12 - Immunomodulation & suppression Flashcards
Immunomodulation definition
The act of manipulating the immune system using immunomodulatory drugs to achieve
a desired immune response
Immunomodulation definition
Medicinal products produced using molecular biology techniques including recombinant DNA technology
e.g. monoclonal antibodies + fusion bodies
Definition of passive immunisation
transfer of specific, high-titre antibody from donor to recipient. Provides immediate but transient protection
Passive immunisation problems
Risk of transmission of viruses
Serum sickness
Passive immunisation types
Pooled specific human Ig
Animal sera
Passive immunisation uses
Hep B prophylaxis and treatment
Botulism, VZV (pregnancy), diphtheria, snake bites
Active immunisation definition
To stimulate the development of a protective immune response and immunological memory
Active immunisation immunogenic material
Weakened form of pathogen
Killed inactivated pathogens
Purified materials (proteins, DNA)
Adjuvants
Active immunisation problems
Allergy to any vaccine component
Limited usefulness in immunocompromised
Delay in achieving protection
What stimulates immunosuppression?
Corticosteroids Cytotoxic agents Anti-proliferative agents DMARD's Biological DMARD's
Action of corticosteroids
Decreased neutrophil margination
Reduced production of inflammatory cytokines
Inhibition of phospholipase A2 (less arachidonic acid metabolite production)
Lymphopenia
Decreased T cells proliferation
Reduced immunoglobulins production
Corticosteroids - side effects
CHO and lipid metabolism - diabetes and hyperlipidaemia
Reduced protein synthesis - poor wound healing
Osteoporosis
Glaucoma and cataracts
Psychiatric complications
Corticosteroid - uses
Autoimmune disease
Inflammatory disease
Malignancies (lymphoma)
Allograft rejection
Drug targeting lymphocytes
Antimetabolites
Calcineurin inhibitors
M-TOR inhibitors
IL-2 receptor mABs
Antimetabolites e.g.
Azathioprine (used to treat Crohn’s)
Mycophenolate mofetil
Calcineurin inhibitors
Ciclosporin A
Tacrolimus
M-TOR inhibitors
Sirolimus
IL-2 receptor for mABs
Basiliximab
Daclizumab
Calcineurin inhibitors - how do they work
Bind to intracellular protein cyclophilin
Prevents activation of NFAT
Stops factors that stimulation cytokines
Reversible inhibition of T-cell activation, proliferation and clonal expansion
Sirolimus (aka rapamycin) what is it, how work
Macrolide antibiotic
Binds to FKBP12 but different effects
Inhibits mammalian target of rapamycin (mTOR)
Inhibits response to IL-2
Cell cycle arrest of T cells at G1-S phase
Calcineurin/mTOR - side effects
Hypertension Hirsutism Nephrotoxicity Hepatotoxicity Lymphomas Opportunistic infections Neurotoxicity Multiple drug interactions (induce P450)
Calcineurin - clinical use
Transplantation - allograft rejection
Autoimmune diseases
Antimetabolites - what do
Inhibit nucleotide (purine) synthesis
Antimetabolites - AZA
guanine anti-metabolite
Antimetabolites - MMF
Non-competitive inhibitor of IMPDH
Antimetabolites - T and B cell effects
Impaired DNA production
Prevents early stages of activated cell proliferation
Antimetabolites - MTX
Methotrexate
Folate antagonists
Antimetabolites - cyclophosphamide
Cross-link DNA target
Cytotoxic - side effects
Bone marrow suppression
Gastric upset
Hepatitis
Susceptibility to infections
Cyclophosphamide - cystatis
MTX - pneumonitis
Cytotoxics - clinical use for AZA/MMF
AZA/MMF - autoimmune diseases (SLE, vasculitis, IBD), allograft rejection
Cytotoxics - clinical use for MTX
MTX - RA, PsA, polymyositis, vasculitis, GvHD in BMT
Cytotoxics - clinical use for cyclophosamide
Vasculitis (Wagner’s, CSS)
SLE
Biological DMART’s
Anticytokines Anti-B cell therapies Anti-T cell activation Anti-adhesion molecules Complement inhibitors
Anticytokines - types
Anti-TNF
Anti-IL-6
Anti-IL-1
Anticytokines - anti-TNF
first therapy for RA
Also used in Crohn’s, psoriasis, ankylosing spondylitis
Caution: increased risk of TB
Anticytokines - anti-IL-6
Tocilizumab
Blocks IL-6 receptor
Used in therapy of RA and AOSD
May cause problems with control of serum lipids
Anticytokines - anti-IL-1
Used in AOSD and autoinflammatory syndromes
AOSD stands for?
Adult’s onset still’s disease
Rituximab what is it
Chimeric mAb against CD20-B cell surface
Rituximab uses
Lymphomas, leukaemias
Transplant rejection
Autoimmune disorders
Adoptive immunotherapy
BMT
SCT
BMT stands for
bone marrow transplant
SCT stands for
stem cell transplant
Adoptive immunotherapy uses
Immunodeficiencies (SCID)
Lymphomas & leukaemias
Inherited metabolic disorders (osteopetrosis)
Autoimmune disease
Immunomodulators - allergy
Immune suppressants
Allergen specific immunotherapy
Anti-IgE monoclonal therapy
Anti-IL-5 monoclonal treatment
Allergen specific immunotherapy - indications
Allergic rhino-conjunctivitis not controlled on max medical therapy
Anaphylaxis to insect venoms
Allergen specific immunotherapy - mechanisms
Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
Development of T reg cells and tolerance
Allergen specific immunotherapy - routes
SC or sublingual for aero-allergens
Allergen specific immunotherapy - side-affects
Localised and systemic allergic reactions
Omalizumab
mAb against IgE
Used in Rx of asthma
Also useful in Rx of chronic urticaria and angioedema
may cause severe systemic anaphylaxis
Mepolizumab
mAb against IL-5
prevents eosinophil recruitment and activation
limited effect on asthma
no clinical efficacy in hypereosinophilic syndrome
