Future autoimmune disease treatments

Question 1

Aims of T-cell receptor antagonism (peptide based immunotherapy)

Answer 1

Develop a peptide that can be administered as a drug

Must form a complex with MHC

Must bind to the T-cell receptor without inducing signals that activate the T-cell

Must prevent the native peptide from co-ordinating with the T-cell receptor and bringing about autoimmune disease

Question 2

COP-1

Answer 2

peptide of 18 amino acids in length that competes with myelin antigens for T-cell receptor binding sites

Question 3

Copaxone

Answer 3

Synthetic COP-1 drug that suppresses experimental models of MS and slow disease progression in humans

Forms complex with MHC - outcompete MHC/myelin complex formation

Does not stimulate TCR

Question 4

MS clinical trials

Answer 4

stopped because of adverse reactions, e.g. anxiety, chest pain fever

Question 5

CCR1

Answer 5

chemokine receptor on phagocytes

Question 6

Rantes

Answer 6

CCR1 ligand found in high levels in joints
Binds to CCR1 on macrophages, promoting migration of phagocytes to inflamed joints

Question 7

CCR1 antagonists in RA

Answer 7

4-hydroxypiperidines are highly potent and selective

Prevent binding of Rantes and therefore migration of macrophages to joints

Specific chemokine receptor blockade can result in relevant biological effects in patients with active RA

Less macrophages in joints after treatment

Not preventing macrophage activation but stopping them from getting to disease site

Question 8

Two signal hypothesis for lymphocyte activation

Answer 8

Signal 1 – peptide antigen cross linking MHC and the T-cell receptor

Signal 2 – additional receptor signals provided by antigen presenting cells activated by invading pathogens

Question 9

Co-stimulatory receptors on APCs

Answer 9

CD80 and CD86

Question 10

CD80

Answer 10

binds to CD28 on T-cells → ACTAVATION

Question 11

CD86

Answer 11

binds to CTLA-4 on T-cells → NEGATIVE REGULATION

Question 12

Blocking CD80 and CD86 expression

Answer 12

In experimental models of autoimmune disease, anti CD80 abs
reduce disease severity, while anti CD86 abs exacerbate the
disease

HOWEVER, abs are only effective at preventing primary immune response → only effective in initial priming of immune response

THEREFORE, to be effective drugs, they must be given prior to development
of symptoms

NOT POSSIBLE – THEREFORE, ALTHOUGH RESEARCH CONTINUES
NO EFFECTIVE DRUGS EXIST