Drug-specific CD4 Research Articles

Characterization of Drug-Specific CD4+ T-Cells Reveals Possible Roles of HLA Class II in the Pathogenesis of Carbamazepine Hypersensitivity Reactions

Carbamazepine (CBZ) is an aromatic anticonvulsant known to cause drug hypersensitivity reactions, which range in severity from relatively mild maculopapular exanthema to potentially fatal Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). These reactions are known to be associated with human leukocyte antigen (HLA) class I alleles, and CBZ interacts preferentially with the related HLA proteins to activate CD8+ T-cells. This study aimed to evaluate the contribution of HLA class II in the effector mechanism(s) of CBZ hypersensitivity. CBZ-specific T-cells clones were generated from two healthy donors and two hypersensitive patients with high-risk HLA class I markers. Phenotype, function, HLA allele restriction, response pathways, and cross-reactivity of CBZ-specific T-cells were assessed using flow cytometry, proliferation analysis, enzyme-linked immunosorbent spot, and enzyme-linked immunosorbent assay. The association between HLA class II allele restriction and CBZ hypersensitivity was reviewed using Allele Frequency Net Database. Forty-four polyclonal CD4+ CBZ-specific T-cell clones were generated and found to be restricted to HLA-DR, particularly HLA-DRB1*07:01. This CD4+-mediated response proceeded through a direct pharmacological interaction between CBZ and HLA-DR molecules. Similar to the CD8+ response, CBZ-stimulated CD4+ clones secreted granulysin, a key mediator of SJS-TEN. Our database review revealed an association between HLA-DRB1*07:01 and CBZ-induced SJS-TEN. These findings implicate HLA class II antigen presentation as an additional pathogenic factor for CBZ hypersensitivity reactions. Both HLA class II molecules and drug-responsive CD4+ T-cells should be evaluated further to gain better insights into the pathogenesis of drug hypersensitivity reactions.

M013 THE UTILITY OF PATCH TESTING IN GUIDING ANTIBIOTIC SELECTION IN PATIENTS WITH DRESS SYNDROME

DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) is a severe drug-induced hypersensitivity reaction caused by drug-specific CD4+T cells. In this case we utilized patch testing to determine the inciting drug in a patient with DRESS to guide antibiotic management.

HLA DRB1*15:01-DQB1*06:02-Restricted Human CD4+ T Cells Are Selectively Activated With Amoxicillin-Peptide Adducts.

Amoxicillin-clavulanate is the most common cause of idiosyncratic drug-induced liver injury (DILI). Drug-specific CD4+ T cells have been detected in patients with DILI, suggestive of an immune etiology. Furthermore, genetic associations including the human leucocyte antigen (HLA) DRB1*15:01-DQB1*06:02 haplotype influence susceptibility. Amoxicillin forms protein adducts that are postulated to activate T cells, by conjugating with lysine residues. However, a role for such adducts has not been described. This study aimed to (1) investigate whether amoxicillin-modified HLA-DRB1*15:01-DQB1*06:02 binding peptides selectively activate DILI patient T cells and (2) define the nature of the T-cell response with respective to antigen structure. Peptides carrying lysine residues for amoxicillin binding in positions (KP) 2-6 and anchors for the HLA-DRB1*15:01-DQB1*06:02 haplotype were designed. The amoxicillin-modified peptides were characterized by mass spectrometry prior to culturing with patient peripheral blood mononuclear cell. T-cell clones were then tested for specificity with amoxicillin, unmodified- and amoxicillin-modified peptides, and structural variants. Amoxicillin-modified KP-2 and KP-3 peptide-specific CD4+ clones proliferated and secreted interferon gamma (IFN-γ), interleukin (IL)-10, perforin and/or IL-17/IL-22 in a dose-dependent manner and displayed no cross-reactivity with amoxicillin, unmodified peptide or with positional derivatives. The T cells response was HLA class II restricted and the amoxicillin-modified peptides bound selectively to HLA-DRB1*15:01 and/or DQB1*06:02. To conclude, we show that amoxicillin-modified peptides bind to both components of the risk haplotype to stimulate DILI patient T cells and describe the importance of the position of nucleophilic lysine residue in the HLA binding peptide sequence.

