Classical Delayed-type Hypersensitivity Reaction Research Articles

Nickel allergic contact dermatitis

The article provides basic information about nickel-associated allergic contact dermatitis (NACD). Nickel is a common metal that is commonly used in alloys for jewelry, accessories and household items. Contact with this metal often leads to the development of allergic contact dermatitis in sensitized individuals. The prevalence of NACD among the population is high: up to 19% among adults and about 10% among children and adolescents. It is noted that in female’s sensitization to nickel is observed several times more often than in males. On the risk of developing an allergic reaction to nickel, the integrity of the skin barrier, the frequency of contacts with nickel-containing household items, the presence of piercings, high humidity and hyperhidrosis are of decisive importance. Nickel ions entering the body through the alimentary route are capable of both sensitizing the body and forming tolerance to it. The pathogenesis of NACD is based on the classic delayed-type hypersensitivity reaction. The main clinical forms of this allergic dermatosis, as well as the characteristic features of the course of the disease are presented. The features of the course of NACD in patients with atopic dermatitis (AD) are analyzed in detail. The presented data clearly demonstrate that contact allergy to nickel can not only maintain, but also significantly aggravate the course of AD. The main criteria for the differential diagnosis between simple contact and allergic contact dermatitis are shown schematically. The need for early identification and termination of contact with nickel-containing household items is noted as the initial stage of NACD treatment. The main treatment for NACD is local therapy with topical glucocorticosteroids.

Multi-Scale Optical Imaging of the Delayed Type Hypersensitivity Reaction Attenuated by Rapamycin

Neutrophils and monocytes/macrophages (MMs) play important roles in the development of cell-mediated delayed type hypersensitivity (DTH). However, the dynamics of neutrophils and MMs during the DTH reaction and how the immunosuppressant rapamycin modulates their behavior in vivo are rarely reported. Here, we take advantage of multi-scale optical imaging techniques and a footpad DTH reaction model to non-invasively investigate the dynamic behavior and properties of immune cells from the whole field of the footpad to the cellular level. During the classic elicitation phase of the DTH reaction, both neutrophils and MMs obviously accumulated at inflammatory foci at 24 h post-challenge. Rapamycin treatment resulted in advanced neutrophil recruitment and vascular hyperpermeability at an early stage (4 h), the reduced accumulation of neutrophils (> 50% inhibition ratio) at 48 h, and the delayed involvement of MMs in inflammatory foci. The motility parameters of immune cells in the rapamycin-treated reaction at 4 h post-challenge displayed similar mean velocities, arrest durations, mean displacements, and confinements as the classic DTH reaction at 24 h. These results indicate that rapamycin treatment shortened the initial preparation stage of the DTH reaction and attenuated its intensity, which may be due to the involvement of T helper type 2 cells or regulatory T cells.

Establishment and characterization of a sustained delayed-type hypersensitivity model with arthritic manifestations in C57BL/6J mice

IntroductionRheumatoid arthritis (RA) is a chronic progressive, inflammatory and destructive autoimmune disease, characterised by synovial joint inflammation and bone erosion. To better understand the pathophysiology and underlying immune mechanisms of RA various models of arthritis have been developed in different inbred strains of mice. Establishment of arthritis models with components of adaptive immunity in the C57BL/6J strain of mice has been difficult, and since most genetically modified mice are commonly bred on this background, there is a need to explore new ways of obtaining robust models of arthritis in this strain. This study was undertaken to establish and characterise a novel murine model of arthritis, the delayed-type hypersensitivity (DTH)-arthritis model, and evaluate whether disease can be treated with compounds currently used in the treatment of RA.MethodsDTH-arthritis was induced by eliciting a classical DTH reaction in one paw with methylated bovine serum albumin (mBSA), with the modification that a cocktail of type II collagen monoclonal antibodies was administered between the immunisation and challenge steps. Involved cell subsets and inflammatory mediators were analysed, and tissue sections evaluated histopathologically. Disease was treated prophylactically and therapeutically with compounds used in the treatment of RA.ResultsWe demonstrate that DTH-arthritis could be induced in C57BL/6 mice with paw swelling lasting for at least 28 days and that disease induction was dependent on CD4+ cells. We show that macrophages and neutrophils were heavily involved in the observed pathology and that a clear profile of inflammatory mediators associated with these cell subsets was induced locally. In addition, inflammatory markers were observed systemically. Furthermore, we demonstrate that disease could be both prevented and treated.ConclusionsOur findings indicate that DTH-arthritis shares features with both collagen-induced arthritis (CIA) and human RA. DTH-arthritis is dependent on CD4+ cells for induction and can be successfully treated with TNFα-blocking biologics and dexamethasone. On the basis of our findings we believe that the DTH-arthritis model could hold potential in the preclinical screening of novel drugs targeting RA. The model is highly reproducible and has a high incidence rate with synchronised onset and progression, which strengthens its potential.

