Immunotherapeutics Flashcards
Define immunomodulation
The act of manipulating the immune system using immunomodulatory drugs to achieve a desired response
What may a therapeutic effect of immunomodulation lead to?
- immunosuppression
- immunopotentiation
- induction of immunological tolerance
What are mechanisms of immumodulation?
- Immunisation
- Replacement therapy
- Immune stimulants
- Immune suppressants
- Anti-inflammatory agents
- Allergen immunotherapy (desensitisation)
- Adoptive immunotherapy
What are biological immunomodulators?
Medicinal products produced using molecular biology techniques including recombinant DNA technology
What are the main classes of immunomodulators?
- Substances (nearly) identical to the body’s own key signalling proteins
- Fusion proteins
- Monoclonal antibodies
What are ways to achieve immunopotentiation?
- Immunisation (active/passive)
- Replacement therapies
- Immune stimulants
Describe passive immunisation
- Transfer of specific, high-titre antibody from donor to recipient
- Provides immediate but transient protection
- Used for Hep B, Botulism, VZV, snake bites, diphtheria
- Problems: serum sickness, risk of transmission of viruses
- Types: Animal sera, pooled specific human immunoglobulin
Describe active immunisation
- Stimulate development of a protective immune response & memory
- Weakened/killed/inactivated pathogens
- Purified materials (DNA, proteins)
- Adjuvants
- Problems: allergy to vaccine, delay in achieving protection, limited usefulness in immunocompromised
What are replacement therapies?
- Pooled human immunoglobulin
- G-CSF/GM-CSF
- IL-2
- α-interferon
- β-interferon
- γ-interferon
How can immunosuppression be achieved?
- Corticosteroids
- Cytotoxic/agents
- Anti-proliferative/activation agents
- DMARDs
- Biologic DMARDs
How do corticosteroids work?
- Decreased neutrophil margination
- Reduced production of inflammation cytokines
- Inhibition phospholipase A2
- Lymphopenia
- Decreased T cell proliferation
- Reduced immunoglobulins production
What are the side effects of corticosteroids?
- Carbohydrate and lipid metabolism (diabetes, hyperlipidaemia)
- Reduced protein synthesis (poor wound healing)
- Osteoporosis
- Glaucoma & cataracts
- Psychiatric complications
What are the uses of corticosteroids?
- Autoimmune diseases (CTD, RA, vasculitis)
- Inflammatory diseases (Crohn’s, sarcoid, GCA)
- Malignancies (lymphoma)
- Allograft rejection
What drugs are used to target lymphocytes?
- Antimetabolites (Azathioprine)
- Calcineurin inhibitors (Ciclosporin A)
- M-TOR
- IL-2 receptor mABs
Describe Calcineurin inhibitors
- CyA=Binds to intracellular protein cyclophilin
- Tacrolimus=Binds to intracellular protein FKBP-12
- Prevents activation of NFAT
- Factors which stimulate cytokines gene transcription
- Reversible inhibition of T-cell activation, proliferation & clonal expansion
- Transplantation (allograft rejection), autoimmune diseases
Describe Sirolimus
- AKA rapamycin
- Inhibits response to IL-2
- Cell cycle arrest at G1-S phase
- Macrolide antibiotic also binds to FKBP12 but different effects, inhibits mammalian target of rapamycin
What are the side effects of Calcineurin/mTOR
- Hypertension
- Hirsutism
- Nephrotoxicity
- Hepatotoxicity
- Lymphomas
- Opportunistic infections
- Neurotoxicity
- Multiple drug interactions (induce P450)
Describe antimetabolites
- Inhibit nucleotide (purine) synthesis
- AZA= Guanine anti-metabolite, rapidly converted to 6-mercaptopurine
- MMF= non-competitive inhibitors of IMPDH, prevents production of guanosine triphosphate
- Impaired DNA production, prevents early stages of activated cells proliferation in T & B cells
What are other antimetabolites & cytotoxic drugs?
- Methotrexate= folate antagonist
- Cyclophosphamdie=cross-link DNA
What are the side effects of cytotoxics?
- Bone marrow suppression
- Gastric upset
- Hepatits
- Susceptibility to infections
- MTX= pneumonitis
- Cyclophosphamide= Cystitis
What are the clinical uses of cytotoxic?
- AZA/MMF= autoimmune diseases, allograft rejetion
- MTX= Polymyositis, vasculitis, RA, PsA, GvHD in BMT
- Cyclophosphamide= SLE, vasculitis
What are biologic DMARD’s
- Anti-cytokines (TNF, IL-6, IL-1)
- Anti-B cell therapies
- Anti-T cell activation
- Anti-adhesion molecules
- Complement inhibitors
Describe anti-cytokines
- Anti-TNF= inc risk of TBused in inflammatory conditions- RA, Crohn’s, ankylosing spondylitis, psoriasis
- Anti-IL-6= Blocks IL-6 receptors, used in RA & AOSD therapy, may cause problems with control of serum lipids
- Anti-IL-1= used in treatment of AOSD 7 auto inflammatory syndromes
Describe Rituximab
- Chimeric mAb against CD20 B cell surface
- Autoimmune disorders, transplant rejection, lymphomas, leukaemias
- Treatment of chemotherapy resistant DLCL
What are the uses of adoptive immunotherapy?
- Immunodeficiencies (SCID)
- Lymphomas & leukaemias
- Autoimmune diseases
- Inherited metabolic disorders (osteopetrosis)
What are types of adoptive immunotherapy?
- Bone marrow transplant
- Stem cell transplant
What immunomodulators can be used in allergies?
- Immune suppressants
- Allergen specific immunotherapy
- Anti-IgE monoclonal therapy
- Anti-IL-5 monoclonal treatment
What are the indications, side-effects, routes and mechanism for allergen specific immunotherapy?
- M= Switching of immune response from Th2 to Th1
- S= localised & systemic allergic reactions
- R= SC/sublingual for aero-allergens
- I=allergic rhinoconjutivitits not controlled on max medical therapy, anaphylaxis to insect venoms
Describe Omalizumab
- mAb against IgE
- May cause severe systemic anaphylaxis
- Used in asthma & chronic urticaria & angioedema
Describe Mepolizumab
- mAb against IL-5
- Prevents eosinophil recruitment & activation
- Limited effect on asthma
- No clinical efficacy in hypereosinophilic syndrome