Characterization of Healthy Donor-Derived T-Cell Responses Specific to Telaprevir Diastereomers.

Telaprevir, a protease inhibitor, was used alongside PEGylated interferon-α and ribavirin to treat hepatitis C viral infections. The triple regimen proved successful; however, the appearance of severe skin reactions alongside competition from newer drugs restricted its use. Skin reactions presented with a delayed onset indicative of a T-cell mediated reaction. Thus, the aim of this study was to investigate whether telaprevir and/or its diastereomer, which is generated in humans, activates T-cells. Telaprevir in its S-configured therapeutic form and the R-diastereomer were cultured directly with peripheral blood mononuclear cells from healthy donors prior to the generation of T-cell clones by serial dilution. Drug-specific CD4+ and CD8+ T-cell clones responsive to telaprevir and the R-diastereomer were generated and characterized in terms of phenotype and function. The clones proliferated with telaprevir and diastereomer concentrations of 5-20 µM and secreted IFN-γ, IL-13, and granzyme B. In contrast, the telaprevir M11 metabolite did not stimulate T-cells. The CD8+ T-cell response was MHC I-restricted and dependent on the presence of soluble drug. Flow cytometric analysis showed that clones expressed chemokine receptors CCR4 (skin homing) and CXCR3 (migration to peripheral tissue) and 1 of 3 distinct TCR Vβs; TCR Vβ 2, 5.1, or 22. These data show the propensity of both R- and S-forms of telaprevir to generate skin-homing cytotoxic T-cells that may induce the adverse reactions observed in human patients.

Up-Regulation of T-Cell Activation MicroRNAs in Drug-Specific CD4+ T-Cells from Hypersensitive Patients.

Dysregulation in the expression of microRNAs (miRNAs), single-stranded RNAs which regulate gene expression, has been associated with diseases such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), although their cellular origin has not been explored. Thus, the focus of this work was to study expression patterns of reported miRNAs involved in T-cell activation following drug-specific stimulation in peripheral blood mononuclear cells (PBMCs) and drug-specific CD4+ T-cell clones (TCC) from patients with different cutaneous manifestations of delayed-type drug hypersensitivity reactions. CD4+ T-cells from hypersensitive patients were stimulated to proliferate, secreted cytokines (IFN-γ and IL-22), cytolytic molecules (Granzyme B) and up-regulate miRNAs 24 to 48 h after drug exposure. Carbamazepine-specific CD4+ T-cells that proliferated to the greatest extent and secreted the highest levels of IFN-γ showed an up-regulation of miR-18a and miR-155. In contrast, piperacillin-specific CD4+ T-cells displaying high expression of miR-9 and miR-21 showed an association with the extent of proliferation, but not IFN-γ secretion. MiR-155 up-regulation was detected in PBMCs from all hypersensitive patients 24 h after drug treatment, while miR-18a and miR-21 expression was up-regulated after 48 h. These findings demonstrate that miRNAs are expressed during drug-specific CD4+ T-cell activation and shows a new regulation path for drug hypersensitivity reactions.

Identification of drug- and drug-metabolite immune responses originating from both naive and memory T cells

Identification of drug- and drug-metabolite immune responses originating from both naive and memory T cells

Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome.