The Induction and Functions of Murine T-Helper Cell Subsets

Through the release of distinct sets of cytokines, Th1 and Th2 cells exert characteristic and often mutually exclusive or antagonistic immune effector functions. In the present report, we document and discuss several findings on the induction mechanisms of these cellular subtypes and present recent findings on their respective functions in vivo. The preferential induction of Th1 or Th2 cytokine patterns in mature CD4+ T cells is generally attributed to the action of cytokines. In addition, there is evidence that prolonged T-cell receptor occupancy may induce the development of the Th2 phenotype. Prolonged occupancy of the T-cell receptor provides enough autocrine interleukin-4 to permit induction of the Th2 phenotype. Both Th1 and Th2 cells may be derived from a single mature CD4+ T cell, providing strong evidence for post-thymic modulation of the T-cell cytokine profile and rendering the possibility of predetermined cytokine patterns in T cells unlikely. CD4+ Th1 cells mediate the tumor necrosis factor- and interferon-gamma-dependent classic delayed type hypersensitivity reaction. We found that Th2 cells were also capable of mediating local inflammatory reactions that depended on their prototypic lymphokine interleukin-4, and, in high tumor necrosis factor-producing mouse strains, upon tumor necrosis factor-alpha. Both Th-cell subsets induced cellular infiltrates that were not distinguishable on histologic grounds. In contrast to the widely accepted belief that only Th1 cells can mediate delayed hypersensitivity reactions, our results demonstrate that T cells with either lymphokine profile can cause tissue inflammation with leukocytic infiltrates.

The induction and functions of murine T-helper cell subsets.

Through the release of distinct sets of cytokines, Th1 and Th2 cells exert characteristic and often mutually exclusive or antagonistic immune effector functions. In the present report, we document and discuss several findings on the induction mechanisms of these cellular subtypes and present recent findings on their respective functions in vivo. The preferential induction of Th1 or Th2 cytokine patterns in mature CD4+ T cells is generally attributed to the action of cytokines. In addition, there is evidence that prolonged T-cell receptor occupancy may induce the development of the Th2 phenotype. Prolonged occupancy of the T-cell receptor provides enough autocrine interleukin-4 to permit induction of the Th2 phenotype. Both Th1 and Th2 cells may be derived from a single mature CD4+ T cell, providing strong evidence for post-thymic modulation of the T-cell cytokine profile and rendering the possibility of predetermined cytokine patterns in T cells unlikely. CD4+ Th1 cells mediate the tumor necrosis factor- and interferon-gamma-dependent classic delayed type hypersensitivity reaction. We found that Th2 cells were also capable of mediating local inflammatory reactions that depended on their prototypic lymphokine interleukin-4, and, in high tumor necrosis factor-producing mouse strains, upon tumor necrosis factor-alpha. Both Th-cell subsets induced cellular infiltrates that were not distinguishable on histologic grounds. In contrast to the widely accepted belief that only Th1 cells can mediate delayed hypersensitivity reactions, our results demonstrate that T cells with either lymphokine profile can cause tissue inflammation with leukocytic infiltrates.

