L5 - Immunotherapy of autoimmune disease Flashcards
- Categorise different immunotherapeutic by therapeutic target, explaining the benefits and limitations of different approaches for the treatment of autoimmune disease - Appraise the antigen-specific immunotherapeutic approach comparing this therapeutic strategy with non-antigen specific approaches to treating autoimmunity
What are autoimmune diseases, and why are they difficult to treat?
Autoimmune diseases occur when the immune system mistakenly attacks healthy tissues in the body. They are difficult to treat and often incurable due to their heterogeneity, varying primary target organs, specific pathogenesis, and genetic associations.
What trends are seen in the frequency of autoimmune diseases and patient demographics?
They show a significant gender bias towards females and vary in frequency and average age of onset. Conditions such as psoriasis and Hashimoto’s thyroiditis are more common than rarer conditions like systemic lupus erythematosus (SLE) and narcolepsy.
What are examples of autoimmune diseases ( some of which will be highlighted in this lecture)
- Type 1 diabetes
- Juvenile idiopathic arthritis ( some forms)
- Psoriasis
- Rheumatoid arthritis
- Multiple sclerosis
- Systemic lupus erythematosus
***
+ Grave’s disease
+ Myocarditis ( some forms)
+ myasthenia gravis - autoimmune hepatitis
+ some forms of uveitis
+ some forms of thyroiditis
What is immunotherapy, and how does it relate to autoimmune diseases?
an umbrella term for treatments that directly target the immune system. It is used to manage autoimmune diseases, allergic conditions, and cancer by modulating immune system activity involved in disease pathology.
How are immunotherapeutic treatments for autoimmune diseases categorised?
structured into a pyramid, ranging from:
- Least specific therapies at the base (broad immune suppression).
- Most specific therapies at the top (targeting specific cells and molecules involved in pathology).
The more specific the therapy, the fewer the expected side effects.
Pyramid of therapies for autoimmunity starting from least to most specific and fewer side effects
- Non specific immunosuppressive drugs (least specific and most side effects)
- Corticosteroids
- Anti-Cytokine and cytokine therapies
- Anti lymphocyte drugs
- Anti lymphocyte drugs
- Anti T cell drugs
- Lymphocyte migration
- Epitope mimetic
- The target antigen ( most specific and least side effects)
Which chronic inflammatory diseases are currently not categorised as autoimmune conditions
Chron’s Disease, ulcerative colitis and spondyloarthropathies e.g. Ankylosing spondylitis and Psoriatic arthritis
What is spondyloarthropathies
a group of chronic inflammatory diseases that affect the joints and spine
Why are inflammatory bowel diseases and spondyloarthropathies discussed alongside autoimmune diseases?
These chronic inflammatory diseases share many mechanisms with autoimmune conditions. While some immunologists debate whether they are true autoimmune diseases, their shared pathways make them relevant in this context.
What is the main challenge when using immunotherapy for autoimmune diseases?
The challenge lies in separating the therapeutic benefits from side effects, which can often outweigh the advantages.
Why are general immunosuppressants problematic in treating autoimmune diseases?
They suppress the entire immune system, compromising normal immune functions such as cancer surveillance and infection resistance, often leading to severe side effects.
What are the long-term concerns with general immunosuppressants?
Prolonged immune suppression over a person’s lifetime increases the risk of toxicity, infection, and even cancer.
How do general immunosuppressants work on a cellular level?
Many inhibit DNA synthesis to prevent the rapid expansion of autoreactive immune cells.
What are some examples of general immunosuppressants, and how do they function?
-Leflunomide (active form: Teriflunomide): Pyrimidine synthesis inhibitor.
- Mitoxantrone, Methotrexate, Cyclophosphamide: Chemotherapeutic agents that disrupt DNA synthesis or induce apoptosis in responding cells.
What is a notable limitation of combining Leflunomide and Methotrexate in rheumatoid arthritis patients?
The combination fails in over 50% of cases due to adverse side effects.
What are glucocorticoids, and why are they important in immunosuppression?
