4. Immunotherapy of autoimmune disease Flashcards
(93 cards)
1
Q
What are some common autoimmune diseases?
A
- Psoriasis
- Graves disease
- Type 1 diabetes
- Vitiligo
- MS
- SLE
- Ulcerative colitis
2
Q
What kind of bias do most autoimmune conditions have?
A
A female gender bias
3
Q
What make autoimmune conditions hard to treat?
A
- Disease heterogeneity
- Everyone is effected differently
4
Q
What is immunotherapy?
A
A method of treatment that directly targets the immune system in a disease where the immune system is directly involved in the pathology.
5
Q
What things can vary in autoimmune diseases?
A
- The primary target organ
- Specific pathogenesis
- Genetic associations
6
Q
What can be treated with immunotherapy?
A
- Autoimmunity
- Allergy
- Cancer
7
Q
What are chronic inflammatory conditions?
A
- A series of chronic conditions that share mechanisms and characteristics with autoimmune diseases but are not classed as autoimmune disease.
- There is debate about this classification
- They share common pathways and treatments with autoimmunity
8
Q
What are some chronic inflammatory conditions?
A
- IBD: Crohn’s disease and ulcerative colitis.
- Spondyloarthopathies: ankylosing spondylitis and psoriatic arthritis
9
Q
What is the spectrum of treatment for autoimmune disease?
A
Least specific - most specific
1. Non-specific immunosuppressive drugs
2. Corticosteroids
3. Anti cytokine and cytokine therapies
4. Anti lymphocyte drugs
5. Anti-T cell drugs
6. targeting Lymphocyte migration
7. Epitope Mimetic
8. Antigen specific treatment
10
Q
What reduces as immunotherapy become more specific?
A
The amount and severity of side effects.
11
Q
What often causes immunotherapy to fail?
A
the side effects experienced by the patient
12
Q
What are non-specific immunosuppressants?
A
- General immunosuppressants that globally dampen immunity.
- Often given for long periods.
- Causes compromised immune function, reduced cancer immunosurveillance and reduced resistance to infection.
- Severe toxicity issues associated with their use and some are potentially carcinogenic.
- Recent studies have shown these fail in 50% of rheumatoid arthritis patients due to the adverse effects.
13
Q
How do many non-specific immunosuppressants work?
A
- They inhibit DNA synthesis
- This aims to prevent rapid expansion of autoreactive cells like immune cells.
- They are often also used as chemotherapeutic agents
14
Q
What are examples of non-specific immunosuppressants?
A
- Leflunamide/teriflunomide (pyrimidine synthesis inhibitors)
- Mitoxantrone
- Methotrexate
- Cyclophosphamide
15
Q
What are Glucocorticoids?
A
- A steroid with numerous immunosuppressive effects
- They were the first immunosuppressants used
- They have severe side effects including immunodeficiency, hyperglycaemia, skin fragility, osteoporosis and muscle break-down.
- They can also prevent regenerative processes used in healing
16
Q
How do glucocorticoids work?
A
- They inhibit the production of proinflammatory cytokines like IL-12, TNF, IL-1ß, IL-2 and IFNy.
- They promote the production of anti-inflammatory cytokines like IL-10.
- They can promote apoptosis in macrophages, dendritic cells and T cells.
17
Q
What are examples of glucocorticoids?
A
- Prednisone
- Prednisolone
18
Q
What are anti-cytokine therapies?
A
- They inhibit specific cytokine signalling to inhibit autoimmune pathogenesis.
- Can inhibit different inflammatory cascades or T cell differentiation
19
Q
What role do cytokines have in the development of autoimmunity?
A
- Pro-inflammatory cytokines have a central role in autoimmune pathogenesis.
- They exist in a complex network of cytokines.
- Inhibiting 1 cytokines can have lots of knock on effects either good or bad.
- This means we can use cytokines as a therapeutic target.
20
Q
What are some targets for anti-cytokines therapy?
