Direct T-cell stimulations by drugs—bypassing the innate immune system
Section snippets
Introduction: hapten, pro-hapten and p-i concept
An immune response to a new antigen requires: (1) the involvement of the innate immune system, which activates antigen presenting cells and thereby provides essential co-stimulation; and (2) the stimulation of T-cells via their antigen specific T-cell receptors. These activated T-cells coordinate the humoral and cellular immune response, which at the end leads to inflammation with clinical symptoms. The same conditions are thought to be needed to develop an immune response to a drug (Pichler,
Co-stimulation
A crucial question for both, the hapten/pro-hapten and p-i concept is, how the innate immune system is involved and provides the necessary co-stimulation to initiate this rather complex and well-regulated immune response? Different possibilities exist (Table 1):
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One hypothesis relies on the observation that co-stimulation occurs by a generalized immune activation—be it in the frame of a strong immune response to a virus (herpes viruses like EBV, CMV, HHV-6 and HIV) or to auto-antigens (like in
p-i concept: explaining the “bizarre” nature of drug hypersensitivity reactions?
Pharmacologists subdivide adverse side effects of drugs into type A–D reactions (Naisbitt et al., 2000). Drug hypersensitivity reactions are type B reactions, whereby “B” stands for “bizarre”, as these reactions are not predictable and have an astonishingly broad clinical spectrum. Moreover, these type B reactions do not follow standard rules of immune responses, implying that other, new concepts may be better suited to explain the clinical phenomena and laboratory data.
The role of the p-i
Bypassing innate immunity through TCR stimulation by drugs
Certain drug hypersensitivity reactions may not be complete (“classical”) immune reactions, which start with the activation of the innate immune system, followed by the stimulation of naïve T-cells able to react with the antigen, their expansion in lymph nodes, their circulation as T-memory cells and finally their recruitment to the affected tissue. Rather, drugs are indeed not real “antigens” but are simply drugs, which happen to bind quite avidly to certain TCR. If this TCR is expressed on a
Conclusion
This p-i concept combined with the here presented hypothesis of “bypassing the innate immunity” has major implications for various aspects of drug hypersensitivity:
Assays to predict the sensitizing potential of a drug are normally based on the development of a new immune response to it. However, as a drug may bypass the well controlled initial steps in an immune response, such assays may not be predictive (mainly false negative), as some drugs can directly stimulate T-memory cells and thereby
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2014, Middleton's Allergy: Principles and Practice: Eighth EditionImmune pathomechanism of drug hypersensitivity reactions
2011, Journal of Allergy and Clinical ImmunologyCitation Excerpt :This p-i concept complements the original thought that the immune-stimulatory capacity of most chemicals and drugs is based on covalent binding and might be predicted by their protein reactivity. Evidence for the p-i mechanism lies in various experimental data and has been reviewed repeatedly.37-39 Aldehyde-fixed antigen-presenting cells (unable to process antigen or to make a prohapten to a hapten) are still able to activate specific T-cell clones if incubated together with the (inert) drug.
Drug Hypersensitivity Reactions: Pathomechanism and Clinical Symptoms
2010, Medical Clinics of North AmericaCitation Excerpt :There are 3 hypotheses to explain how the second (danger) signal , which is believed to be essential to starting an immune response, is delivered by p-i–acting drugs (these may also work in combination): The p-i–stimulating drugs are not proinflammatory, and the innate immune system may not be stimulated.13 Consequently, it is assumed that no generation of an own drug (hapten)-specific immune response occurs.
Drug hypersensitivity and eosinophilia: The decisive role of p-i stimulation
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