A Role for T Helper-1 Cells in the Induction of Airway Hyperresponsiveness

Jo/san Garssen, Ph.D.; F. P N kamp; H. Van Der Vliet; and H. Van Loveren I n a mouse model it was shown that T helper-i celldependent immune reactions directed against the small molecular weight compound, picryl chloride, induces increased airway resistance and airway hyperresponsiveness. Whether this is also true for low molecular weight compounds, such as toluene-diisocyanate, that induce asthmatic complaints in humans, in addition to T help-2 cell-dependent immune responses, remains to be clarified in future studies. Asthma may affect up to 10% of the population and remains yet underdiagnosed. One of the major efforts to subdivide asthma is based upon the absence or presence of allergy, ie, specffic IgE, in asthma patients. A major feature of asthma is an obstruction of the respiratory tract caused by the following: an increased smooth muscle tone, an increased thickness of airway walls, and an increased mucus secretion in the airways. Hyperresponsiveness, a major characteristic of asthma, is characterized as an enhanced response to a wide range of bronchoconstrictor stimuli. Knowledge of the mechanisms leading to hyperresponsiveness can provide insight into the pathogenesis of asthma and improve possibilities for therapy. Induction of bronchial hyperresponsiveness has often been thought to be correlated with the presence of airway inflammation and the capacity of the inflammatory cells to release certain types of inflammatory mediators.’ T cells are prominent in asthmatic airways and yet have received surprisingly little attention. T cells release mediators which can contribute to eosinophil activation2 and mast cell degranulation.’ Recently, Coffman et al proposed that there are at least 2 major subsets of T helper cells in mice, designed T help-i (Thi) and T help-2 (Th2) cells. Both subtypes can be distinguished by their cytokine profile. Cher and Mosmann5 showed that Thi cells are responsible for the classical delayed type hypersensitivity reaction (DTH). In contrast, Th2 cells are responsible for the regulation of immediate type I hypersensitivity reactions (IgE production, eosinophil activation). Research concerning mechanisms of the induction of asthmatic disorders is mainly focussed upon a possible role for Th2 cells. It is shown that expression of 11-5 mRNA in mononuclear cells infiltrating mucosal bronchial biopsies from patients with asthma, correlated with the presence of activated (CD25) CD4 T cells and activated eosinophils.6 In the blood of patients suffering from intrinsic asthma, no IgE antibodies to environmental antigens can be found. The precise mechanisms leading to airway obstruction in intrinsic asthma are still not known. Small molecular weight substances, such as isocyanates, to which antibodies are not

Immunological properties of cephalexin-induced delayed type hypersensitivity reaction in guinea pigs.

Immunological properties of delayed-type hypersensitivity (DTH) reaction induced by cephalexin (CEX) in guinea pigs were investigated. The animals were immunized with CEX using Freund's complete adjuvant. The time course of CEX-induced erythema showed some differences compared with that of classical DTH reaction. The erythema appeared at 6 h after intradermal administration of CEX, reached maximum size at 12 to 24 h and to be visible until 72 h. By enzyme-linked immunosorbent assay, anti-CEX antibody was detected in only one of 15 animals tested. Normal animals (recipients) which had received immune sera from CEX-sensitized animals (donors) showed no skin reaction to CEX. In contrast, reaction to CEX was observed in recipient animals which had received a local transfer of lymphocytes or T cells from CEX sensitized animals. In immunopharmacological study, cyclosporin A suppressed the skin reaction but cyclophosphamide did not. Administration of carrageenan, an inhibitor of macrophage function, had no effect on expression of the reaction. Post administration (1 or 15 h) of clemastine, an anti-histamine drug, did not affect the reaction. By histological examination, the infiltrating cell-types at the reaction site were mainly composed of mononuclear cells and neutrophils, but no basophils, indicating that CEX-induced DTH reaction is tuberculin-type DTH and not a cutaneous basophil hypersensitivity reaction.