Glucocorticoids, such as prednisone and prednisolone, are immune suppressant hormones that are effective in reducing inflammation and promoting immune cell apoptosis.
How do glucocorticoids suppress the immune system?
- Inhibit pro-inflammatory cytokine production.
- Promote apoptosis of macrophages, dendritic cells, and T cells.
- Reduce antibody production by B cells.
What are the side effects of glucocorticoids?
(may be severe e.g.)
- Immune deficiency
- Hypoglycaemia
- Skin fragility
- Osteoporosis
- Muscle breakdown
- Hampered regenerative processes
Why should glucocorticoids be used cautiously?
Their side effects, including interference with tissue repair and long-term health risks, can significantly limit their therapeutic use.
How do Glucocorticoids affect dendritic cells?
they suppress their activity by reducing the expression of MHC class II and co-stimulatory molecules CD80 and CD86. This leads to diminished antigen presentation and reduced activation of T cells.
How do glucocorticoids influence T helper (Th) cells?
decrease the production of IL-12, which is essential for Th cell activation, and induce apoptosis in Th cells, thereby limiting their role in immune regulation.
How do glucocorticoids affect cytotoxic T (Tc) cells?
they reduce the production of IL-2, a key cytokine for Tc cell activation and survival, and promote apoptosis of Tc cells, impairing cytotoxic responses.
How do glucocorticoids modulate macrophage activity?
they suppress macrophage function by reducing IL-1β and TNF production. This dampens inflammation and cytokine signalling in the immune response.
How do glucocorticoids affect natural killer (NK) cells?
they decrease the production of IFN-γ, reducing NK cell cytotoxicity and impairing their ability to kill infected or tumour cells.
How do glucocorticoids influence B cells?
They reduce antibody production by suppressing B cell activation and differentiation, leading to a diminished humoral immune response.
Why were anti-cytokine therapies a significant advancement in treating autoimmune diseases?
They target pro-inflammatory cytokines, which play a key role in the pathogenesis of many autoimmune diseases, offering effective therapeutic options.
What is a potential challenge when inhibiting a single cytokine in anti-cytokine therapy?
Cytokines function within a delicate and complex network, so inhibiting one cytokine may trigger extensive downstream effects, including blocking inflammatory cascades and altering T-cell differentiation.
Which cytokines are commonly targeted in anti-cytokine therapies?
IL-12, IL-23, IL-6, IL-17, and TNF.
How does targeting IL-12 and IL-23 simultaneously with a single monoclonal antibody work?
IL-12 consists of subunits P40 and P35, while IL-23 consists of subunits P40 and P19. A monoclonal antibody targeting the P40 subunit blocks both cytokines simultaneously.
What is the role of IL-12 and IL-23 in T-cell differentiation?
IL-12 is essential for T helper 1 (TH1) cell differentiation, while IL-23 is crucial for T helper 17 (TH17) cell differentiation.
What autoimmune diseases benefit from IL-12 and IL-23 inhibition using the monoclonal antibody ustekinumab?
Psoriasis, Crohn’s disease, ulcerative colitis, and psoriatic arthritis.
what type of monoclinal antibody is ustekinumab
anti IL-12p40 antibody
what does Ustekinumab block
both Th1 and Th17 differentiation through inhibition of IL-12 and IL-23 cytokine signalling
What are some potential side effects of anti-cytokine therapy using IL-12/IL-23 inhibitors / ustekinumab?
Increased risk of infections, particularly tuberculosis (TB).
In what context is IL-6 typically upregulated, and what condition is it especially relevant to?
IL-6 is upregulated during general inflammation and plays a key role in autoimmune diseases, particularly rheumatoid arthritis and juvenile idiopathic arthritis (JIA)
What therapeutic strategies exist for targeting TNF in autoimmune diseases?
Either monoclonal antibodies or receptor constructs are used to inhibit TNF
What is a notable observation regarding TNF and IL-17 targeting in autoimmune diseases?
