Cell-mediated Hypersensitivity Research Articles

Decreased immunological responses by wortmannin-containing rice culture of Fusarium oxysporum and by purified wortmannin in avian species.

Immunological assays were performed in young chicken and duck after they had been fed wortmannin-containing culture of Fusarium oxysporum or purified wortmannin for 2 weeks. The culture significantly decreased humoral response to sheep red blood cell, cell-mediated cutaneous hypersensitivity to phytohemagglutinin and phagocytic activity in isolated peritoneal exudate adherent cells, but only when the concentration was high enough to cause concurrent reduction in body weight gain and hematocrit. Increased dietary metabolizable energy and protein did not affect the toxicity of the culture. On the other hand, purified wortmannin (1 mg/kg diet) significantly inhibited the aforementioned immunological responses prior to the adverse effects on body growth and hematocrit. The data strongly indicate that wortmannin is an immunotoxic substance. The possibility that macrophage is the primary target cell type is discussed.

T Cell non-MHC-restricted antigen-binding molecules secreted or associated with the cell membrane are antigenically distinct

Some T cells produce membrane-associated or soluble molecules which bind nominal antigen specifically (TABM) and effect immunoregulation or events similar to cell-mediated hypersensitivity. We have used polyclonal antisera raised against an azobenzene arsonate (ABA)-specific TABM secreted by an ABA-specific T cell hybrid or against TNP-specific polypeptides produced by immunoregulatory T cells to identify the expression of soluble (secreted) or membrane-associated TABM. Ascites fluid or culture medium containing a T cell hybrid or T cell lines, respectively, contain TABM recognized only by an antiserum specific for the secreted T cell hybrid (ABA-specific) derived TABM. Conversely, an antiserum that recognized the TNP-specific polypeptides detected cell-membrane associated TABM but did not bind TABM secreted by the T cell hybrid or cell lines.

Eosinophil activation and T lymphocyte infiltration in allergen-induced late phase skin reactions and classical delayed-type hypersensitivity.

T lymphocyte infiltration is a well documented feature of classical delayed-type hypersensitivity (DTH) reactions. Recently, we have shown that T lymphocytes and activated (EG2+) eosinophils accumulate in the allergen-induced late phase skin reaction (LPR). To compare the kinetics and phenotypic composition of these T lymphocyte responses, LPR and DTH reactions of comparable induration size were induced in atopic subjects. In addition, DTH and LPR were compared between atopic and nonatopic subjects. In atopic individuals, allergen challenge elicited a perivascular influx of T lymphocytes that was predominantly CD4+. Eosinophil accumulation and activation were also prominent. There was no cellular response to allergen challenge in the nonatropic group. In both groups, DTH responses showed an intense T cell infiltrate which was more dense and dispersed than in the LPR. CD4+ T cells predominated but at 48 h CD8+ numbers were also significantly increased. In DTH, total leukocyte numbers (CD45+) were increasing at 48 h, whereas in the LPR, cell numbers reached a plateau between 24 and 48 h. T cell activation (shown by expression of IL-2R) was more prominent in DTH. Endothelial expression of HLA-DR was increased in both LPR and DTH, implying the local release of inflammatory cytokines in both reactions. Small but significant numbers of activated eosinophils (EG2+) were detected in atopics and non-atopics at 24 h in DTH but not at 48 h. These findings suggest that the allergen-induced LPR induced in atopic subjects is, at least in part, a form of cell-mediated hypersensitivity but with T cell kinetics that differ from classical DTH.

Colchicine is a potent adjuvant for eliciting T cell responses.

The cytotoxic drug colchicine when administered to mice in conjunction with Ag was shown to have a strong adjuvant effect in generating a specific plaque-forming cell response to the protein Ag OVA, human gamma-globulin and BSA. Dissection of this phenomenon revealed that several T cell activities, including Th function, Ag-induced T cell proliferation and T cell-mediated delayed-type hypersensitivity, were also specifically induced by treating mice with colchicine + Ag. The adjuvant effect of colchicine was observed when the drug and Ag were injected in soluble form, i.e., no vehicle (e.g., oil, liposome) was necessary. The potency of colchicine as an adjuvant was equal to or more than that of conventional adjuvants such as CFA or alum.