A
- IL-12 and IL-23 subunit p40
- TNFa
- IL-6R
- IL-2
21
Q
Why can IL-12 and IL-23 be targeted with the same treatment?
A
- They share a common subunit p40.
- When this is the target both cytokines can be targeted with the same treatment.
22
Q
What do IL-12 and IL-23 do?
A
- IL-12 is essential for Th1 differentiation
- IL-23 is essential for Th17 differentiation.
- Both T cells subtypes are important in driving autoimmunity
23
Q
What treatment targets IL-12 and IL-23?
A
Ustekinumab
24
Q
What is Ustekinumab?
A
- A monoclonal anti-IL12p40 antibody.
- It blocks both Th1 and Th17 differentiation through inhibition of IL-12 and IL-23 signalling
- It significantly improves psoriasis and benefits shown in Crohn’s, UC and psoriatic arthritis.
25
What are the downsides of Ustekinumab?
1. It causes an increased risk of infection especially TB.
2. It doesn't work in MS even though Th1 and Th17 cells are important for driving MS
3. It doesn't work in rheumatoid arthritis
26
What does IL-6 do in inflammation?
1. IL-6 is upregulated during general inflammation.
2. It is also implicated in the pathogenesis of rheumatoid arthritis and juvenile idiopathic arthritis.
27
What treatment targets IL-6?
Tocilizumab
28
What is tocilizumab?
1. A humanised monoclonal Anti-IL-6R antibody.
2. It binds to membrane-bound and soluble IL-6R to cause a global blockade of IL-6 signalling.
3. It significantly reduces signs and symptoms of rheumatoid arthritis and delays progression of disease.
4. It is effective against juvenile idiopathic arthritis.
29
What are the downsides of Tocilizumab?
Common side effects of infections and liver enzyme abnormalities
29
What is TNFa?
1. A pro-inflammatory cytokines
2. It is the rate-limiting step in the pathogenesis of several immune-mediated conditions
30
What are the benefits of targeting TNF?
1. TNF blocking is an effective treatment for many conditions
2. Rheumatoid arthritis
3. juvenile idiopathic arthritis
4. Psorasis
5. IBD
and others
30
What treatments target TNF?
1. Chimeric monoclonal antibodies like infliximab
2. Soluble TNF-receptor constructs like Etanercept
31
What are the downsides of targeting TNF?
side effects
1. Potential for lethal reactivation of latent infections like TB and HBV.
2. Increased risk of lymphoma
3. pancytopenia
32
Do all cytokine treatment work on all autoimmune conditions?
no, just because treatment works in 1 autoimmune disease, it doesn't mean it works in another
33
How can we ensure cytokine treatment has the best chance of being effective for a disease?
We need to understand the pathogenesis of each disease to ensure we apply them correctly and don't do more damage than good.
34
What other kind of cytokine therapy can be used?
1. Administration of an anti-inflammatory cytokine like IFNß.
2. this gives broad anti-inflammatory effects
35
How is cytokine administration used to treat autoimmune conditions?
1. It is the most commonly prescribed disease-modifying therapy for active relapsing-remitting MS.
2. It reduces annual relapse rates and lesion load measured by MRI in MS.
3. It also reduces brain atrophy and disability progression.
36
What are the anti-inflammatory effects of administration of IFN-ß?
1. Modulation of antigen presentation and therefore T cell activation.
2. Modifies cytokine production.
3. Promotes T reg differentiation.
37
What are the downsides of the administration of IFN-ß?
1. Many patients don't respond to this treatment.
2. This is due to the production of neutralising antibodies to IFN-ß that block treatment
38
What is CD25?
The high affinity receptor alpha chain for IL-2.
39
How can IL-2 be used in immunotherapy?
1. Low doses of IL-2 can be used to stimulate Tregs to dampen down the immune system.
2. Treg always express CD25 so have higher affinity for IL-2 than other T cells.
3. Tregs suppress lots of immune cells so boosting Tregs could be applied to lots of autoimmune conditions and other diseases of immune dysregulation.