A multidrug regimen including isoniazid, rifampicin, pyrazinamide and ethambutol is commonly used as first-line treatment for tuberculosis. However, this regimen can occasionally result in severe adverse drug reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and drug-induced liver injury. The culprit drug and mechanistic basis for the hypersensitive reaction are unknown. To investigate drug-specific T-cell responses in patients with antituberculosis drug (ATD)-induced cutaneous hypersensitivity and its underlying mechanism. We enrolled eight patients with ATD-induced maculopapular exanthema and DRESS and performed a lymphocyte transformation test. Subsequently, drug-specific T-cell clones were generated from four of the patients who showed proliferation in response to ATDs. We measured the drug-specific proliferative responses and counted the drug-specific interferon (IFN)-γ/granzyme B-producing cells after drug stimulation. Antihuman leukocyte antigen (HLA) class I and class II blocking antibodies were used to analyse human leukocyte antigen-restricted T-cell responses. Positive proliferative responses to ATDs were mostly found in patients with cutaneous hypersensitivity. Furthermore, we isolated isoniazid/rifampicin-specific T cells from patients, which consisted primarily of CD4+ T cells. Drug-specific CD4+ T cells proliferated and secreted IFN-γ/granzyme B when stimulated with isoniazid or rifampicin, respectively. Isoniazid-responsive T-cell clones did not proliferate in the presence of rifampicin and vice versa. Drug-specific T-cell responses were blocked in the presence of anti-HLA class II antibodies. This study identifies the presence of isoniazid/rifampicin-specific T cells in patients with ATD-induced maculopapular exanthema and DRESS. Furthermore, it highlights the important role of drug-specific T-cell immune responses in the pathogenesis of these reactions.

Slow desensitization of imatinib-induced nonimmediate reactions and dynamic changes of drug-specific CD4+CD25+CD134+ lymphocytes

BackgroundImatinib is a tyrosine kinase inhibitor indicated for the treatment of gastrointestinal stromal tumors (GISTs) and certain neoplastic diseases; however, nonimmediate adverse reactions are common. ObjectiveTo describe the process of imatinib slow desensitization in patients who experienced nonimmediate reactions to imatinib and the dynamic change in drug-specific CD4+CD25+CD134+ T-lymphocyte percentages. MethodsFive patients diagnosed as having GISTs and with a recent history of imatinib-induced nonimmediate reactions (maculopapular exanthema with eosinophilia, exfoliative dermatitis, palmar-plantar erythrodysesthesia, and drug rash with eosinophilia and systemic symptoms) were desensitized using a slow desensitization protocol. The reintroduced imatinib dosage was stepped up every week starting from 10 mg/d and increasing to 25, 50, 75, 100, 150, 200, and 300 mg/d until the target dose of 400 mg/d was achieved. Prednisolone of up to 30 mg/d was allowed if allergic reactions recurred. The percentages of CD4+CD25+CD134+ T cells present after incubating peripheral blood mononuclear cells with imatinib, at baseline and after successful desensitization, were analyzed using flow cytometric analysis. ResultsBy using a slow desensitization technique, all patients were able to receive 400 mg/d of imatinib, and prednisolone was gradually tapered off. The percentages of imatinib-induced CD4+CD25+CD134+ T cells decreased from a mean (SD) of 11.3% (6.5%) and 13.4% (7.3%) at baseline to 3.2% (0.7%) and 3.0% (1.1%) after successful desensitization, when stimulating peripheral blood mononuclear cells with 1 and 2 μM of imatinib, respectively. ConclusionSlow desensitization is a helpful procedure in treating patients with imatinib-induced nonimmediate reactions other than simple maculopapular exanthema. The reduced percentages of imatinib-induced CD4+CD25+CD134+ T cells in these patients may be associated with immune tolerance.

