Module Two: Immunopharmacology Flashcards
Clinical signs of inflammation?
Heat Redness Pain Swelling Loss of function
What is the original cell that immune cells originate from?
Haematopoietic stem cell in bone marrow.
What lineages are responsible for infections?
Myelomonocytic family: monocytes, neutrophils
Lymphoid: T and B cells
IL-2 for T cell differentiation
IL-4 for B cell differentiation
What comprises the lymphoid tissues?
Nodes, thymus, spleen, adenoids, tonsils, gut associated lymphoid tissue
What is an antibody
Soluble protein specific for foreign molecules/ proteins which react with a specific antigen
What is the function of helper T cells?
Specific to foreign species but activity via activation of other molecules
Cytotoxic T cells?
In groups attack specific foreign species causing invading cell death or damage to cells that are hiding invaders
Bone marrow
B cells produce specific antibody which reacts with specific antigen - antibody mediated immunity
Immunity and inflammation arise due to:
Infections, foreign material, tissue injury, autoimmunity
Reasons to suppress acquired immunity?
Prevention of rejection in organ transplantation
Treatment of autoimmune disease
Treatment of severe allergy
What presents antigen?
Antigen presenting cell - forms an MHC
How is variability generated?
Via gene rearrangement during clonal selection in the thymus
What are the three steps of clonal expansion?
Association of TCR and MHC
Cell-cell signalling interactions - surface secreted proteins
T lymphocyte autocrine signalling - interleukin IL2, a mitotic stimulus which interacts with IL2 receptor causing mitogenesis
What drugs prevent TCR signalling for IL-2 gene transcription?
Cyclosporine, tacrolimus, glucocorticoids
What drugs increase IL-2 mRNA degradation?
Glucocorticoids
What drugs prevent mitogenic response to IL-2R stimulation?
Sirolimus, everolimus, mycophenolate
What drugs prevent activation of T-Cell via TCR?
Anti CD3 antibody
What area regulates gene transcription?
Area upstream (5’) of the coding region - promoter region
Activation of TCR causes
Downstream activation of receptor associated tyrosine kinases (zap-70, lck, fyn) which in turn activates phospholipase Cgamma
What causes calcium release from the endoplasmic reticulum?
Inositol tri phosphate
What is the function of calcineurin?
Activate by calcium release, calcineurin dephosphorylates NF-AT and Oct which allows translocation into the nucleus - acting as a TF and binding to a particular gene sequence in the promoter region
Activation of the surface receptor in NF-kappaB signalling leads to:
Phosphorylation of serine 32 and 36 of I-KB resulting in the degredation of the I-KB subunit from the timeric complex
NF-Kappa B signalling ultimately results in:
Increased IL2 gene transcription
GC act as what
RNA-binding protein which binds to the AU rich regions => accelerating mRNA decay
Normal function of mTOR
Phosphorylates p27 which results in the degredation of it in late phase G1 - releases CDK2/cyclin E complex resulting in the transition from G1 to S phase
mTOR targets (phosphorylates) what two proteins?
EIF-4E-BP1 -release of EIF-4E
P70s6 kinase - formation of ribosome via 40-S and 60-S
Cons of anti-CD3
Requires IV dosing
Very effective- affects entire immune system resulting in decreased immunity
What is CD3
Protein of TCR which contributes to signalling
How are cyclosporin, tacrolimus, sirolimus and everolimus eliminated?
CPY34A
How is mycophenolate eliminated .
Glucoronidated (phase II) in the liver - excreted into bile the. Reabsorbed and renally excreted
How to improve the risk benefit ratio
Multiple drug targets
Optimising tissue exposure with TDM
