CBH reactions in a pattern similar to that in DH reactions, but the intensity of staining was appreciably less. Thus, fibrin accumulation further distinguishes DH from CBH reactions and is very likely responsible for the induration characteristic of DH reactions.
A skin test to assess T-cell mediated delayed hypersensitivity (DH) and cutaneous basophil hypersensitivity (CBH) was evaluated in the interdigital skin of young chickens. Three-day-old chickens were sensitized with Mycobacterium tuberculosis, and the DH reaction was elicited in the interdigital skin in 10-, 17-, 24-, and 31-day-old chickens by intradermal injection of tuberculin. Cutaneous basophil hypersensitivity was elicited in the interdigital skin of 10- and 14-day-old chickens by a single intradermal injection of phytohemagglutinin-P (200 micrograms). The effect of immunosuppression on the results of interdigital skin test for DH and for CBH was evaluated in chickens that were treated with dexamethasone daily for 4 days before testing. The DH reaction, as indicated by a significant (P less than 0.01) increase in the mean interdigital skin thickness, was detectable in 10-day-old chickens and was consistently evident in 17-, 24-, and 31-day-old chickens. The DH response in the interdigital skin of 24-day-old chickens was comparable with that elicited in the standard wattle test. The CBH reaction, as indicted by a significant increase (P less than 0.005) in skin thickness, was evident in the interdigital skin of 10- and 14-day-old chickens. Treatment with dexamethasone significantly decreased (P less than 0.01) the DH and CBH reactions. Results of the study indicated that the interdigital skin test may be used to evaluate normal and suppressed cell-mediated DH and CBH reactions in chickens as young as 10 and 14 days old.
Relationships among tuberculin type hypersensitivity, Jones-Mote type hypersensitivity and activation of helper T cells were studied in AKR mice by means of footpad reaction, migration inhibition test and antibody production against the trinitrophenyl group. (1) Immunization with SRBC in saline, Freund's incomplete adjuvant (FIA) or complete adjuvant (FCA) and fixed-SRBC (FRBC) in FIA- or FCA-induced delayed hypersensitivity as demonstrated by footpad swelling. (2) Migration inhibition was positive in the groups immunized with SRBC or FRBC in FCA, but negative in those immunized with SRBC in saline or FIA or FRBC in FIA. This may suggest that the former has to be assigned to tuberculin type and the latter to Jones-Mote type. (3) Both pre-treatment with BCG and with cyclophosphamide (CY) augmented delayed footpad reaction in the mice immunized with SRBC in saline. However, migration inhibition was positive only in the group pre-treated with BCG. BCG may convert the reaction from Jones-Mote type to tuberculin type, while CY may augment the reaction of Jones-Mote type. (4) FRBC in saline scarcely induced delayed footpad reaction, whereas they activated helper function efficiently. Thus, three types of immunological phenomena attributable to the functions of T cells may depend upon distinct subpopulations of differentiated T cells which are raised by different methods of immunization.
A 63-year-old female, with type II diabetes mellitus, diagnosed in 1967, was started on combination therapy with sulphonylureas and human depot insulin in May 1989, because of inadequate blood sugar control with sulphonylureas alone. Within 3 months she began to develop nodular skin reactions at the site of injection, 12-24 hours after insulin injections. Intradermal testing demonstrated delayed (Gell and Coombs type IV) hypersensitivity to protamine. No specific IgE or IgG antibodies were demonstrable. She was changed to protamine-free human delayed action insulin. After an initial reaction-free period, red urticarial lesions, attributable to immediate (Gell and Coombs type I) hypersensitivity to human insulin, appeared at the injection sites. There were no other complications with continued insulin therapy, and after about 6 weeks no further local reactions were detectable. When an allergic reaction to an insulin preparation is suspected, careful immunological investigation should be performed, to ensure adequate treatment without risk to the patient.