Acute Generalized Exanthematous Pustulosis

An 80-year-old woman presented with fever and a generalized, erythematous pruritic eruption of 3 days duration. Four days prior to the eruption, she was treated with terbinafine 250 mg po daily for onychomycosis. She denied any recent viral illness. There was no personal or family history of skin disease. On examination, her temperature was 38.50C. Dermatological examination revealed generalized, symmetrical erythematous macules/patches and multiple, scattered small nonfollicular pustules with surrounding erythema on the trunk and upper extremities. Mucosal surfaces were spared. Nikolsky sign was negative. Her white blood cell count was 17.6 x 109/L. Gram staining and bacterial culture of the pustule were negative. A punch biopsy taken from one of the lesions revealed subcorneal and intraepidermal pustules, widespread spongiosis, and neutrophilic perivascular infiltration. Acute generalized exanthematous pustulosis (AGEP) is a rare and potentially severe cutaneous adverse reaction most commonly in response to drug therapy. The main culprit drugs are antibiotics (macrolides, beta-lactam antibiotics, sulphonamides), calcium-channel blockers (diltiazem), antifungal agents (terbinafine, ketoconazole), antipyretics (paracetamol), and antimalarials (hydroxychloroquine, chloroquine). AGEP usually occurs within 5 days of starting the offending medication. AGEP is a type IV hypersensitivity reaction. Drug specific CD4+ and CD8+ T cells play a crucial role. Viral and bacterial infections and hypersensitivity reaction to mercury have also been incriminated. Clinically, AGEP manifests with an acute onset of widespread bilateral symmetrical edematous erythematous macules/patches studded with numerous small scattered non-follicular sterile pustules. The eruption is often pruritic or burning and accompanied by fever and leukocytosis. AGEP can occur at any age. The sex ratio is approximately equal. The disease is generally self-limited and resolves within 15 days once the offending agent is withdrawn. Treatment is mainly symptomatic. Mortality occurs mainly in elderly patients with significant comorbidities.

The predominant drug-specific T-cell population may switch from cytotoxic T cells to regulatory T cells during the course of anticonvulsant-induced hypersensitivity

Delayed hypersensitivity is responsible for severe cutaneous adverse drug reactions (cADRs), especially in Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome (DIHS) (also known as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome). The drug-induced lymphocyte stimulation test (DLST), or lymphocyte transformation test (LTT), is used to identify the culprit drug in severe cADR cases. The aim of this study was to examine the immune reactions in cADR patients through the identification of the drug-specific proliferating cells by flow cytometric DLST (FCM-DLST). The peripheral blood mononuclear cells of 16 anticonvulsant-induced cADR patients were investigated by conventional DLST and a FCM-DLST protocol in which CFSE dilution and BrdU incorporation were combined. FCM-DLST allowed for the identification of the drug-specific proliferating cells in six cases. Three of these cases were DIHS cases, whereas there was one case of SJS, one case of maculopapular rash (MP), and one case of erythema multiforme (EM) among the six cases. In FCM-DLST, drug-specific proliferating T cells were detected as CFSE(low) BrdU(high) cells. These cells corresponded to the cells incorporating (3)H-thymidine in conventional DLST. Although CD4(+) T-cell proliferation dominated the observed proliferation in most of the cases (in the recovery stage of the three DIHS cases, the MP case, and the EM case), drug-specific CD8(+) cytotoxic T lymphocytes (CTLs) were detected, especially in the acute stages of the SJS case and one of the DIHS cases. There was a dramatic switch in the predominant drug-specific proliferating T-cell population in the course of one of the cases of DIHS in which CD8(+) CTLs were predominant initially, whereas CD4(+) T cells were predominant later. Moreover, drug-specific CD4(+) CD25(+) Foxp3(+) regulatory T cells (Tregs) proliferated during the recovery stage in one DIHS case. FCM-DLST revealed that the cell proliferation detected by conventional DLST is a heterogeneous proliferation of both CD8(+) CTLs and CD4(+) T cells that likely includes Tregs. However, the number of cADR cases in this study was limited, which limits the conclusions that can be drawn from it.

