T2-L5: Immunomodulation and Immunosuppression Flashcards
What is the definition of immunomodulation?
The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response.
A therapeutic effect of immunomodulation may lead to immunopotentiation, immunosuppression, or induction of immunological tolerance.
Give examples of fusion immunomodulator biologics?
- Adalimumab
- Infliximab
- Etanercept
- Cetrolizumab
For passive immunopotentation, give the following:
- Definition
- Issues
- Types
- Uses
- Definition - Transfer of specific, high-titre antibodies from donor to recipient. Provides immediate but transient protection.
- Issues: Risk of transmission of viruses and risk of serum sickness (type 3 hypersensitivity response).
- Types:
- Convalescent plasma - given plasma with high tire antibodies to someone suffering an acute infection e.g. as see in the COVID pandemic
- Pooled specific human immunoglobulin - richer preparation with many more active antibodies than the plasma
- Animal sera - antitoxins as antivenins e.g. toxins for snake bites - Uses: COVID-19, Hep B prophylaxis and treatment. Also botulism, VZV, diphtheria and snake bites.
For active immunopotentation, give the following:
- Definition
- Immunogenic material
- Issues
- Definition - To stimulate the development of a protective immune response and immunological memory.
- Immunologenic material -
• Weakened forms of pathogens
• Killed inactivated pathogens
• Purified materials (proteins, DNA, RNA) - recombinant vaccines generated by injecting DNA/RNA sequencing to stimulate the body to produce viral proteins so that you can generate an immune response
• Adjuvants - chemicals that can stimulate a type of immune repose. - Issues - Allergy to any vaccine component, limited uselessness in immunocompromised and delay on achieving protection -on average 2-4 weeks.
Give examples of replacement therapy that can be used in immune stimulation.
- Pooled human immunoglobulin (IV or SC)
• Used in Rx of antibody deficiency states - G-CSF/GM-CSF
• Small peptides that can be administered that act on bone marrow to increase production of mature neutrophils - γ-interferon
• Can be useful in treatment of certain intracellular infections (atypical mycobacteria), also used in chronic granulomatous disease and IL-12 deficiency. These stimulate macrophages and so help combat infections such as salmonella as these are found inside the cells and so macrophages are particularly important.
What is the action, uses and side effects of steroids?
Action:
• Decreased neutrophil margination
• Reduced production of inflammatory cytokines
• Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
• Lymphopenia
• Decreased T cells proliferation
• Reduced immunoglobulins production
Uses:
- Carbohydrate and lipid metabolism - leading to diabetes and hyperlipidaemia
- Reduced protein synthesis - poor wound healing
- Osteoporosis
- Glaucoma and cataracts
Psychotic complications
Side effects:
- Autoimmune diseases - CTD, vasculitis and RA
- Used at the beginning to induce remission and establish control
- Inflammatory disease such as Crohn’s, sarcoid, GCA/polymyalgia rheumatica
- Malignancies - at a big dose cause T cell death and so used in Lymphoma. Can be used to prevent adverse response associated with other therapies
Allograft rejection
What type of drugs are Azathioprine, cyclosporin and sirolimus?
Drugs that target lymphocytes.
Azathioprine - Anti-metabolite
Cyclosporin - Calcineurin inhibitor
Sirolimus - m-TOR inhibitors.
The other type is a IL-2 receptor monoclonal antibody such as Basiliziman.
What is the mode of action of Calcineurin inhibitors?
Cyclosporin is a naturally occurring compound found in fungus. It binds to the intracellular protein cyclophillin. Tacrolimus (FK506) binds to an intracellular protein FKB12.
The effects of this prevents activation of nuclear factor activation of T cells (NFAT). It therefore prevents transcription of cytokines such as IL2 and INF-gamma important for further T cell stimulation.
The effects of these are reversible. When you want to treat patients with autoimmune disease, or organ transplant etc. you want to modulate immune suppression to the point it is not too harmful but can dampen the response. You can therefore titrate the immunosuppression to achieve the desirable effect.
What is the effect on T cells of sirolimus?
Macrolide antibiotic - Also binds to FKBP12 but has different effects. It inhibits mammalian target of rapamycin (mTOR). The T cells cannot regress further than the initial stages of maturation. It arrests the T cell cycle at G1-S phase and so inhibits response to IL-2.
What are side effects of calcineurin and mTORs? What is there clinical use?
- Hypertension
- Hirsutism
- Nephrotoxicity
- Hepatotoxicity
- Lymphomas
- Opportunistic infections
- Neurotoxicity
- Multiple drug interactions (induce P450)
Clinical use:
- Allograft rejection
- Autoimmune disease treatment
- Prevention of some diseases
How do azathioprine and MMF work?