40
What doses of IL-2 can be used to treat autoimmunity?
Low doses
41
What can high dose IL-2 be used to treat?
1. Cancer
2. High doses of IL-2 are given to cancer patients to stimulate killer T cells to attack cancer.
3. This means doses used to treat autoimmunity need to be carefully measured to ensure they don't exacerbate disease.
42
How can IL-2 be targeted via CD25?
1. Monoclonal antibodies that preferentially bind to the high affinity receptor containing CD25. ( could target the low affinity receptor in cancer treatment)
2. Making a mutant IL-2 with an altered tertiary structure so it preferentially binds to CD25. This is in some phase 1 trials for SLE and arthritis.
43
What is a mutein?
a mutant protein
44
What therapy targets lymphocytes specifically?
Alemtuzumab
Brand name: Campath-1H
45
What is Alemtuzumab?
1. An anti-CD52 monoclonal antibody
2. It depletes lymphocytes.
3. First used to treat chronic lymphocytic leukaemia.
4. It reduced relapse rates in MS patients, reduced accumulation of disability and reduced lesions.
46
What is CD52?
1. A glycoprotein expressed on mature lymphocytes.
2. Both T and B cells
3. Under in cancer therapy and applied to autoimmunity
47
What are the down sides of alemtuzumab?
1. Once the T and B cells are depleted, you get T cell expansion that triggers secondary autoimmunity.
2. This can be thrombocytopenic purpura or autoimmune thyroid disorders.
3. Serious side effects include stroke and intracranial haemorrhage.
4. It was reviewed by the European medicines Agency and it was given more restrictions.
48
What do the restrictions on Alemtuzumab mean it can be used in?
1. It is only licensed for use in highly active disease where they have already failed disease modifying treatment before or in rapidly advancing relapsing-remitting MS.
2. This is for MS
49
What immunotherapies target B cells?
1. Rituximab
2. Ocrelizumab
50
What are Rituximab and Ocrelizumab?
1. Anti-CD20 antibodies
2. They deplete B cells to Reduce autoantibody production, reduce antigen presentation and reduce pro-inflammatory cytokine production.
3. Reduce antigen presentation reduces T cell activation
51
What is CD20?
1. A protein that is only expressed on B cells.
2. CD20 concentration increases as the B cell matures
52
What is Rituximab licensed to treat?
Rheumatoid arthritis and pemphigus vulgaris
53
What is Ocrelizumab licensed to treat?
Relapsing-remitting MS and primary progressive MS
54
What are the down sides of Rituximab and Ocrelizumab?
1. It is only effective in some SLE patients. (surprising as its mainly antibody based)
2. Can cause increased infection risk, and reactivation of latent infections.
3. can cause cytokine release syndrome
4. Rare severe adverse effect called progressive multifocal leukoencephalopathy.
55
What is Progressive Multifocal Leukoencephalopathy (PML)?
1. It is the reactivation of polyomavirus JC.
2. This causes demyelination and progressive damage in the CNS.
3. Patients present with various neurological defects.
4. JC virus is present in a high percentage of the population but only becomes dangerous in very immunocompromised people like AIDS patients.
5. There is no effective treatment but all immunosuppression needs to be reversed. This can have other effects.
56
What therapies can target T cells?
1. Otelixizumab
2. Daclizumab
3. Abatacept
57
What is Otelixizumab?
1. A anti-CD3 monoclonal antibody.
2. It aims to induce T cell apoptosis and anergy and induce Tregs through TGFß.
3. It is shown to maintain ß-cell function in type 1 diabetes.
4. Percentage of patients fail to respond to therapy.
5. Transient EBV reactivation
58
What is Daclizumab?
1. An anti CD25 monoclonal antibody.
2. It aims to block recently activated self reactive T cells expressing CD25.
3. Showed reduced relapse rate in MS patients, reduced disability accumulation and reduced lesions.
4. Increased risk of infection.
5. However, it was withdrawn in 2018 due to severe safety concerns as it caused inflammatory brain disorders.
59
How does Otelixizumab work?