Involvement of drug-specific CD4 + and CD8 + T-cells in trimethoprim-mediated hepatitis

Involvement of drug-specific CD4 + and CD8 + T-cells in trimethoprim-mediated hepatitis

Delayed drug hypersensitivity reactions – new concepts

Immune reactions to small molecular compounds such as drugs can cause a variety of diseases mainly involving skin, but also liver, kidney, lungs and other organs. In addition to the well-known immediate, IgE-mediated reactions to drugs, many drug-induced hypersensitivity reactions appear delayed. Recent data have shown that in these delayed reactions drug-specific CD4(+) and CD8(+) T cells recognize drugs through their T cell receptors (TCR) in an MHC-dependent way. Immunohistochemical and functional studies of drug-reactive T cells in patients with distinct forms of exanthems revealed that distinct T cell functions lead to different clinical phenotypes. Taken together, these data allow delayed hypersensitivity reactions (type IV) to be further subclassified into T cell reactions, which by releasing certain cytokines and chemokines preferentially activate and recruit monocytes (type IVa), eosinophils (type IVb), or neutrophils (type IVd). Moreover, cytotoxic functions by either CD4(+) or CD8(+) T cells (type IVc) seem to participate in all type IV reactions. Drugs are not only immunogenic because of their chemical reactivity, but also because they may bind in a labile way to available TCRs and possibly MHC-molecules. This seems to be sufficient to stimulate certain, probably preactivated T cells. The drug seems to bind first to the fitting TCR, which already exerts some activation. For full activation, an additional interaction of the TCR with the MHC molecules is needed. The drug binding to the receptor structures is reminiscent of a pharmacological interaction between a drug and its (immune) receptor and was thus termed the p-i concept. In some patients with drug hypersensitivity, such a response occurs within hours even upon the first exposure to the drug. The T cell reaction to the drug might thus not be due to a classical, primary response, but is due to peptide-specific T cells which happen to be stimulated by a drug. This new concept has major implications for understanding clinical and immunological features of drug hypersensitivity and a model to explain the frequent skin symptoms in drug hypersensitivity is proposed.

Delayed Allergic Reaction to Suxamethonium Driven by Oligoclonal Th1-Skewed CD4+CCR4+IFN-γ+ Memory T Cells

Background: Muscle relaxants represent the drugs most frequently involved in intraoperative anaphylaxis during surgical procedures. Our aim was to report the case of a delayed reaction to suxamethonium and analyze specific T cell lines with regard to their specificity, phenotype and cytokine profile. Methods: We generated a drug-specific T cell line from a biopsy at the site of positive intradermal reactions and analyzed the immunophenotype, T cell receptor Vβ domain expression and cytokine profile. Results: T cells isolated from positive intradermal test reactions to suxamethonium showed a strict dose-dependent proliferation in response to drug-pulsed autologous antigen-presenting cells. The drug-specific CD4+ T cells were oligoclonal memory CD3+CD4+ T cells and expressed the skin homing receptors cutaneous lymphocyte antigen (CLA) and CCR4. Furthermore CD4+ suxamethonium-reactive T cell lines were IFN-γ-positive and synthesized high levels of IFN-γ and TNF-α. Conclusion: The study describes a delayed hypersensitivity to suxamethonium, driven by an oligoclonal T helper cell 1-skewed CD4+ memory T cell population, expressing the skin homing receptors CLA and CCR4.

Síndrome neuroléptico maligno por deprivación de baclofén intratecal

This chapter elaborates studies focusing on neuromuscular blocking agents and skeletal muscle relaxant. The mechanism of a delayed hypersensitivity reaction to suxamethonium has been studied by harvesting the patient's T cells from a biopsy at the site of positive intradermal reactions and analyzing the immunophenotype, T cell receptor Vβ domain expression, and cytokine profile. The T cells proliferated dose-dependently in response to drug-pulsed autologous antigen-presenting cells. The drug-specific CD4+ T cells were oligoclonal memory CD3+CD4+ T cells and expressed the skin-homing receptors cutaneous lymphocyte antigen (CLA) and CCR4. The adverse effects of botulinum toxin type A were reviewed and subjected to systematic review in an analysis of data from nine double-blind, placebo-controlled studies in 792 patients with spasticity after stroke. Most of the patients (69%) received only one injection. After follow-up for a mean of 18 of the patients who had been given toxin type A group and 163 (63%) of those who had been given placebo reported at least one adverse event. The most frequent adverse events were respiratory infections, seizures, incoordination, and injection site pain, none of which occurred at a significantly higher rate with the toxin. Most of the adverse events were rated as mild or moderate in intensity.