These are antimetabolites that interfere with DNA synthesis.
Azathioprine for example interferers with purine synthesis, it is a guanine anti-metabolite. Mycophenolate mofetil (MMF) prevents production of guanosine triphosphate. They therefore impair DNA production at B and T cells and prevent early stages of activated cells proliferation.
How do methotrexate and cyclophosphamide work?
- Methotrexate (MTX)
• Folate antagonists and interferers with DNA synthesis - Cyclophosphamide
• Cross-link DNA - stops replication in rapidly dividing cells
What is the side effects of cytotoxic drugs?
The T cells activated are the ones rapidly dividing. In autoimmune conditions, or preventing rejection, T cells rapidly activating are those directed against self-antigens or the organs. Using anti-metabolites means those affected more are those rapidly dividing. The auto-reacted T cells are targeted preferentially in theory. But this is not such a clear cut mechanism. They can also target other rapidly dividing cells and so you can predict the side effects of immune suppression by the tissues and organs that contain cells that are rapidly dividing e.g.
- Bone marrow suppression
- Gastric upset - these cells divide rapidly to protect against the acidic environment
- Hepatitis
- Susceptibility to infections
Specifically Cyclophosphamide can cause cystitis in certain individuals and MTX can cause pneumonitis.
What are the clinical uses of cytotoxic drugs?
- AZA/MMF - autoimmune diseases and allograft rejection
- MTX - RA, Psoriatic arthritis, Polymyositis, vasculitis and GvHD in BMT
- Cyclophosphamide- Vasculitis and SLE
Give examples of biologics.
- Anti-cytokines (TNF, IL6 and IL1)
- Anti-B cell therpaies
- Anti-T cell activation
- Anti-adhesion molecules
- Complement inhibitors
- Checkpoint inhibitors
What are the uses of Rituximab?
Chimeric monoclonal antibody against CD20 - B cell surface. Invented for diffuse large cell lymphoma in 97. It has many uses in:
· Lymphomas, leukaemia
· Transplant rejection
· Autoimmune disorders
In autoimmune disorders, it targets a specific proportion of B cells. Rituximab only binds to the population in the circulation - it does not affect those in the bone marrow or plasma cells that generate long loved antibodies. This means:
- You wipe out a B cell activation involved in immune response but allow the immune system to regenerate
- Allow long lived plasma cells to provide protection
What are uses of adoptive immunotherapy?
Therapies that include: - Bone marrow transplant (BMT) - Stem cell transplant (SCT) Uses include: • Immunodeficiencies (SCID) - curative therapy as you are replacing the immune system • Lymphomas and leukemias • Inherited metabolic disorders (osteopetrosis) • Autoimmune diseases
What are check point inhibitors?
Used in treatment of malignancies. During normal T cell activation, APC can either stimulate the immune cells by interaction with TCR and provide co-stimulator response. Tumour cells can however block this co-stimulatory response necessary for T cell activation, or express certain molecules such as PD-L1 which inhibits activation of T cells. There are monoclonal antibodies which interfere with these processes. Anti-CTLA-4 suppress CTLA-4 on the T cell preventing T cell inactivation.
Anti-PD-LA1 blocks PD-LA1 produced by T cells to reduce T cell activation. These are used in combination with conventional chemotherapy and showing promising results.
How can immunomodulators be used in allergy?
Treatments include:
• Immune suppressants
• Allergen specific immunotherapy:
Allergy specific immunotherapy is treatment whereby we inject an allergy to immune tolerance.
Indications: Used in allergic respiratory disease, such as rhinoconjutivitis, which are not controlled on maximum medical therapy and those who have life threatening anaphylaxis to insect therapy.
• Anti-IgE monoclonal therapy
• Anti-IL-5 monoclonal treatment
What is the use of Omalizumab and Mepolizumab?
Omalizumab
• Monoclonal antibody against IgE
• Used in Rx of asthma
• NICE approved for chronic urticaria and angioedema
• May cause severe systemic anaphylaxis but not anymore than a biological therapy
Mepolizumab • Monoclonal antibody against IL-5 (important cytokine that activates eosinophils) • Prevents eosinophil recruitment and activation • NICE approved for asthma
Give an example of anti-cytokines.
Anti-TNF
• First of the biologics to be successfully used in therapy of RA
• Used in a number of other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis)
• Caution: causes increased risk of TB as TNF is critical for activation of macrophages important in cleaning TB infection
Anti-IL-6 (Tocilizumab)
• Blocks IL-6 receptor
• Used in therapy of RA and AOSD (a type of inflammatory arthritis)
• May cause problems with control of serum lipids
Anti-IL-1
Used in treatment of AOSD and autoinflammatory syndromes. This is a very potent treatment.
