IDRs

Define Adverse Drug Reactions (ADRs)

Toxicity at pharmaceutical dose levels

What is type A of ADRs?

Exaggerated pharnacological effect (ON target toxicity)

What is type B of ADRs?

Idiosyncratic drug reactions

Not related to pharmacological effect, not predictable, individual specific

What is type C of ADRs?

Not related to pharmacological effect, toxic metabolite, predictable (off target toxicity)

What are the most common targets of IDRs?

• Skin (SJS/TEN)

• Livere (iDILI)

• Blood cells/bone marrow (haemolytic anaemia/agraulocytosis)

What does idiosyncrasy mean?

Specific to an individual

Give egs of drugs associated with IDR

• Penicillin

• Anti-viral drugs

• Antibiotics

How are IDRs often reverted?

Stopping therapy

List the evidence for occurrence of adaptive immune response in IDRs

• Delayed onset of reaction/stronger response upon re-challenge

• Accumulation of B and T cells at target organ

• Anti-drug antibodies found

• Isolated T cells of patients react to drug ex vivo

Define (Pro-)hapten hypothesis

Certain small-molecule drugs trigger allergic drug reactions or hypersensitivity by interacting with the body's immune system

What is a hapten?

A small molecule (<1,000 Daltons) that is too small to be recognised by the immune system on its own

What type of cells are IDRs often directed to?

Cells with high metabolic capacity eg hepatocytes, keratinocytes

On which cells are MHC I found?

All nucleated cells

On which cells are MHC II found?

APCs (macrophages, dendritic cells, B cells)

What does MHC I present?

Self protein fragments and foreign proteins of invaders

What does MHC II present?

Protein fragments of engulfed invaders

What does MHC I activate?

CD8+ T cells

What does MHC II activate?

CD4+ T cells

Step 1: How drug becomes antigen

• Drug covalently binds to larger host proteins -> hapten carrier-complex

• APCs process modified protein and display drug-peptide

Describe sulphamethoxazole and (pro)hapten hypothesis

1. Hydroxylamine can leave liver

2. Reactive nitroso metbaolite can be formed at other locations eg ROS and UV

3. Form protein adducts

4. After internalisation and processing → presented by MHC and activate T cells

Step 2: From an antigen presentation to B and T cell response

Antigen-presenting cells process modified protein and display drug-peptide fragments on MHC molecules to activate T cells and B cells, triggering an immune or allergic reaction

Step 3: Destruction of T cells

1. Cytotoxic T cell finds MHC class I

2. T cell activated and releases perforins and fragmentins → pore formation

3. Induce necrosis and apoptosis in target cells

Eg of disease involving destruction of host cells

Contact dermatitis

Define P-I hypothesis

Certain drugs trigger hypersensitivity reactions by binding directly and reversibly to immune receptors without needing prior metabolic processing

Which diseases is Carbamazepine associated with?

Idiosyncratic liver toxicity and SJS/TEN

What does carbamazepine have a high affinity for?

Certain TCRs of certain T cell clonotypes

Which HLA does carbamazepine binding of complex facilitate to?

HLA-B*1502

How does negative/clonal selection of T cells work?

T cells that are highly responsive to self antigens are normally forced to undergo apoptosis in thymus

How can drugs affect negative/clonal selection?

Drug binding to TCR (or HLA) can change specificity to self of surviving T cells

Define altered peptide repertoire hypothesis

Certain small-molecule drugs trigger severe T-cell-mediated hypersensitivity reactions by binding inside the peptide-binding groove of human leukocyte antigen (HLA) molecules and shifting which self-peptides are presented to the immune system

Give eg of drug involved in altered peptide repertoire

Abacavir

What is abacavir

Anti HIV inhibitor

Abacavir consequence as IDR

Severe dermal toxicity (SJS/TEN) in some patients

Which HLA is associated with Abacavir in SJS/TEN

HLA-B*57.01

What is protein reactive in Abacavir

The metabolites, not the protein itself

Abacavir binding mechanism

1. Abacavir binds (reversibly) intracellularly to binding groove of HLA-B57-01

2. This changes binding possibilities of self-peptides

3. Other peptides than normal are now bound

4. Immune reaction induced to “neo” self peptide (binds to another MHC protein than normally)

How does metabolic idiosyncrasy explain IDRs?

• Polymorphism of toxifying or detoxifying pathways (slow metaboliser) sometimes is a risk factor

  • Eg GsT M1 and GsT T1 null genotype → increases risk of iDILI

• Often adducts are formed in many people, but no reaction

How does HLA and TCR subtypes explain IDRs?

• Fits with hapten, P-I and altered peptide repertoire hypotheses

• TCR and HLA = extremely polymorphic

• Hapten hypothesis - haptenated peptides are ligand specific to HLAs

• PI/altered peptide repertoire - drugs only have affinity to certain TCR or HLA clonotypes

List the ways of how immune tolerance is normally acquired?

• Negative selection of auto-reactive T cells in thymus

• Reg T cells

• Oral tolerance

• Immune checkpoint proteins

What is the danger signal hypothesis in IDRs?

Occurrence of IDRs reported to be more frequent in association with cellular stress or disease rather than self or non self antigens

What are danger associated molecular patterns?

Intracellular components released when a cell is lysed eg extracellular DNA, ATP etc.

How can uric acid be a danger signal?

Upregulates receptors and increases risk of IDR

What are immune checkpoint proteins?

Proteins that induce immune tolerance (highly expressd in liver)

In terms of checkpoints, what are known to be able to induce IDR-like reaction?

Synthetic checkpoint inhibitors

How does checkpoint inhibition work?

Ligands of PDL-1 actively act as an inhibitory signal when bound to PD-1 receptor on T cell → inhbits T cell killing of tumour cell

What is oral tolerance?

Any foreign antigens in bloodstream via oral route, but seldom immunological reaction

Which cells are invovled in oral tolerance?

Suppressor cells (reg T cells) (enterocytes and cells in the liver)

Why is oral tolerance mediated in terms of antigens?

Exposure to incomplete antigens

What is molecular mimicry?

Self-antigens have structures that resemble the hapten

What happens if a hapten has molecular mimicry as self-antigen?

Tolerance against self-antigen → also tolerance agains