Delayed drug hypersensitivity reactions.

Immune reactions to small molecular compounds, such as drugs, can cause a variety of diseases involving the skin, liver, kidney, and lungs. In many drug hypersensitivity reactions, drug-specific CD4+ and CD8+ T cells recognize drugs through their alphabeta T-cell receptors in an MHC-dependent way. Drugs stimulate T cells if they act as haptens and bind covalently to peptides or if they have structural features that allow them to interact with certain T-cell receptors directly. Immunohistochemical and functional studies of drug-reactive T cells in patients with distinct forms of exanthema reveal that distinct T-cell functions lead to different clinical phenotypes. In maculopapular exanthema, perforin-positive and granzyme B-positive CD4+ T cells kill activated keratinocytes, while a large number of cytotoxic CD8+ T cells in the epidermis is associated with formation of vesicles and bullae. Drug-specific T cells also orchestrate inflammatory skin reactions through the release of various cytokines (for example, interleukin-5, interferon) and chemokines (such as interleukin-8). Activation of T cells with a particular function seems to lead to a specific clinical picture (for example, bullous or pustular exanthema). Taken together, these data allow delayed hypersensitivity reactions (type IV) to be further subclassified into T-cell reactions, which through the release of certain cytokines and chemokines preferentially activate and recruit monocytes (type IVa), eosinophils (type IVb), or neutrophils (type IVd). Moreover, cytotoxic functions by either CD4+ or CD8+ T cells (type IVc) seem to participate in all type IV reactions.

Acute Generalized Exanthematous Pustulosis: Role of Cytotoxic T Cells in Pustule Formation

Extensive formation of nonfollicular sterile pustules on erythematous background combined with fever and peripheral blood leukocytosis are the characteristics of acute generalized exanthematous pustulosis. This uncommon eruption most often is an allergic reaction because of drugs such as aminopenicillins and sulfonamides inter alia. We recently demonstrated the important role of drug-specific T cells in the pathogenesis of this disease, showing that they produce high amounts of the neutrophil-attracting chemokine interleukin-8 and therefore stand out as a special subgroup of T cells, differing from the usual Th1 and Th2 subsets. In this study we use immunohistochemistry as well as cytotoxicity assays (4- and 18-hour assays) and fluorescence-activated cell-sorting analysis of drug-specific circulating T cells and of cells eluted from the skin of five patients with acute generalized exanthematous pustulosis, to analyze whether cytotoxic T-cell functions are important in the pathogenesis of this disease, in particular for the formation of vesicles. The data reveal that drug-specific CD4(+) as well as CD8(+) T cells both are activated and cytotoxic; perforin/granzyme B and to a variable degree the Fas/FasL-killing mechanism is involved in tissue destruction. These features allow the formation of vesicles. Additional secretion of interleukin-8 by T cells and keratinocytes attracts neutrophils that fill the vesicles and transform them into pustules.

Acute generalized exanthematous pustulosis, a clue to neutrophil-mediated inflammatory processes orchestrated by T cells.

