Transfection of Drug-Specific T-Cell Receptors into Hybridoma Cells: Tools to Monitor Drug Interaction with T-Cell Receptors and Evaluate Cross-Reactivity to Related Compounds

Schmid, D.; Depta, J P H; Lüthi, Michael; Pichler, Werner J.

doi:10.1124/mol.105.021576

Cited by 42 publications

(42 citation statements)

References 41 publications

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“…IL-2 secretion has been previously reported in the literature to serve as an appropriate marker of T cell activation in T cell hybridoma lines; this response is specific to TCR stimulation, with quantitative differences in IL-2 levels observed with different peptide binding (26,27). In the 1B6 hybridoma cells, the levels of IL-2 production from stimulation with the various peptides correlated with the apoptotic responses (Fig.…”

Section: Peptide Avidity Defines Cellular Responsementioning

confidence: 78%

Quantitative Network Signal Combinations Downstream of TCR Activation Can Predict IL-2 Production Response

Kemp

Wille

Lewis

et al. 2007

The Journal of Immunology

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Proximal signaling events activated by TCR-peptide/MHC (TCR-pMHC) binding have been the focus of intense ongoing study, but understanding how the consequent downstream signaling networks integrate to govern ultimate avidity-appropriate TCR-pMHC T cell responses remains a crucial next challenge. We hypothesized that a quantitative combination of key downstream network signals across multiple pathways must encode the information generated by TCR activation, providing the basis for a quantitative model capable of interpreting and predicting T cell functional responses. To this end, we measured 11 protein nodes across six downstream pathways, along five time points from 10 min to 4 h, in a 1B6 T cell hybridoma stimulated by a set of three myelin proteolipid protein 139–151 altered peptide ligands. A multivariate regression model generated from this data compendium successfully comprehends the various IL-2 production responses and moreover successfully predicts a priori the response to an additional peptide treatment, demonstrating that TCR binding information is quantitatively encoded in the downstream network. Individual node and/or time point measurements less effectively accounted for the IL-2 responses, indicating that signals must be integrated dynamically across multiple pathways to adequately represent the encoded TCR signaling information. Of further importance, the model also successfully predicted a priori direct experimental tests of the effects of individual and combined inhibitors of the MEK/ERK and PI3K/Akt pathways on this T cell response. Together, our findings show how multipathway network signals downstream of TCR activation quantitatively integrate to translate pMHC stimuli into functional cell responses.

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Section: Peptide Avidity Defines Cellular Responsementioning

confidence: 78%

Quantitative Network Signal Combinations Downstream of TCR Activation Can Predict IL-2 Production Response

Kemp

Wille

Lewis

et al. 2007

The Journal of Immunology

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“…In this scenario no sensitization is required because there is direct stimulation of memory and effector T cells analogous to the concept of superantigens. 4 Although these mechanistic classifications of drug-induced allergic reactions are useful, not all drug-induced allergic reactions can be categorized based on these limited mechanisms of hypersensitivity.…”

Section: Epidemiology and Classification Of Adverse Drug Reactionsmentioning

confidence: 99%

Drug allergy

Khan

Solensky

2010

Journal of Allergy and Clinical Immunology

228

211

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Drug allergy is one type of adverse reaction to drugs and encompasses a spectrum of hypersensitivity reactions with heterogeneous mechanisms and clinical presentations. A thorough history is essential to the management of drug allergy. Laboratory testing has a very limited role in the management of drug allergy. Graded dose challenges and procedures to induce drug tolerance might be required in patients with drug allergy when there is a definite need for a particular agent. Management of reactions to specific agents, including beta-lactam antibiotics, sulfonamides, local anesthetics, radiocontrast media, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, and biologic modifiers, will be discussed in further detail.

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“…T cell stimulation required the presence of HLA molecules but the immunogenic peptides bound to HLA were exchangeable. Even the HLA molecules were exchangeable, as some TCC maintained reactivity in the presence of allogeneic APC [52,53,54,55,56]. Of note, most of these characteristics were shown for CD4 + TCC, restricted by MHC class II molecules.…”

Section: P-i Hla and P-i Tcrmentioning

confidence: 99%

Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors

Pichler

Adam

Watkins

et al. 2015

Int Arch Allergy Immunol

157

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Small chemicals like drugs tend to bind to proteins via noncovalent bonds, e.g. hydrogen bonds, salt bridges or electrostatic interactions. Some chemicals interact with other molecules than the actual target ligand, representing so-called ‘off-target' activities of drugs. Such interactions are a main cause of adverse side effects to drugs and are normally classified as predictable type A reactions. Detailed analysis of drug-induced immune reactions revealed that off-target activities also affect immune receptors, such as highly polymorphic human leukocyte antigens (HLA) or T cell receptors (TCR). Such drug interactions with immune receptors may lead to T cell stimulation, resulting in clinical symptoms of delayed-type hypersensitivity. They are assigned the ‘pharmacological interaction with immune receptors' (p-i) concept. Analysis of p-i has revealed that drugs bind preferentially or exclusively to distinct HLA molecules (p-i HLA) or to distinct TCR (p-i TCR). P-i reactions differ from ‘conventional' off-target drug reactions as the outcome is not due to the effect on the drug-modified cells themselves, but is the consequence of reactive T cells. Hence, the complex and diverse clinical manifestations of delayed-type hypersensitivity are caused by the functional heterogeneity of T cells. In the abacavir model of p-i HLA, the drug binding to HLA may result in alteration of the presenting peptides. More importantly, the drug binding to HLA generates a drug-modified HLA, which stimulates T cells directly, like an allo-HLA. In the sulfamethoxazole model of p-i TCR, responsive T cells likely require costimulation for full T cell activation. These findings may explain the similarity of delayed-type hypersensitivity reactions to graft-versus-host disease, and how systemic viral infections increase the risk of delayed-type hypersensitivity reactions.

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Transfection of Drug-Specific T-Cell Receptors into Hybridoma Cells: Tools to Monitor Drug Interaction with T-Cell Receptors and Evaluate Cross-Reactivity to Related Compounds

Cited by 42 publications

References 41 publications

Quantitative Network Signal Combinations Downstream of TCR Activation Can Predict IL-2 Production Response

Quantitative Network Signal Combinations Downstream of TCR Activation Can Predict IL-2 Production Response

Drug allergy

Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors

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