L16 - immunotherapy Flashcards
What are conventional immunosuppressive drugs?
Corticosteroids
Cytotoxic drugs
Cyclosporin A
Rapmycin
What do corticosteroids do?
Inhibit inflammation
What do cytotoxic drugs do?
interfere with DNA synthesis - kill immune cells
What does cyclosporin A do?
suppresses IL-2 and T-cell proliferation - inhibit NFAT
What does Rapmycin do?
inhibits mTOR pathway - cell proliferation. translation & autophagy
Define immunotherapy?
Treating disease via immune modulation (activation, suppression, skewing)
Types of immunotherapy?
Soluble mediators
Antibody therapy
Cell based
Skewing/suppression
What are the soluble mediators used in immunotherapy?
Recombinant cytokines
Cytokine antagonists
Adjuvants
Miscellaneous
What are recombinant cytokines?
treat neutropenia in cancer patients & BM donors
PEGylated IFNa
IFNy treated CGD
What are cytokine antagonists?
target autoinflammatory disease and Muckle Wells Syndrome
Etanercept - recombinant TNFa receptor-fusion protein
Therapeutic uses of monoclonal antibodies?
Rheumatoid arthritis, Crohn’s = Infliximab, Efalizumab
B-cell leukaemia = Rituximab
Breast cancer = Herceptin/Trastuzumab
What are problems with monoclonal antibody therapy?
Repeat doses often immunogenic - neutralise anti-antibody antibodies
suffix -Omab?
Fully mouse
suffix -Ximab?
Chimeric
suffis -Zumab?
Humanised
Suffix -Umab?
Fully human
What do adjuvants do?
enhance immune response and the quality of response
physically link antigens to adjuvants
How can conjugated adjuvants enhance/skew immune response?
antigen linked to PAMP - will engage signalling via PRR
mature in phagosome presenting peptides on surface to T helper cells
allergen without adjuvant = Th2 (bad for allergens)
allergen with adjuvant = Th1
What are IgE mediated allergies?
activate mast cell degranulation - inflammation and tissue damage
Diff between anti-histamine and immunotherapies for treatment?
antihistamine treats symptoms
immunotherpaies change Th2 to Th1/T reg response
What is Skewing therapy for suppressing IgE response?
CpG, TLR4 agonists + allergen = Th1 (IgG) response
What is tolerance therapy for suppressing IgE response?
increase dosage - increase Treg
SLIT/SCIT may be used
mutate allergens so presented by DCs in different way = tolerogenic response
What are Anti-IgE antibodies?
Omalizumab
binds to free IgE
decreases expression of high-affinity receptors
Decreases mediator release
Decreases allergic inflammation
How can the Th2 response be a good thing?
many autoimmune/ auto-inflammatory are caused by Th1/Th17
e.g. IBS, Type 1 diabetes, MS, Rheumatoid arthritis
What can skew the immune system away from a Th1 response?
Helminth
DC-mediated immune skewing
How can the immune system be suppressed by tolerogenic DC therapy?
DCs crucial for establishing appropriate response
correct growth factor
How can innapropriate response to transplantation be prevented?
corticosteroids - long term immunosuppressive
Immune induction therapy - induce T cell unresponsiveness - reset tolerogenic mechanisms
How is immunotherapy used in cancer?
monoclonal antibodies, soluble mediators
imiquimod - TLR 7/8 agonist
Therapeutic strategies to overcome tumour suppression?
Activate T cells
Blockade of inhibitory receptor
super T cells
upregulate MHCI IFN-y treatment
What is a dendritic cell vaccination?
pulse patients DCs with cancer antigen plus adjuvant then re inject
antigen presentation and activation of tumour specific CD8 T cells
What are “super” T cells/CAR-T therapy?
change extracellular domain to have antibody on outside
intracellular domain has multiple activating domains
boost T cel response
T cells can recognise lipids and carbs - not normally recognise
What is host-directed therapy for infectious disease (viral)?
Target host response rather than pathogen
e.g.
IFN therapies against viral infection
target host-dependent life cycle
HIV - alter conformation of CCR5 = no entry
microRNA-122 host factor - increases HCV
What is host-directed therapy for infectious disease (bacterial)?
Target Mtb in macrophages
fungal - statins, imiquimod
When immunotherapy goes wrong?
TGN1412 activated T-cells - huge inflammation