Haematological changes and free-radical involvement in an experimental foot-pad oedema model

A foot-pad oedema model was used to investigate some early peripheral blood changes associated with the development of an acute inflammatory response. The inflammatory model used was an example of a cell-mediated hypersensitivity reaction. Male rats were inoculated in the scruff with Freund's Complete Adjuvant (FCA) on day 0 and then challenged 6 days later with FCA in one hind paw. An acute inflammatory reaction was initiated over the following 72 hours. Within 8 hours of induction a significant increase in neutrophils was detected in the peripheral blood reaching peak levels at 24 hours. The peak level of monocytes was not seen until 48 hours after challenge. Lymphocyte numbers, haemoglobin and haematocrit values all remained within the normal range. Plasma iron levels fell by approximately 85% within 24 hours whereas plasma α-1-acid glycoprotein and the copper-containing protein caeruloplasmin were found to increase steadily throughout the development of the inflammatory response. These findings are discussed in relation to previously published work using the same model. An important inter-relationship between phagocytic cells, iron and free radical production at the site of the acute inflammatory reaction is suggested.

Evaluation of alveolitis by studies of lung biopsies

Immunocytochemical studies of lung biopsies from patients with cryptogenic fibrosing alveolitis and those having fibrosing alveolitis associated with scleroderma show that numerous T-cells occur in the alveolar walls and septa of all patients with these diseases, implying that cell-mediated hypersensitivity reactions are involved in the pathogenesis. However, B-lymphocytes, mainly within lymphoid follicles, are also present and, in the CFA group, such patients, and those with less than 50% T-suppressor/cytotoxic cells in the diffuse T-cell infiltrates, may have a poorer prognosis. Interleukin-2 receptor expression indicates that T-cell activation is occurring within the lungs, and there is evidence that interstitial monocytes/macrophages and alveolar epithelial cells may play a more important role in antigen presentation than alveolar macrophages. These observations on the features of the inflammatory response in the interstitial tissues of patients with fibrosing alveolitis need to be incorporated into the existing hypothesis on pathogenetic mechanisms based mainly on lavage findings of alveolar macrophages and granulocytes.

Immunologic Aspects of Atopic Dermatitis

The immunology of atopic dermatitis is complex, multilayered, and multifaceted. In one realm are the IgE-mediated, type I hypersensitivity reactions that can be elicited in at least 80% of patients. A second realm is that associated with cell-mediated immunity and delayed-type hypersensitivity (type IV) reactions. Scattered between these immunologic paradigms are the various splinters: immune complex abnormalities, putative late-phase reactions, and cutaneous basophil hypersensitivity. The inflammatory lesion of atopic dermatitis probably is a composite of the many model reactions that investigators have glimpsed but never resolved into a reasonable concept.

Correlation between immediate hypersensitivity and cell-mediated hypersensitivity to human dander in atopic dermatitis

Correlation between immediate hypersensitivity and cell-mediated hypersensitivity to human dander in atopic dermatitis

金属アレルギーの発現に関する実験的研究

In recent years, increased attention has been given to allergy to dental metal materials. It has been assumed that the allergic reaction to metals was cell-mediated type hypersensitivity reaction. But it has not yet been clarified in detail. Several traditional techniques have failed to induce contact allergy to metals in the animal. In this study, for the purpose of inducing the experimental allergy to nickel, rats were sensitized to peritoneal macrophages that engulfed nickel particles, as antigen. Rats were inoculated twice at one week interval with the antigen intraperitoneally. A week after the latest inoculation, the rats were inoculated again with the antigen into the gingiva. The rats were sacrificed on 6, 12 and 48 hours after the gingival inoculation. Using immunoperoxidase labeling technique, we examined the distribution of cells which bound anti-interleukin-2 receptor (IL-2R) monoclonal antibodies in the gingival tissues and submandibular lymph nodes, for the purpose of investigating the mechanism of the expression of allergic reaction to metals. In submandibular lymph nodes, IL-2Rs were not or hardly observed 6 hours after the gingival inoculation. After 12 hours, however, IL-2Rs were slightly observed in medulla and were clearly observed after 48 hours. The result suggested that antigen signal was transmitted to submandibular lymph nodes, IL-2R appeared on the surface of T cells, B cells and macrophages, and then T cells proliferated. In gingival tissues, polymorphonuclear leukocytes infiltrated after 6 hours. After 12 hours, mast cells characteristically were distributed and degranulated. The result suggested that antibody dependent type I hypersensitivity was involved in this reaction. After 48 hours, IL-2Rs were clearly observed. The result suggested that sensitized T cells were distributed in gingival tissues, and the cells responded to the antigen and secreted lymphokines. These results suggested that type I hypersensitivity was involved in early experimental allergic reaction to nickel, and type IV hypersensitivity was predominated after that.