1. It binds to CD3 which causes internalisation or shedding of the CD3 component of the TCR.
2. If a T cell doesn't have a TCR, it becomes unresponsive.
3. It can induce anergy.
4. It can cause T cell apoptosis with leads to TGFß production from macrophages which regulates immunity and induces Tregs.
60
What is Abatacept?
1. A CTLA-4-Ig fusion protein.
2. It aims to block co-stimulation by binding to CD80/86 on APC and preventing CD28 interaction and T cell activation.
3. The binding domain of CTLA-4 is fused to an Ig Fc domain.
4. Licenced to treat RA as it showed reduced signs and symptoms of RA and slowing of disease progression and joint damage.
5. It is not effective for the treatment of all autoimmune disease especially SLE.
61
What is VLA4?
1. An integrin expressed on immune cells that is essential for their migration and extravasation.
2. It binds to VCAM1 to initiate cell rolling
3. VLA4:VCAM1 interactions are essential in MS to allow T cells to cross the blood brain barrier.
62
What is Natalizumab?
1. An anti-VLA4 monoclonal antibody.
2. it inhibits T cell migration into the CNS by prevent VLA4 binding to VCAM1
3. It is licenced to treat highly active relapsing remitting MS.
63
What are the down sides of Natalizumab?
1. Increased opportunistic infections.
2. Blocking of leukocyte migration inhibits normal immunosurveillance of the CNS
3. can cause PML.
4. Reviewed due to safety concerns but not withdrawn as the benefits outweigh the risk.
64
How can the effects of anti-VLA4 treatment be visualised?
1. Using animal models with fluorescently labelled T cells
2. Intravital 2 photon microscopy can used to see the cells in the blood vessels in the CNS.
3. You can see the massive reduction in T cell migration
65
How do T cells move in and out of the lymph node?
1. Naive and central memory T cells circulate between the blood and lymph.
2. They home to the lymph nodes via CCR7.
3. To exit the lymph nodes, the sphingosine 1- phosphate receptor must be activated by S1P
4. This overrides the CCR7 mediated retention to the lymph nodes and the T cells can exit.
66
What treatment can keep the T cells in the lymph node?
Fingolimod
67
How does Fingolimod work?
1. It binds to the sphingosine 1-phosphate receptor 1.
2. This causes the internalisation of S1P1.
3. T cell no longer respond to S1P signals and are retained in the lymph nodes.
4. Fingolimod preferentially targets CCR7+ naive T cells and central memory cells due to CCR7 mediated retention of these in the lymph node.
5. This prevents the migration of these cells.
6. It is important in MS treatment as >90% of T cells isolated from MS patient CFS are T central memory cells
68
What can fingolimod treat?
1. Relapsing remitting MS
2. Reduced the frequency and severity of relapse and reduced CNS lesions.
69
What are the downsides of fingolimod treatment?
1. Peripheral blood lymphocyte counts reduce by 75% after 1 month of treatment.
2. Increased risk of infection
3. Cardiovascular events like bradycardia (most resolve quickly)
4. Mild hypertension over time
5. Increased risk of skin cancers and lymphoma due to reduced immunosurveillance.
6. risk of congenital deformity in pregnancy
7. Risk of liver injury
70
What is an epitope mimic?
a random polymer that looks like a target epitope from the disease
71
What is an example of an epitope mimic?
Glatiramer acetate
72
What is Glatiramer acetate?
1. A synthetic amino acid polymer with a composition similar to myelin basic protein.
2. It was developed in the animal model EAE.
3. It has fixed ratios of tyrosine, glutamate alanine and lysine.
4. 40-100 residues long.
5. It was one of the first first-line therapies for relapsing-remitting MS.
6. IT reduces relapse rates by about 1/3.
7. The mechanism is not fully understood
73
What are the proposed mechanisms of Glatiramer acetate function?