TNF inhibition works well for arthritis, psoriasis, and IBD but not for MS. Conversely, IL-17 targeting improves conditions like psoriasis but exacerbates IBD.
What is the name of a humanised monoclonal anti IL-6R antibody
Tocilizumab
what are some common side effects for tocilizumab / humanised monoclonal anti IL 6R antibody
infections, liver enzyme abnormalities, neutropenia and intestinal perforations.
what is a chimeric monoclonal antibody that targets TNF
Infliximab
what is a soluble TNF receptor construct that targets TNF
Etanercept
what is TNF
we don’t do more damage than good in trying to apply them.
which autoimmune disorders are TNF blockers effective treatments for
Rheumatoid arthritis, Juvenile idiopathic arthritis (JIA), Crohn’s disease, psoriasis, psoriatic arthritis, ulcerative colitis and ankylosing spondylitis
what are potential side effects for TNF blockers
potential for lethal re-activation of latent infections e.g. TB, HBVm increased risk of lymphoma and pancytopenia and then long term use increases the risk of other autoimmune disease development e.g. MS and SLE
What is the risk of applying the same cytokine therapy across different autoimmune diseases?
Cytokine therapies can have contrasting effects. For example, targeting IL-17 is effective in some conditions like psoriasis and arthritis but exacerbates IBD, or targeting TNF can be effective for rheumatoid arthritis, Juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and IBD but exacerbates MS. Misapplication can cause harm rather than benefit.
What is an alternative to blocking cytokines in autoimmune disease therapy?
Administering anti-inflammatory cytokines, e.g. IFN-b which widely used to treat active relapsing-remitting MS, reducing relapse rates, lesion loads (as measured by MRI), brain atrophy, and disability progression.
How does IFN-b work in MS treatment?
It has broad anti-inflammatory effects, including modulating antigen presentation (thus T cell activation) modifying cytokine production, and promoting T regulatory cell differentiation.
Why might some MS patients not respond to interferon beta therapy?
Many patients produce antibodies against the therapeutic interferon beta, neutralising its effect and preventing it from working
What molecule do T regulatory cells express
CD25
What is CD25, and why is it significant for T regulatory cells (Tregs)?
CD25 is the alpha chain of the high-affinity IL-2 receptor. Tregs constitutively express CD25, giving them a high affinity receptor for IL-2, which helps regulate immune responses.
what is the difference between the high affinity and low affinity IL-2 receptor
The high-affinity receptor includes the alpha chain (CD25) and is expressed by Tregs, while the low-affinity receptor consists only of gamma and beta chains and is found on conventional T cells.
How can low-dose IL-2 receprors be used in immunotherapy for autoimmune diseases?
Low-dose IL-2 receptors can selectively stimulates T regulatory cells (Tregs) without activating effector T cells at very low doses of IL-2, helping dampen autoimmune responses.
What types of trials are currently exploring the use of low-dose IL-2 in autoimmune diseases?
Phase 1 and 2A trials are underway for 11 autoimmune diseases, investigating whether low-dose IL-2 can expand Tregs and improve disease symptoms (proving this concept)
Why is the use of IL-2 in immunotherapy described as a “double-edged sword”?
While low-dose IL-2 can stimulate Tregs for autoimmune disease treatment, high-dose IL-2 is used in cancer therapy to activate killer T cells, which may clear tumour cells (need to understand the subtleties and don’t want to be stimulating self reactive T cells to make the autoimmune disease worse)
How can monoclonal antibodies be used to target IL-2 in therapy?
Monoclonal antibodies can induce conformational changes in WT IL-2 to preferentially bind to either the high-affinity receptor (for autoimmune diseases) or the low-affinity receptor (for cancer treatment).
What is a “mutein” in the context of IL-2 therapy?
A mutein is a mutant IL-2 protein engineered to change its tertiary structure, promoting selective binding to either the high-affinity or low-affinity IL-2 receptor
What autoimmune diseases are currently being studied in phase 1 trials using IL-2 muteins?
Trials are investigating the use of IL-2 muteins in conditions such as arthritis and systemic lupus erythematosus (SLE).