Analysis of naturally occurring delayed-type hypersensitivity reactions in leprosy by in situ hybridization.

Analysis of tissue lesions of the major reactional states of leprosy was undertaken to study the immune mechanisms underlying regulation of cell-mediated immunity and delayed-type hypersensitivity (DTH) in man. In situ hybridization hybridization of reversal reaction biopsy specimens for INF-gamma mRNA expression revealed a 10-fold increase in specific mRNA-containing cells over that observed in unresponsive lepromatous patients. Expression of huHF serine esterase, a marker for T cytotoxic cells, were fourfold increased in reversal reaction and tuberculoid lesions above that detected in unresponsive lepromatous individuals. Immunohistology of reversal reactions confirmed a selective increase of Th and T cytotoxic cells in the cellular immune response. Of interest, the microanatomic location of these serine esterase mRNA-containing cells was identical to the distribution of CD4+ cells. Analysis of erythema nodosum leprosum (ENL) lesions revealed differences in the underlying immune processes in comparison with reversal reaction lesions. Although phenotypic Th cells predominated in ENL lesions, IFN-gamma and serine esterase gene expression were markedly reduced. We suggest that reversal reactions represent a hyperimmune DTH response characterized by a selective increase of CD4+ IFN-gamma producing cells and T cytotoxic cells, which result in the clearing of bacilli and concomitant tissue damage. In contrast, ENL reactions may be viewed as a transient diminution of Ts cells and activity leading to a partial and transient augmentation in cell-mediated immunity, perhaps sufficient to result in antibody and immune complex formation, but insufficient to clear bacilli from lesions.

Monokine production by hypersensitivity (Schistosoma mansoni egg) and foreign body (Sephadex bead)-type granuloma macrophages. Evidence for sequential production of IL-1 and tumor necrosis factor.

The present study examined the potential role of IL-1 and TNF in granuloma formation. Mice were given i.v. injections of Schistosoma mansoni eggs or Sephadex beads to induce synchronous immune T cell-mediated (hypersensitivity type) or nonimmune (foreign-body type) granulomas, respectively. Granuloma macrophages isolated at 2, 4, 8, 16, and 32 days of granuloma formation were evaluated for their capacity to produce IL-1 and TNF in response to 1 microgram/ml LPS. This was related to circulating levels of the acute phase protein, serum amyloid P (SAP) and expression of Ia Ag by monocytes and macrophages. Macrophages from nonimmune bead lesions were generally weak producers of IL-1 and TNF. In contrast, those from T cell-mediated egg lesions produced significant levels of both monokines. Moreover, there was a clear pattern of sequential monokine production such that IL-1 was produced in greatest amounts early (2 to 4 days), whereas TNF was produced later (8 to 16 days). Levels of SAP showed an initial sharp rise following particle embolization, then decreased rapidly in bead injected animals. However, mice with immune granulomas showed a prolonged elevation in SAP levels that corresponded to the period of maximal IL-1 production (2 to 4 days). Macrophage/monocyte Ia Ag expression was greatest at 8 to 16 days, corresponding to the period of TNF production. Bead injected animals showed low levels of Ia expression over the study period. These findings suggest that IL-1 may be important in the early recruitment stages of granuloma formation while TNF may take part in later maintenance or effector functions. The extent of production of both is likely influenced by the local or systemic milieu of lymphokines.

