Hypersensitivity immune response

A number of chimerized, humanized, and one human mAb have now been approved for therapeutic use in humans in the treatment of autoimmunity, malignancy, infection and cardiovascular disease (Table 1). Some of the currently licensed mAb will be discussed here. A much larger number of mAb are currently being evaluated in Phase I, II and III trials. In general, chimeric, humanized and human mAb are very well tolerated with few side effects. Chimeric or humanized mAb still have the potential to evoke host immune response to the variable domains or CDRs of the antibody so-called HACA (human anti-chimeric antibody) or HAHA (human anti-human antibody) responses, although these responses are uncommon. Short-lived and occasionally severe infusion-related acute hypersensitivity reactions such as fever, skin itching, shivering, respiratory compromise and low blood pressure sometimes occur-. Such effects may... 

Hypersensitivity (or allergy) describes an inappropriate immune response to foreign substances, allergens, giving rise to irritant or harmful reactions. 

Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 16-3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-associated GI inflammation. They are most useful for maintaining remission of IBD or reducing the need for long-term use of corticosteroids. Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions resulting in pancreatitis, fever, rash, hepatitis, and leukopenia.25,26... 

It is also more or less accepted that T-cells, in particular T-helper cells (CD4+), may develop into either Thl cells or Th2 cells. By doing so, T-helper cells orchestrate the ensuing immune response by the types of cytokines they produce. Thl cells, by producing IL-12 and y-IFN, stimulate macrophages and/or cytotoxic T-cells to kill and destroy infected or malignant cells, or to initiate a delayed type hypersensitivity (DTH) reaction Th2 cells, by producing IL-4, IL-5, IL-10, IL-13, trigger B-cells to initiate antibody production. 

Immunoenhancement, which, as adverse effect, may lead to immune-mediated diseases such as hypersensitivity reactions and autoimmune diseases. Hypersensitivity reactions are the result of normally beneficial immune responses acting inappropriately, causing inflammatory reactions and tissue damage. The two most frequent manifestation of chemical-induced allergy are contact hypersensitivity and respiratory sensitization, both of which can have a serious impact on quality of life and represent a common occupational health problem. Hypersensitivity reactions are often considered to be increased at such a rate to become a major health problem in relation to environmental chemical exposure. 

This chapter presents specific information with regard to the effects of environmental and occupational exposure to arsenic on inflammatory processes, the immune system, and host defense. While the focus is on the in vivo and in vitro effects of arsenic on host immune responses (e.g., immunotoxicity and hypersensitivity) and their relationship to clinically observed manifestations of arsenic toxicity (e.g., inflammation and skin cancer), information on the potential mechanisms through which arsenic may exert its biological effects is also provided. 

Ingested arsenic localizes to the skin [2, 7], where it may alter cutaneous immune responses. The delayed type hypersensitivity (DTH) response to 2,4-dinitrochlorobenzene (DNCB) was suppressed in Bowen s disease patients [8], Langerhans cells (LC) in skin lesions and perilesioned skin from arsenic-induced Bowen s disease and carcinomas were reduced in number and were morphologically altered, having a notable loss of dendrites [9], These data suggest that chronic exposure to arsenic in drinking water may... 

Another question is whether an endpoint reflecting the status of CMI should be included in any DIT protocol.1719 For the measurement of CMI, roundtable participants suggested that a validated DTH or T-cell responses to anti-CD3 be evaluated.38 The DTH assay is considered by the NTP as part of the Tier II test panel.3 Although reports indicate that the delayed-type hypersensitivity (DTH) response can be assessed in weanling rats.41 roundtable participants agreed that data are lacking as to whether cell-mediated immune (CMI) assessments in younger animals are feasible.38 Ultimately, the characterization of a validated endpoint which measures CMI, and the determination of whether such an endpoint should be an essential part of a DIT framework remain critical research needs. 

For effective sensitization, a chemical must therefore be inherently protein-reactive or must be converted in the skin to a protein-reactive metabolite. Chemicals that are unable to associate effectively with proteins will fail to stimulate a cutaneous immune response. For those chemical contact allergens that require metabolism to a protein reactive species, it is possible that genetic differences in metabolism may play a role in the differential susceptibility of individuals to the development of contact hypersensitivity responses to these materials. 

The development of respiratory hypersensitivity requires an induction phase where exposures to the sensitizer lead to an interaction with immune cells and the eventual development of specific effecter immune molecules (e.g., antibodies) and cells (e.g., T lymphocytes) [5], The induction phase can require months to years of exposure before there is a detectable immune response and/or onset of symptoms typical of respiratory hypersensitivity, including asthma. Classic IgE mediated responses have been described as Th2 cell dominant responses. A subset of CD4+ T cells known as Th2 cells push the immune response to the development of IgE and IgG4 antibodies in humans along with secretion of cytokines that attract and activate inflammatory cells such as eosinophils. 

The potential sequelae to an immune response (formation of neutralizing antibodies, provoking an autoimmune or a hypersensitivity response), and pathology due to immune precipitation, and so on ... 

Direct adverse immune responses to the agent itself in the form of hypersensitivity responses (anaphylaxis and delayed contact hypersensitivity). 

Autoimmunity. In autoimmunity, as with hypersensitivity, the immune system is stimulated by specific responses that are pathogenic, and both tend to have a genetic component that predisposes some individuals more than others. However, as is the case with hypersensitivity, the adverse immune response of drug-induced autoimmunity is not restricted to the drug itself, but also involves a response to selfantigens. 

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