Immunotherapeutics Flashcards
define immunomodulation
The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response.
what mechanisms can be used for immunomodulation
- Immunization
- Replacement therapy
- Immune stimulants
- Immune suppressants
- Anti-inflammatory agents
- Allergen immunotherapy (desentization)
- Adoptive immunotherapy
define immunomodulators.
medicinal products produced using molecular biology techniques including recombinant DNA technology, in order to modular the immune system,
What are the main classes of immunomodulators.
Monoclonal antibodies- made using specific technology and they target specific cell types.
fusion proteins- 2 proteins with different biological function.
Substances that are identical to body’s own signalling problems.
Give a example of an immunomodulator
TNF
define immunopotentiation
to encourage a immune response by administration of another product.
how is immunopotentiation carried out
immunisation
replacement therapies
immune stimulanats
define passive immunity
transfer of specific, high-titre antibody from donor to recipient. Provides immediate but transient protection
problems with passive immunity
Risk of transmission of viruses- as it is a blood product
Serum sickness- increased immunoglobulin, forms complex and activates complement.
uses of passive immunisation
Hep B prophylaxis and treatment
Botulism, VZV (pregnancy), diphtheria, snake bites
define active immunity
To stimulate the development of a protective immune response and immunological memory
what kinds of immune material are used in an active immunisation
weakened forms of the pathogen
killed inactivated pathogens
purified materials
components vaccines- e.g. bacterial cell wall.
adjuvants (substance added to vaccine to increase body’s immune response to it)
problems with active immunity
allergy to vaccine component
delay in protection
limited usefulness in the immunocompromised.
how is replacement therapy carried out
• Pooled human immunoglobulin (IV or SC)- plasma form lots of donors and therefore has lots of antibodies
how does immune stimulation take place (examples)
- G-CSF/GM-CSF – colony stimulating factor (specific to certain cells). Act on bone marrow to increase production of mature neutrophils.
- IL-2 (Stimulates T cell activation- rarely used).
- α-interferon (Main use in treatment of Hep C)
- β-interferon (Used in therapy of MS)
Names of drugs or molecules used in immunosuppression
- Cortocosteroids- majority
- Cytotoxic/ agents
- Anti-proliferative/activation agents
- DMARD’s
- Biologic DMARD’s
How do corticosteroids work
- Decreased neutrophil margination- so they don’t enter the tissue.
- Reduced production of inflammatory cytokines
- Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
- Lymphopenia
- Decreased T cells proliferation- increased doses toxic to T cells
- Reduced immunoglobulins production – make T cells less likely to respond to proliferation.
main side effects of corticosteroids.
• Carbohydrate and lipid metabolism – Diabetes – Hyperlipidaemia • Reduced protein synthesis – Poor wound healing • Osteoporosis • Glaucoma and cataracts • Psychiatric complications
Uses of corticosteorids.
• Autoimmune diseases
– CTD, vasculitis, RA
– Used as induction agent- short term and long term in a cocktail of drugs.
• Inflammatory diseases
– Crohn’s, sarcoid, GCA/polymyalgia rheumatica
• Malignancies
– Lymphoma- corticosteroid toxic to T or B cell so can treat B/T cell lymphoma.
• Allograft rejection – transplantation
Name the drugs used in T cel targeted immunosuppression
Anti-IL-2 receptor mAbs, CyA, Tacrolimus, Sirolimus, Azathioprine MMF.
What types of drugs target lymphocytes
Antimetabolites- Azathioprine, MMF Calcineurin inhibitors (Ciclosporin A, tACROLIMUS M-TOR inhibitors- sirolimus IL2 receptor mABs- Basilximab Daclizumab
What is the function of calcineurin inhibitors
prevent T cell activation
interfere with initial signals after T cell receptor activation
mode of action of CyA and effect on T cell
– Binds to intracellular protein cyclophilin.
– Prevents activation of NFAT
– Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription.
– Reversible inhibition of T-cell activation, proliferation and clonal expansion
mode of action tacrolimus and effect on T cell
– Binds to intracellular protein FKBP-12.
Prevents activation of NFAT
– Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription.
– Reversible inhibition of T-cell activation, proliferation and clonal expansion
mode os action sirolimus (rapamycin) and effect on T cell
• Mode of action
– Inhibits response to IL-2
• T cell effects
– Cell cycle arrest at G1-S phase
side effects of calcineurin and mTOR
- Hypertension
- Hirsutism
- Nephrotoxicity
- Hepatotoxicity
- Lymphomas
- Opportunistic infections
- Neurotoxicity
- Multiple drug interactions (induce P450)
clinical use of alcineurin and mTOR
transplantation- allograft rejection
autoimmune diseases.
How do antimetabolities- against T and B cells work
Inhibit nucleotide (purine) synthesis- needed in DNA synthesis. prevents T and B cell proliferation.
which base metabolite is AZA
guanine
MMF prevents the production of what
guanosine triphosphate.
Name a folate antagonist
methotrexate
Name a drug which cross links DNA
Cyclophosphamide
Side effects of antimetabolities.
– Bone marrow suppression
– Gastric upset
– Hepatitis
– Susceptibility to infections
Cytotoxic clinical use
AZA/MMF
– Autoimmune diseases (SLE, vasulitis, IBD)
– Allograft rejection
clinical use MTX
– RA, PsA, Polymyositis, vasculitis
– GvHD in BMT
clinical use of Cyclophosphamide
– Vasculitis (Wagner’s, CSS)
– SLE
Biologic DMARD’s use what types of immune manipulations
- Anti-cytokines (TNF, IL-6 and IL-1)
- Anti-B cell therapies
- Anti-T cell activation
- Anti-adhesion molecules
- Complement inhibitors
what drug was used to treat RA initially
Anti TNF
what conditions is Anti TNF used to treat
RA, Crohns, ankolysing spondylitis.
what conditions is Anti IL6 used to treat
RA, AOSD (adult onset stills disease)
what conditions is Anti IL1 used to treat
AOSD (adult onset stills disease)
Ritiximab is a monoclonal antibody against
CD20- B cell surface
what conditions is Ritiximab used to treat
lymphoma, leukaemia, transplant rejection
adoptive immunotherapy includes
- Bone marrow transplant (BMT)
* Stem cell transplant (SCT)
uses of adoptive immunotherapy.
– Immunodeficiencies (SCID)
– Lymphomas and leukemias
– Inherited metabolic disorders (osteopetrosis)
– Autoimmune diseases
immunotherapy can be provided for what specifically.
allergen
how does immunotherapy work
• Give allergen subcutaneous or sublingually over time and increase the dose slowly every time- over time tolerance will be induced via a specific
2 types of monoclonal antibodies
Omalizumab
Mepolizumab
what is omalizumab used for
• mAb against IgE- remove Ig E from mast and basophils.
what condition is omalizumab used for
asthma, chronic urticaria and angioedema
major side effect of omalizumab
systemic anaphylaxis
what is mepolizumab used for
- mAb against IL-5
* Prevents eosinophil recruitment and activation
how does immunmodulation work biochemically.
– Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
– Development of T reg cells and tolerance
Name 4 immunomodulators which are used in allergies
- Immune suppressants
- Allergen specific immunotherapy
- Anti-IgE monoclonal therapy
- Anti-IL-5 monoclonal treatment