What type of cells of the immune system can Tregs suppress
both cells of the innate and adaptive immune system therefore by boosting Treg, IL-2 therapy may be effective in treating a range of auto immune diseases
What is an example of an immunotherapy that targets lymphocytes specifically
Alemtuzumab (Campath-1H)
What is Alemtuzumab (Campath-1H)
an anti-CD52 monoclonal antibody that depletes mature T and B lymphocytes. It is used to treat chronic lymphocytic leukaemia and highly active multiple sclerosis (MS - reducing accumulation of disability and lesions as seen by MRI)
What are the potential side effects of Alemtuzumab in autoimmune disease treatment?
homeostatic expansion of remaining T cells which can trigger secondary autoimmunity (e.g., thrombocytopenic purpura and thyroid disorders), (rarer) stroke, and intracranial haemorrhage.
Why is Alemtuzumab only licensed for certain MS patients?
Due to its severe side effects, Alemtuzumab is restricted to patients with rapidly advancing or severe relapsing-remitting MS after one disease-modifying therapy has failed.
How do Rituximab and Ocrelizumab target B cells in autoimmune diseases?
They are monoclonal antibodies against CD20, which depletes B cells, reducing autoantibody production, antigen presentation to T cells, and inflammatory cytokine production.
What is Rituximab licenced to treat
rheumatoid arthritis and pemphigus vulgaris
What is Ocrelizumab licenced to treat
relapsing remitting MS and primary progressive MS
What are some risks associated with B cell-depleting therapies?
Increased risk of infections, reactivation of latent infections, cytokine release syndrome, and the rare but fatal condition progressive multifocal leukoencephalopathy (PML).
What is interesting about immunotherapies targeting B lymphocytes and SLE
it is only effective in some SLE patients which is interesting as this is an immune disorder caused by autoantigens
What causes Progressive Multifocal Leukoencephalopathy (PML)?
PML is caused by the reactivation of the JC polyomavirus in the CNS, leading to demyelination and neurological defects in immunocompromised individuals…. patients will typically present with neurological deficits and uni or multifocal lesions of the white matter of the brain.
How is JC polyomavirus typically controlled in the population?
Although present in a high percentage of the population, it remains dormant unless immune suppression occurs.
What is the only way to manage PML in patients?
There is no effective treatment but you can manage it by reversing immune suppression to allow the immune system to control the JC virus.
What is Daclizumab and how does it work?
Daclizumab is an anti-CD25 monoclonal antibody that targets recently activated self-reactive T cells by blocking CD25, which is transiently upregulated during T cell activation to enhance IL-2 mediated proliferation.
What was Daclizumab licensed for, and why was it withdrawn?
It was licensed in 2016 for multiple sclerosis (MS) but was withdrawn in 2018 due to severe safety concerns, including cases of inflammatory brain disorders.
What is Otelixizumab and what does it target?
an anti-CD3 monoclonal antibody that binds to CD3 and causes internalisation or shedding of the T cell CD3 complex making the T cell unresponsive. It can also induce T cell apoptosis, anergy and promotes immune regulation via TGF-beta production by macrophages (this helps with the induction of regulatory T cells and dampens down effector T cell activity
What condition has Otelixizumab been shown to help, and what side effects are associated with it?
It has been shown to maintain beta-cell function in Type 1 diabetes patients, though transient Epstein-Barr virus reactivation has been observed in some cases.
What is Abatacept and how does it work?
Abatacept is a CTLA-4Ig immunoglobulin fusion protein that blocks CD80/86 on antigen-presenting cells, preventing CD28 binding on T cells, and inhibits the second signal required for T cell activation.
what is CTLA4
the negative co inhibitory counterpart to CD28
What condition is Abatacept used to treat, and what are its limitations
It is licenced to treat rheumatoid arthritis (RA), where it slows disease progression and symptoms, but it is ineffective in some autoimmune diseases like lupus.
What is Natalizumab and what is its mechanism of action?