Experimental allergic encephalomyelitis in the absence of a classical delayed-type hypersensitivity reaction. Severe paralytic disease correlates with the presence of interleukin 2 receptor-positive cells infiltrating the central nervous system.

One characteristic of experimental allergic encephalomyelitis (EAE) in all species is the presence of a considerable leukocyte infiltrate in the central nervous system (CNS). By adoptive transfer of EAE into irradiated or nonirradiated Lewis strain rats we now show that the bulk (greater than 90%) of infiltrating cells in the CNS are superfluous to the induction of disease, as lethally irradiated recipients, despite having very few infiltrating cells in the CNS, acquire severe paralytic EAE. The reduction in the level of infiltration in irradiated recipients is selective, however, as both irradiated and nonirradiated diseased animals have very similar numbers of cells expressing IL-2-R. Disease in irradiated recipient animals is associated with substantial submeningeal hemorrhage in the spinal cord and brain stem and similar hemorrhages are found in recipients rendered leukopenic with cytotoxic drugs. Clinical signs of disease and hemorrhage are preventable, however, by administration to the recipient rats of mAbs specific for the CD4 antigen. Classic delayed-type hypersensitivity (DTH) reactions are transferable with the same cells that produce EAE in both irradiated and nonirradiated recipient rats, but such transfer of DTH is observed only in nonirradiated recipient animals and not in irradiated rats. Collectively, the findings reported herein support the conclusion that the paralysis characteristic of acute EAE is mediated by the direct action of very small numbers of activated CD4+ lymphocytes that infiltrate the CNS and produce their effects by inducing vascular damage. The findings are not consistent with reports that the lesions in EAE are produced by a classic DTH reaction.

Cutaneous basophil hypersensitivity.

Cutaneous basophil hypersensitivity is a distinct form of hypersensitivity reaction with a delayed-time course that is different from both the classic delayed-type hypersensitivity reaction and immediate hypersensitivity reaction. It occurs in humans, guinea pigs, and other animals. It may be induced by sensitization with a variety of antigens (viruses, allografts, parasites, fungal antigens, etc.) in incomplete Freund's adjuvant and elicited by skin testing 7 days later with the specific antigens. The cutaneous reaction in basophil hypersensitivity is characterized clinically by less indurated erythema than in classic delayed hypersensitivity, and microscopically by numerous basophils in the papillary dermis. The reaction is mediated by both T- and B-lymphocytes. A basophil chemotactic factor as a mediator of the reaction has also been identified. The reaction may be inhibited by Fc fragments. Basophils on arrival at the local site may degranulate and the released vasoamine may have protective or regulatory effects depending on particular circumstances.

The influence of the cellular infiltrate on the evolution and intensity of delayed hypersensitivity reactions.

When a delayed-type hypersensitivity (DTH) reaction is elicted in a sensitive animal at a skin site in which an accumulation of mononuclear cells has been induced by a prior injection of a nonspecific stimulus, those properties characteristic of a DTH reaction, i.e. erythema, edema, and induration, become evident much more rapidly and intensely than a reaction in an unprepared skin site. This rapid, intense reaction has the histology of a classical delayed reaction and persists as long or longer than a classical DTH reaction in the same animal. Two facts are evident from these observations. Firstly, early in the development of a delayed reaction, the slow accumulation of mononuclear cells may be completely independent of the presence of specific antigen. Secondly, there is a reaction between specific antigen and an antibody-like substance which may or may not be attached to cells. The reaction develops so rapidly at a prepared site that the pharmacological mediators which are responsible for edema must be presumed to be released abruptly. A classical delayed reaction is attributable to the time needed for the accumulation of cells in sufficient numbers. It follows that the rate-limiting step in a classical delayed reaction is the process of cell accumulation. The present observations indicate that this process is independent of the presence of specific antigen.