Future Autoimmune Treatment Flashcards
(25 cards)
What are the three future treatments that modify/prevent immune response in autoimmune disease?
- T-cell receptor antagonists (altered peptide ligands)
- Antagonists of the co-stimulatory receptor CD80
- Chemokine receptor antagonists
What is the result of using immune-modifying treatments for autoimmune disease?
- They prevent disease
- Treatment of symptoms is not necessary
What are the pharmaceutical development goals for peptide-based immunotherapy?
- Develop peptide that can be administered as a drug
- Must form a complex with MHC
- Must bind to T-cell receptor without activating it
- Must prevent native agonistic peptide from binding T-cell receptor
What is COP-1?
- Example of peptide-based immunotherapy
- Peptide of 18 amino acids
- Competes with myelin antigens for T-cell receptor binding sites
- Authorised drug is Copaxone
What is the composition of COP-1?
- L-alanine
- L-glutamine
- L-lysine
- L-tyrosine
What are the effects of COP-1 found in clinical trials?
- Suppresses experimental (animal) models of MS
- Slows disease progression in humans
How does COP-1 function with MHC?
- Forms complex with MHC molecules
- Prevents myelin-derived peptides from forming complexes with MHC
- Acts as a competitive inhibitor
Why must COP-1 not stimulate the T-cell receptor?
- To avoid activating T-cells and initiate an immune response
- Its structure differs slightly from myelin peptides
How does COP-1 binding differ from myelin peptides?
- Binds to T-cell receptor but lacks second interaction required for activation
- Does not cause T-cell response
- Binds with greater affinity than myelin antigen
- Prevents immune response to myelin proteins
What are altered peptide ligands?
- T-cell receptor antagonists
- Differ from native antigen by as little as one amino acid
Why were clinical trials for altered peptide ligands in MS stopped?
- Adverse reactions occurred in both trials
- Clinical indications not fully defined
What causes tissue damage in rheumatoid arthritis?
- Activated T-cells and macrophages secrete cytokines
- Cytokines activate synovial cells
- Synovial cells produce proteolytic enzymes
- Enzymes mediate tissue damage
What is CCR1?
- Chemokine receptor found on phagocytes
- Binds chemokine RANTES
Where is RANTES secreted and what does it do?
- Secreted from inflamed joints
- Binds to CCR1 on macrophages
- Promotes migration of phagocytes to inflamed joint
What is the potential role of CCR1 antagonists in rheumatoid arthritis?
- May block migration of phagocytes to joints
- Could reduce inflammation and disease progression
What are 4-hydroxypiperidines?
- Highly potent and selective CCR1 antagonists
- Effective at 1–40 nM concentrations
- IC50 at CCR1 ≈ 6 nM
- IC50 at another receptor = 5000 nM
- Complex structure with 7 CCR1 binding sites
How do 4-hydroxypiperidines work?
- Prevent RANTES from binding CCR1
- Block macrophage migration to joints
- Do not prevent activation of T-cells and phagocytes
What were the results of the clinical trial for CCR1 antagonist in RA?
- Double blind, placebo controlled
- 16 patients with active RA treated for 14 days
- Synovial biopsies taken on days 1 and 15
- Significant reduction in CCR1+ macrophages in treated patients
What was concluded about CCR1 antagonists in the clinical trial?
- Specific chemokine receptor blockade shows biological effects in active RA patients
- Clinical trials continue
What are the key co-stimulatory receptors and their roles?
- CD80 on APC binds CD28 on T-cells → T-cell activation
- CD86 on APC binds CTLA-4 on T-cells → Negative regulation
Why target CD80 in autoimmune disease?
• Blocking CD80 may prevent T-cell activation and autoimmune disease
What were findings from blocking CD80 and CD86 in the 1990s?
- Blocking both prevented T-cell immune reactions
- Anti-CD80 antibodies reduced disease severity
- Anti-CD86 antibodies exacerbated disease
Why are anti-CD80 antibodies not used clinically?
- Only prevent primary immune response
- Would need to be given before symptoms develop
- Not feasible due to toxicity and cost concerns
What do traditional autoimmune therapies include?
- NSAIDs
- Immunosuppressants
- DMARDs
- Glucocorticoids
- Anti-cytokine therapy