Natalizumab is an anti-VLA-4 monoclonal antibody that blocks VLA-4 (alpha-4 beta-1 integrin) on T cells from interacting with VCAM-1 on endothelial cells, preventing T cell migration into the CNS (e.g. brain and spinal cord in MS)
What is Natalizumab used for and what safety concerns are associated with it?
It is licensed for highly active relapsing-remitting multiple sclerosis (MS). Safety concerns include an increased risk of opportunistic infections and rare cases of PML due to JC virus reactivation. but the benefits to MS patients did outweigh the risks so it is still licensed
What two signals are required for T cell activation?
Signal 1 is the T cell receptor binding to peptide-MHC on APCs, and Signal 2 is CD28 binding to CD80/86 on APCs for co-stimulation.
How does CTLA-4 regulate T cell activity?
CTLA-4 competes with CD28 by binding CD80/86 on APCs, downregulating T cell activity and preventing activation.
How are animal models used to study MS therapies?
CD4 T cells with TCRs specific for myelin basic protein are labelled with green fluorescent protein and used to mimic autoimmune pathology in MS using Intravital two-photon microscopy to visualise the T cells in CNS blood vessels. mice were pre treated with anti - LFA1 (no effect) then anti-VLA4 which inhibits T cell crawling to compare the difference
What happens when anti-VLA-4 antibodies are introduced in animal model?
The antibodies block T cell crawling and transmigration across blood vessels, demonstrating the effectiveness of therapies like Natalizumab in reducing T cell migration into the CNS.
What do naive and central memory T cells (TN and TCM) do, and how do they move?
Naive and central memory T cells circulate between the blood and lymph nodes. They enter lymph nodes using the CCR7 receptor and exit (into the efferent lymph) when activated by sphingosine-1-phosphate (S1P), which binds to the S1P receptor-1 (S1P1).
What is S1P and S1P1?
S1P (sphingosine-1-phosphate) is a molecule that binds to its receptor S1P1 to allow T cells to exit lymph nodes.
What does fingolimod target?
Fingolimod binds to the S1P1 receptor on naive and central memory T cells, causing its internalisation of the receptor
What happens when the S1P1 receptor is internalised?
T cells become trapped in the lymph nodes and cannot migrate, reducing inflammation.
Why doesn’t fingolimod affect effector memory T cells?
Effector memory T cells do not rely on S1P1 or CCR7 for movement, so they are unaffected.
How does fingolimod help MS patients?
It traps naive and central memory T cells, preventing their migration into the CNS, where 90% of T cells in MS patients are central memory T cells.
What type of MS is fingolimod used for?
It is used for relapsing-remitting MS to reduce relapse frequency and severity.
By how much does fingolimod reduce peripheral lymphocytes?
It reduces peripheral lymphocyte counts by approximately 75% after one month.
What are the main risks of fingolimod treatment?
Increased risk of infection, cardiovascular events e,g, bradycardia atrioventricular block (most resolve within 24 hours) , increase in blood pressure over time (mild), increased risk of skin cancer and lymphoma, congenital deformities in pregnancy, and liver injury.
What monitoring is required for fingolimod?
Liver function tests and careful contraceptive measures for women.
What is glatiramer acetate, and what does it resemble?
It is a synthetic amino acid polymer (40-100 residues long of tyrosine, glytamate, alanine and lysine in defined ratios) that mimics myelin basic protein, a component of the myelin sheath targeted by self reactive T cells in MS.
How was glatiramer acetate developed
in animal model for MS, experimental autoimmune encephalomyelitis (EAE) and was licenced in 1996
What does glatiramer acetate do?
It reduces relapse rates by about a third and is thought to promote anti-inflammatory cytokines, dampen self-reactive T cells, and induce regulatory T cells.
How safe is glatiramer acetate?
It has a long safety record and is well tolerated, with minimal side effects.
What is the proposed mechanism of Glatiramer acetate (GA / copaxone) action
- encouraging anti inflammatory production by T cells
- antagonising MBP-specific cells inducing apoptosis
- Promoting FoxP3+ Tregs
What is the goal of antigen-specific immunotherapy?
