Immunotherapeutics Flashcards
Define immunomodulation
The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response.
What are some possible effects of immunomodulation?
A therapeutic effect of immunomodulation may lead to immunopotentiation, immunosuppression, or induction of immunological tolerance.
What are some mechanisms of immunomodulation?
Immunization Replacement therapy Immune stimulants Immune suppressants Anti-inflammatory agents Allergen immunotherapy (desentization) Adoptive immunotherapy
What are biologics- immunomodulators?
Medicinal products produced using molecular biology techniques including recombinant DNA technology
What are the main classes of immunomodulators?
Substances that are (nearly) identical to the body’s own key signaling proteins
Monoclonal antibodies
Fusion proteins
What is immunopotentiation?
Immunization Active Passive Replacement therapies Immune stimulants
What is passive immunisation?
transfer of specific, high-titre antibody from donor to recipient. Provides immediate but transient protection
What are the risks of passive immunisation?
Risk of transmission of viruses
Serum sickness
What are the types of passive immunisation?
Pooled specific human immunoglobulin Animal sera (antitoxins an antivenins)
What are the uses of passive immunisation?
Hep B prophylaxis and treatment
Botulism, VZV (pregnancy), diphtheria, snake bites
Define active immunisation
To stimulate the development of a protective immune response and immunological memory
What is immunogenic material?
Weakened forms of pathogens
Killed inactivated pathogens
Purified materials (proteins, DNA)
Adjuvants
What are the problems with active immunisation
Allergy to any vaccine component
Limited usefulness in immunocompromised
Delay in achieving protection
What does G-CSF/GM-CSF
do?
Acts on bone marrow to increase production of mature neutrophils
What is α-interferon used for?
treatment of Hepatitis C
What is β-interferon used for?
therapy of MS
What is γ-interferon used for?
treatment of certain intracellular infections (atypical mycobacteria), also used in chronic granulomatous disease and IL-12 deficiency
What drugs cause immunosuppression?
Cortocosteroids Cytotoxic/ agents Anti-proliferative/activation agents DMARD’s Biologic DMARD’s
What is the action of corticosteroids?
Decreased neutrophil margination
Reduced production of inflammatory cytokines
Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
Lymphopenia
Decreased T cells 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 and cataracts Psychiatric complications
What are corticosteroids used for?
Autoimmune diseases CTD, vasculitis, RA Inflammatory diseases Crohn’s, sarcoid, GCA/polymyalgia rheumatica Malignancies Lymphoma Allograft rejection
What drugs target lymphocytes?
Antimetabolites
- Azathioprine (AZA)
- Mycophenolate mofetil (MMF)
Calcineurin inhibitors
- Ciclosporin A (CyA)
- Tacrolimus (FK506)
M-TOR inhibitors
- Sirolimus
IL-2 receptor mABs
- Basiliximab
- Daclizumab
How do caclineurin inhibitors work?
Prevents activation of NFAT
Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription
causing reversible inhibition of T-cell activation, proliferation and clonal expansion
How does sirolimus work?
Inhibits response to IL-2, causing cell cycle arrest at G1-S phase
What are the side effects of calcineurin?
Hypertension Hirsutism Nephrotoxicity Hepatotoxicity Lymphomas Opportunistic infections Neurotoxicity Multiple drug interactions (induce P450)
What are calcineurins used for?
Transplantation
- Allograft rejection
Autoimmune diseases
What do antimetabolites do?
Inhibit nucleotide (purine) synthesis, causing impaired DNA production which prevents the early stages of activated cells proliferation
What are the side effects of cytotoxics?
ALL Bone marrow suppression Gastric upset Hepatitis Susceptibility to infections Cylophosphamide Cystatis MTX pneumonitis
What are the clinical uses of cytotoxic drugs?
–AZA/MMF–
Autoimmune diseases (SLE, vasulitis, IBD)
Allograft rejection
–MTX–
RA, PsA, Polymyositis, vasculitis
GvHD in BMT
–Cyclophosphamide–
Vasculitis (Wagner’s, CSS)
SLE
What are biologic DMARD’s?
Anti-cytokines (TNF, IL-6 and IL-1) Anti-B cell therapies Anti-T cell activation Anti-adhesion molecules Complement inhibitors
What is anti-TNF?
anti-cytokine
First biologics to be successfully used in therapy of RA (5 different agents now licensed)
Used in a number of other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis)
Caution: increase risk of TB
What is Anti-IL-6 (Tocilizumab)?
anti-cytokine
Blocks IL-6 receptor
Used in therapy of RA and AOSD
May cause problems with control of serum lipids
What is Anti-IL-1?
anti-cytokine
3 different agents available (anakinra, rilonacept and canakinumab)
Used in treatment of AOSD and autoinflammatory syndromes
What is rituximab?
Chimeric mAb against CD20- B cell surface
Many uses:
Lymphomas, leukaemias
Transplant rejection
Autoimmune disorders
What is adoptive immunotherapy?
Bone marrow transplant (BMT)
Stem cell transplant (SCT)
Uses
- Immunodeficiencies (SCID)
- Lymphomas and leukemias
- Inherited metabolic disorders (osteopetrosis)
- Autoimmune diseases
What immunomodulators are used in allergy?
Immune suppressants
Allergen specific immunotherapy
Anti-IgE monoclonal therapy
Anti-IL-5 monoclonal treatment
What are the indications of allergen specific immunotherapy?
Allergic rhinoconjutivitis not controlled on maximum medical therapy
Anaphylaxis to insect venoms
What are the mechanisms of allergen specific immunotherapy?
Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
Development of T reg cells and tolerance
What is omalizumab?
mAb against IgE
Used in Rx of asthma
Also useful in Rx of chronic urticaria and angioedema
May cause severe systemic anaphylaxis
What is Mepolizumab?
mAb against IL-5
Prevents eosinophil recruitment and activation
Limited effect on asthma
No clinical efficacy in hypereosinophilic syndrome