1. Encouraging anti-inflammatory production by T cells.
2. Antagonising MBP-specific cells inducing apoptosis
3. Promoting Foxp3+ Tregs
74
What is MBP?
1. Myelin basic protein
2. component of the myelin sheath.
3. Target in MS
75
What is the gold standard for the treatment of autoimmune disease?
Antigen specific treatment
76
What do antigen specific treatments target?
1. The self reactive CD4+ T cells that are the orchestrators of autoimmune disease.
2. These are targeted via their antigen-specific TCR.
77
What is the goal of antigen specific treatment?
1. By targeting their TCR, we can cause downregulation of the T cells through antigen specific tolerance.
2. This targets only the disease causing cells that control the autoimmune disease.
3. It also preserves the rest of immunity, including infection response and cancer immunosurveillance.
78
What do you need to know for antigen specific treatment?
Which antigens are targeted by the self-reactive TCR in particular autoimmune disease. This is hard
79
What do clinical trials of antigen-specific immunotherapy show?
1. The patient is exposed to a peptide antigen.
2. The T cells switch to producing IL-10.
3. This is like a reverse vaccine.
80
Why is antigen specific immunotherapy sometimes referred to as a reverse vaccine?
1. We are targeting a self antigen recognising CD4 T cells and using that antigen to try and switch the cells off.
2. This prevents autoimmune disease.
3. This is the opposite of a vaccine.
81
What sort of antigens can be used to induce antigen specific tolerance in immunotherapy?
1. Disease relevant antigens.
2. You need to know which antigen(s) the autoreactive T cells are specific for and responding to in a particular disease.
3. You cannot use an intact antigen as it also activates antibody secretion and can activate mast cells and basophils.
4. Intact antigen can also stimulate cytotoxic T cells.
5. Peptide antigen are the preferred antigen to be used.
82
How can the antigen be delivered to the autoreactive cells?
1. Artificial APC specific for the antigen.
2. Tolerogenic dendritic cells loaded with the antigen.
3. Using a liposome or nanoparticle. You can then include drugs that boost the tolerogenic response.
4. Natural synthetic peptides in solution.
83
What type of antigen is used to induce antigen specific tolerance in immunotherapy?
1. Soluble peptide mimic that naturally processed antigen when bound to MHC2 so they can target self-reactive T cells specifically.
2. They need to bind to peptide receptive MHC2.
3. They need to be presented by steady-state/immature DC.
84
how does the antigen need to be introduced to the T cell?
1. Dosing regimen of the antigen is important to drive tolerance induction.
2. Slowly increasing doses is safest.
85
What did the Tg4 EAE model show when treated with antigen specific treatment?
1. It was given repetitive peptide administration of MBP Ac1-9.
2. Antigen specific tolerance was induced in the self reactive T cells.
3. The mice were no longer susceptible to autoimmunity.
4. Pre-treatment prevented 100% of EAE development.
5. Treatment, once EAE developed, showed a reduction in the severity.
6. It can work as prophylaxis or as treatment
86
What is the Tg4 mouse?
A transgenic mouse where >95% of the CD4+ T cells recognise the myelin peptide MBP Ac1-9.
87
What gene expression changes occurred in the Tg4 EAE models once treated with antigen-specific immunotherapy?
1. Activation of lots of genes promoting immunological tolerance.
2. IL-10 induction
3. Induction of co inhibitory molecules
88
What can upregulation of IL-10 in antigen specific treatment also cause?
1. Bystander suppression
2. This regulates other immune responses through cytokine production.
3. This can control responses to other antigens as well
89
What is ATX-MS-1467?
A cocktail of the most common MBP peptides used as antigens in MS.
90
What did treatment with ATX-MS-1467 show?
1. 78% reduction of the lesion load and a reduction in sites of inflammation and damage.
2. once the dosing stopped the lesion load increased.
3. This suggests you need continuous stimulation with the antigen to prevent disease
91
Is treatment with ATX-MS-1467 safe?
1. Yes
2. It is safe and well tolerated in patients.