To induce tolerance in self-reactive T cells by targeting them with specific antigens without harming normal immune responses so normal cancer immune surveillance and infection control remains in tact (very specific response
What does Dr Bronwen believe to be the gold standard for the treatment of auto immune diseases
antigen specific immunotherapy
Why is antigen-specific immunotherapy challenging?
It requires identifying the exact self-antigens involved in each autoimmune disease.
What type of antigens are used in antigen-specific immunotherapy?
Carefully selected disease relevant PEPTIDE antigens to avoid activating B cells, mast cells, or cytotoxic T cells ( as intact antigens can stimulate antibody secretion and activate mast cells / basophils by cross linking IgE ).
What is the nature of the antigen used to induce antigen specific tolerance in immunotherapy
- soluble peptides that mimic the naturally processed antigen when bound to MHC II and specifically target self reactive T cells for the induction of tolerance
- Bind to peptide receptive MHC class II
- Presented by Steady state immature DC
- dosing regimen is important to drive the tolerance induction
What are the key delivery methods for peptide antigens?
Artificial antigen-presenting cells, tolerogenic dendritic cells, liposomes/nanoparticles, or soluble synthetic peptides.
Why is dosing important in peptide therapy?
Slowly escalating doses are safer and help induce tolerance in self reactive T cells
What was the Tg4 experimental autoimmune encephalomyelitis (EAE) model done on mouse for multiple sclerosis
model is used to study multiple sclerosis in mice. It involves T cell receptor transgenic animals, where the majority of CD4 T cells recognise a specific myelin peptide (MBP Ac1-9), making them highly susceptible to CNS autoimmune diseases.
How does repetitive peptide dosing affect autoimmunity in the EAE mouse model?
Repetitive dosing of the specific myelin peptide induces antigen-specific tolerance in self-reactive CD4 T cells. This prevents the development of autoimmunity in 100% of treated animals.
Can peptide therapy treat autoimmunity after it has been induced in the EAE model?
Yes, peptide therapy can reduce the severity of autoimmune disease even after autoimmunity is induced in the EAE mouse model. It works both prophylactically and therapeutically.
What mechanisms underlie the immunological tolerance induced by peptide therapy?
Peptide therapy induces the upregulation of genes promoting immunological tolerance in self-reactive T cells, including:
Increased expression of IL-10 (immunoregulatory cytokine)
Upregulation of transcription factors regulating IL-10
Increased co-inhibitory molecules that dampen the immune response.
What was the ATX 1467 clinical trial
ATX-1467 is a cocktail of four myelin basic protein peptides developed for relapsing-remitting MS patients. Repetitive peptide dosing over 16 weeks reduced lesion load by 78%, indicating reduced inflammation and demyelination.
What happened after ATX 1467 dosing stopped?
Lesion load increased again, suggesting continuous dosing is needed for sustained benefits.
What were the safety outcomes of ATX-1467 in clinical trials?
ATX-1467 was safe and well-tolerated, with only minor adverse effects related to injection sites or underlying disease. There were no unexpected safety signals.
How does peptide therapy induce tolerance?
It promotes regulatory T cells (Tregs), increases IL-10 production, and suppresses the immune response via co-inhibitory molecules.
What is bystander suppression in the context of peptide immunotherapy?
when T regulatory cells specific for one antigen secrete immunoregulatory cytokines, such as IL-10, which suppress the immune response to other antigens.
How are monoclonal antibody names structured?
Random prefix
Target (e.g., immune-modulating, interleukin, toxin)
Species origin (e.g., -zu for human, -xi for chimeric)
“-mab” for monoclonal antibody
What is the “reverse vaccine” concept?
Delivering antigens to downregulate self-reactive T cells instead of activating them, unlike traditional vaccines.
What makes antigen-specific therapy advantageous?
It spares normal immune responses, preserving cancer surveillance and infection defences.
What are the challenges of intact antigen use?
t risks activating harmful immune responses, such as antibody secretion and cytotoxic T cell activation.