Circumstantial evidence exists that certain neutrophilic inflammatory processes are regulated by T cells, but how this occurs is not well understood. The present review presents data on how T cells may directly orchestrate a neutrophilic inflammation by specific release of the neutrophil-attracting chemokine CXCL8 (formerly known as interleukin-8). Acute generalized exanthematous pustulosis (AGEP) is an uncommon cutaneous eruption that is most often provoked by drugs, by acute infections with enteroviruses, or by mercury. It is characterized by acute, extensive formation of nonfollicular sterile pustules on an erythematous background, fever and elevated numbers of blood neutrophils. Involvement of T cells in drug-induced AGEP was suggested by positive patch tests and lymphocyte transformation tests. Moreover, drug-specific CD4+ and CD8+ T cells could be isolated and propagated in vitro from patch test sites and blood from AGEP patients. Their main characteristic is a high level of CXCL8 production. T cells are involved even in some neutrophil-rich inflammatory responses, and they may orchestrate the immune reaction directly by high CXCL8 production or indirectly via interleukin-17 production, which induces CXCL8 production in various cell types. AGEP serves as a valuable model for characterizing T cells with a particular function--namely production of CXCL8--leading to neutrophilic inflammation. It is tempting to speculate that elucidation of this pathomechanism will help to improve our understanding of similar neutrophilic eruptions (e.g. pustular psoriasis) and may reveal new targets for pharmacotherapeutic interventions in such diseases.

Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept.

Drug allergies are examples of immune reactions to small molecular compounds. In many drug allergies drug specific CD4+ and CD8+ T-cells can be detected, which recognize small chemicals via their alphabeta-T-cell receptor in a major histocompatibility complex dependent way. In this review a new concept of drug presentation to T-cells is presented. Drugs were stimulatory for T-cells if they bound covalently to peptides or proteins, but also if the drug had structural features allowing it to bind in a labile way (noncovalently) to the major histocompatibility peptide complex. This latter binding method has some similarities to superantigen stimulations and can explain allergies to drugs that are not metabolized. It has been described in patients with maculopapular, bullous and neutrophilic drug eruption, as well as in contact dermatitis. Noncovalent drug presentation leads to the stimulation of immune cells, namely T-cells. The drug needs two surface molecules (one inert serving as a scaffold, major histocompatibility complex, and one reactive, T-cell receptor) to exert its function. Although two receptor structures are involved, the process is reminiscent of a pharmacological interaction between a drug and its receptors and, from the phrase pharmacological interaction with immune receptors, was thus termed the p-i concept.

T cells in drug allergy.

In recent years, increasing evidence has indicated an important role for T cells in various drug-induced diseases. A detailed analysis of patients with various drug allergies revealed the existence of drug-specific T cells in the circulation or in eluate from skin infiltration in bullous, pustular, and maculopapular drug eruptions. The drug-specific T cells use the ab-T cell receptor CD4+ or CD8+ and react with drugs acting as haptens (covalently bound to larger molecules, such as penicillins), but also recognize drugs if they are bound only in a labile way to major histocompatibility complex molecules (noncovalent drug presentation). Functional analysis revealed a predominant IL-5 production by drug-specific CD4+ T cells in maculopapular exanthema (MPE) and bullous skin diseases, while patients with acute generalized exanthematous pustulosis have a peculiar T cell subset secreting high amounts of IL-8. Moreover, in MPE CD4+, perforin+ T cells were found in vitro and in immunohistology that had cytotoxic potential and killed keratinocytes in vitro and in vivo.

Predictive drug allergy testing: an alternative viewpoint

T- and B-cells recognise drugs when bound as haptens to carrier molecules. Recent studies suggest that drugs might also bind in a non-covalent form to MHC–peptide complexes and T cell receptors, and are thereby able to stimulate T cells. This has, however, only been shown for drug-specific T cell clones. Functional analysis revealed that drug-reactive T cells secrete high amounts of IL-5 and are cytotoxic. Cytotoxicity is mediated by drug-specific CD4 + and CD8 + cells and, as revealed by the immunohistochemical analysis of drug-induced exanthems, might be involved in the killing of keratinocytes thus explaining the drug-induced exanthem. Further work is needed to clarify the type and exact location of the rather labile drug binding to MHC and T cell receptors, and to evaluate what drug allergies might be caused by such an unusual presentation and immune stimulation. This new model as well as findings from the analysis of clinical drug allergies may have major implications on how to test and predict the allergenic potential of drugs. A change and expansion of currently performed test procedures is required to predict the allergenic potential of drugs.