Immunomodulation of cimetidine in healthy volunteers

The effect of cimetidine, a histamine H2-receptor antagonist, on the immune system in man was investigated in 11 healthy volunteers. Cimetidine was administered orally in daily doses of 800 mg for a period of 7 days. At the end of the administration period the number of peripheral CD8+ (cytotoxic/suppressor) cells had diminished significantly (P less than 0.05) along with a corresponding increase in the CD4+ (helper/inducer): CD8+ (cytotoxic/suppressor) cell ratio (P less than 0.01). Compared with pretreatment values, a significant in vitro blastogenic response to mitogen stimulation with concanavalin A (P less than 0.005), phytohemagglutinin (P less than 0.01), and pokeweed mitogen (P less than 0.05) was observed in lymphocytes of volunteers after cimetidine intake. The cell-mediated hypersensitivity as assessed by skin testing of seven recall antigens was also enhanced significantly (P less than 0.001). Using Spearman's coefficient of correlation to compare mitogen-stimulation tests and skin tests of delayed hypersensitivity to the CD4+:CD8+ ratio, yielded a positive correlation (r = 0.89; r = 0.85, respectively). These effects were reversible 96 h after the last cimetidine dose. In contrast, leukocytes, total T lymphocytes (CD2+, CD3+), CD4+ (helper/inducer) cells, natural killer cells (Leu7+), immunoglobulins, and total complement, C3, C4 were unaffected by cimetidine administration.

Bronchoalveolar Lavage T-Cell and la Antigen Quantitation by Flow Cytometry in Acute and Chronic Experimental Hypersensitivity Pneumonitis

Increasing evidence implicates effector T-cells in the pathogenesis of hypersensitivity pneumonitis. We utilized T-cell- and Ia-specific antibodies, flow cytometry, and computer analysis to quantitate T-cell numbers and Ia expression on lung cells of established rabbit models of acute and chronic hypersensitivity pneumonitis (HSP). We used analysis of variance (ANOVA) and Turkey's follow-up to evaluate group differences. In the acute HSP group, increased percentages of T-cells and greater Ia expression were present on bronchoalveolar lavage (BAL) cells at 24 h after inhalational allergen challenge. Increased BAL T-cell numbers were found in the chronic HSP group produced by repeated inhalation of antigen and muramyl dipeptide, compared to "desensitized" animals and control groups. Both chronic HSP and desensitized groups demonstrated increased Ia expression on BAL cells. Pathology scores for individual animals in both acute and chronic protocols correlated significantly (Pearson correlation coefficients) with total numbers of BAL cells, percentages of T-cells, and percentages of Ia-positive cells recovered. Findings are consistent with the hypothesis that cell-mediated hypersensitivity is a central mechanism in the pathogenesis of experimental hypersensitivity pneumonitis.

Fixed cutaneous eruptions to seminal-plasma challenge: a case report

Reactions to human seminal plasma may present as immediate hypersensitivity, cell-mediated hypersensitivity, or fixed eruptions. There are no typical responses to semen. An abnormal skin lesion or systemic response after intercourse may be the only clue to identifying those who are reacting to semen. The use of condoms has proven to be the most consistent preventive modality. However, the use of condoms is unacceptable to some regardless of the relief provided. Although conventional therapy for hypersensitivity reactions to human seminal plasma is suboptimal, one should be aware of MA in the treatment of an atypical cause of human seminal plasma induced reactions.

Immunomodulatory properties of cimetidine in ARC patients

The immunomodulatory potency of cimetidine, a histamine H 2 receptor antagonist, was investigated in 33 AIDS-related complex (ARC) patients performing detailed immunological and clinical evaluations. Cimetidine was administered orally in daily doses of 1200 mg for a period of 5 months with an interruption of therapy after the first 3 months for an interval of 3 weeks. Significant ( P < 0.05) elevations of immunoglobulins (IgG, IgA), complement C4, B-lymphocytes, and OKT4+(helper/inducer) cells were found after cimetidine intake. The in vitro lymphocyte proliferative response to plant mitogens was significantly increased, and the in vivo cell-mediated hypersensitivity reaction assessed by intradermal application of seven recall antigens improved significantly. These effects were both reversible with the discontinuation of cimetidine and reproducible with repeated administration of the drug. Clinical data such as performance status, body weight, and fever were influenced favorably ( P < 0.05) by cimetidine. The frequency of diarrhea and the lymph node size were also diminished significantly. The data suggest that cimetidine may at least partially restore immunofunctions in AIDS-related complex.

T cell localization in rabbit models of acute and chronic experimental hypersensitivity pneumonitis

Cell-mediated hypersensitivity has been increasingly implicated in immunologic diseases of the lung, including hypersensitivity pneumonias (HSP) (extrinsic allergic alveolitis). We used a T cell-specific monoclonal antibody (L11/135) to localize T cells in the parenchyma and bronchus-associated lymphoid tissue of ethanol-fixed, paraffin-embedded lung sections in rabbit models of experimental HSP to define further their possible role in pathogenesis. T cells appeared within 4 hours in early lesions of rabbit models of acute HSP and heavily infiltrated alveolitis lesions at 8 and 24 hours after aerosol challenge. T cells were also present in lesions of rabbit models with chronic alveolitis and occurred peripherally in granulomas. Variable aggregate and follicular forms of bronchus-associated lymphoid tissue rich in T cells occurred in both experimental and control animals. Our findings document early and continuing presence of T cells in lesions in rabbit models of experimental HSP.