A child with a 4-year history of acute and chronic respiratory symptoms of unknown aetiology was investigated for hypersensitivity pneumonitis. Lung disease due to inhalation of material from a contaminated central humidifier was suggested by the clinical history, the presence of precipitating antibodies in the serum against the humidifier water, a pulmonary response to challenge with the humidifier water, and marked improvement after removal of the humidifier. No fungi were cultured from the humidifier nor were antibodies against a number of fungal antigens identified by radioimmunoassay inhibition techniques. Antigenic material was found in the humidifier water and the household water prior to its reaching the humidifier. This antigenic material was not found in laboratory tap water supplied from the same general source (Lake Michigan) but from a different pumping station. Three of the child's siblings gave histories suggestive of a single concurrent episode of acute hypersensitivity pneumonitis and one sibling had a history suggestive of chronic hypersensitivity lung disease. No association could be found between HLA-haplotypy and disease in the patient and the siblings.
Skin testing represents a direct method of assessing immune responses in vivo. Twenty-six patients with metastatic cancer of the lung, kidney, or melanoma were treated with adoptive transfers of autologous tumor-infiltrating or blood lymphocytes and continuous infusions of interleukin-2 (IL-2). Prior to therapy, cutaneous anergy to recall antigens was observed in 19 patients (73%), whereas 6 (27%) displayed normal delayed-type hypersensitivity (DTH) responses. When tested again at the end of therapy, DTH responses could not be elicited in any of the patients. Proliferative responses to skin test antigens, lectins, and IL-2 diminished progressively during therapy but returned to baseline values at 1 month. Unexpectedly, 14 of these patients (53%) developed immediate skin test responses to candida antigens and 5 (19%) to mumps antigens. These immediate responses were characterized by local erythema and induration that developed within minutes of injecting antigen. Biopsies displayed marked dermal edema and infiltration by eosinophils. Although serum IgE levels were not increased, immediate reactivity could be transferred by a heat-sensitive serum factor. The implications of this novel response are uncertain, and its development did not correlate directly with the anti-tumor effects of therapy. We conclude that adoptive immunotherapy with IL-2 produces a reduction in cutaneous DTH and diminished responses to mitogens while simultaneously promoting cutaneous allergy. We hypothesize that this may reflect diminished IL-2 production by antigen-specific helper T cells and that other lymphokines may promote these immediate hypersensitivity responses.
Cross-reactivity associated with delayed type hypersensitivity (DTH) arising from cephem antibiotics with a tetrazolyl group in the C-3 side chain was investigated by clinical testing and animal experiments. Clinical cross-reaction testing was performed with the leucocyte migration inhibition test (LMIT) with respect to sixteen patients with hypersensitivity induced by cephems with a tetrazolyl group in the C-3 side chain. The proportion of positive LMIT cross-reactions to cephems with a tetrazolyl group in the C-3 side chain was 78% (25/32), to cephems without a tetrazolyl group, 5% (1/22), and to penams, 0% (0/12). The proportion of positives in tests performed with methyl-tetrazolethiol (MTT) and hydroxyethyl-tetrazolethiol (HTT), which essentially represent the structures of the C-3 side-chains in the allergenic drugs, was 29% (4/14), while the corresponding proportion for 7-aminocephalosporanic acid (7ACA), which represents the skeleton structure of the cephem antibiotics, was 33% (1/3). The animal experiments were performed with guinea pigs, with latamoxef, cefoperazone and MTT as the sensitizing agents and testing for cross-reactivity by means of delayed type intradermal reactions as well as the LMIT. The results of intradermal testing and the LMIT agreed almost completely, thus providing strong support for the clinical results. Latamoxef and cefoperazone displayed the same cross-reactivity, manifesting cross-reactions with MTT, HTT and 7ACA as well as with cephems having a tetrazolyl group in the C-3 side chain. Moreover, DTH induced by MTT displayed cross-reactivity with cephems possessing tetrazolyl groups in the C-3 side chain. The above results indicate that free MTT radicals, as well as the skeleton ring structure represented by 7ACA, are strongly involved in DTH arising from cephem antibiotics with a tetrazolyl group in the C-3 side chain.