Atopic dermatitis and aeroallergen contact sensitivity

Atopic dermatitis (AD) may be worsened by ingested foods or contact with irritants. We have identified 10 patients (six male and four female subjects, aged 1 to 54 years) with AD and contact sensitivity to a variety of aeroallergens. Marked improvement in skin symptomatology was noted when these patients were removed from their usual environment. The patients had markedly positive immediate wheal-and-flare reactions to a variety of aeroallergen extracts in response to prick tests and were subsequently patch tested on uninvolved skin with aeroallergen extracts (1:20 wt/vol, 50% glycerine) that elicited positive prick tests. Patch tests were applied for 48 hours, removed, and then were interpreted 24 hours later. Fifty percent glycerine was used as a negative control. Significant delayed cutaneous responses to a variety of aeroallergens were noted: house dust mite, tree, grass and weed pollens, animal danders, and various molds. Positive delayed cutaneous responses correlated strongly with aeroallergens identified in the patient's environment and/or suspected by the patients as provocateurs of their AD. Delayed cutaneous reactions were negative to aeroallergens not historically relevant to their AD. We conclude that aeroallergen contact may play an important role in selected patients with AD. The demonstration of immediate and delayed cutaneous responses in AD suggests both IgE and cell-mediated hypersensitivity as contributory mechanisms.

The Common Mediator of Shock, Cachexia, and Tumor Necrosis

Publisher Summary Complement-mediated injury, anaphylactic shock, and cell-mediated hypersensitivity reactions are often cited as disease processes in which the immune system has worked to the detriment of the host. Cachectin, acting alone and in concert with other mediators, is capable of evoking a “shock” state, in which hypotension, derangements of lipid and glucose metabolism, metabolic acidosis, and end-organ damage may injure or kill the host. When administered at low doses over a prolonged period, cachectin induces a state of anorexia and wasting similar to cachexia as it occurs in chronic infection or cancer. In part through its effects on vascular endothelial cells, cachectin can induce a coagulopathic state localized to certain vascular beds, leading to hemorrhagic necrosis of various tissues. This effect is particularly pronounced in certain tumor vessels, such that the hormone was originally recognized by its ability to provoke the hemorrhagic infarction of transplantable neoplasms, and was termed “tumor nec rosis factor.” On the one hand, as “cachectin,” the molecule was purified as a mediator of shock and wasting in chronic disease. On the other hand, as “tumor necrosis factor,” the molecule was isolated as a mediator of one of the “beneficial” effects of bacterial endotoxin, known as “induction of tumor necrosis.”

Zinc Deficiency and Immune Function

Deficiency in zinc, an essential trace element, is a frequent human dietary problem in the United States and is also associated with such disease states as alcoholism, renal disease, burns, gastrointestinal tract disorders, and acrodermatitis enteropathica. Skin lesions and poor wound healing are observed in severe forms of the deficiency. However, modest deficits in zinc cause lymphopenia and reduced immune capacity among affected humans. With the mouse used as a model because it has an immune system analogues to that of humans, the effects of zinc deficiency on immune function have been well characterized. A suboptimal intake of zinc causes marked atrophy of the thymus, a 50% reduction in leukocytes, a rise in corticosterone levels, and a 40% to 70% reduction in antibody-mediated, cell-mediated, and delayed-type hypersensitivity responses.

Cachectin - Tumour necrosis factor: A cytokine that mediates injury initiated by invasive parasites

The primary role for which the immune system evolved was a protective one, yet there is no doubt that immune mechanisms can also injure the host. Frequently cited examples of immune-mediated injury include complement-induced disease processes, diseases caused by immune complexes, or those that result from cell-mediated hypersensitivity. During the past few years however, it has become clear that the immune system can also express itself through the action of various cytokines. Gradually, it has been appreciated that these agents may cause disease when produced excessively or inappropriately, and in this article Bruce Beuder and Anthony Cerami discuss one of the most important of these cytokines — cochectin or tumour necrosis factor (TNF).