Immunopharmacology Flashcards
what are the 3 main applications of immunosuppressive drugs?
1) suppression of rejection of transplanted organs
2) suppression of “graft-versus-host” disease (GVHD) which my arise from donor lymphocytes reacting against host
3) treat auto-immune diseases
Rheumatoid arthritis is an auto-immune disease primarily affecting the ________.
joints
Lupus is an auto-immune disease affecting ___________. It is characterized by a rash on the ___________.
multiple organs; cheeks
Ulcerative colitis is an auto-immune disease that causes ________ and ________ in the ________.
T cell infiltration; ulceration; colon
Psoriasis is an auto-immune disease that leads to ________ on the skin.
scaly patches
What are the 2 main phases of the immune response?
1) induction phase
2) effector phase
What occurs during the induction phase of the immune response? Be detailed.
general: antigen presentation –> activation and proliferation of naive Th0 cells into Th1 and Th2
detailed:
CD4 T helper cell presents antigen –> IL2 loop stimulated –> differentiate T helper cells
note:
Th1 differentiate into CD8 and more Th1 (T cells)
Th2 differentiate into B cells
What occurs during the effector phase?
T-cell mediated response: Th1 cells secrete cytokines and kill virally infected cells
B-cell mediated response: Th2 cells / B cells produce antibodies
Most drugs will influence:
a) the induction phase
b) the effector phase
a) the induction phase
What are the 5 key drug targets in the immune response?
1) inhibition of IL2 production/action
2) inhibition of cytokine gene expression (glucocorticoids)
3) cytotoxicity (killing immune cells or preventing proliferation)
4) inhibition of nucleic acid synthesis
5) blockage of various T cell surface receptors to prevent immune activation (e.g. antigen presentation machinery)
What are the 3 classes of immunosuppressive drugs?
1) calcineurin inhibitors
2) proliferation signal inhibitors
3) cytotoxic agents
What step of the immune response do calcineurin inhibitors target? Which specific pathway does it inhibit? Describe the pathway.
target step: activation of naive Th0 cells and clonal expansion of T cells
pathway: calcineurin-NFAT (nuclear factor of activated T cells) pathway
- activation of T cell receptor –> Ca2+ signal –> activation of calcineurin (phosphatase) and dephosphorylation of NFAT
- dephosphorylated NFAT migrates to nucleus –> expression of IL2 that is required to activate and proliferate T cells
Cyclosporine binds to ___________. (hint: “cyclo”)
cyclophilin
Tacrolimus binds to ________.
FKBP
cyclosporine is a:
a) calcineurin inhibitor
b) proliferation signal inhibitor
c) cytotoxic agent
d) monoclonal antibody
a) calcineurin inhibitor
tacrolimus is a:
a) calcineurin inhibitor
b) proliferation signal inhibitor
c) cytotoxic agent
d) monoclonal antibody
a) calcineurin inhibitor
Rapamycin (sirolimus) is a:
a) calcineurin inhibitor
b) proliferation signal inhibitor
c) cytotoxic agent
d) monoclonal antibody
b) proliferation signal inhibitor
Azathioprine is a:
a) calcineurin inhibitor
b) proliferation signal inhibitor
c) cytotoxic agent
d) monoclonal antibody
c) cytotoxic agent
Alemtuzumab is a:
a) calcineurin inhibitor
b) proliferation signal inhibitor
c) cytotoxic agent
d) monoclonal antibody
d) monoclonal antibody
Basiliximab is a:
a) calcineurin inhibitor
b) proliferation signal inhibitor
c) cytotoxic agent
d) monoclonal antibody
d) monoclonal antibody
What is the cyclosporine mechanism?
- inhibition of calcineurin by cyclophilin:cyclosporin complex
- this complex prevents NFAT-mediated gene transcription –> inhibit T cell maturation and proliferation
What is the tacrolimus mechanism?
- inhibition of calcineurin by the FKBP:tacrolimus complex
- prevents NFAT-mediated gene transcription –> inhibit T cell maturation and proliferation
What are 4 similarities between cyclosporine and tacrolimus?
1) calcineurin inhibitors
2) IL2 is a major signal affected
3) prevent NFAT-mediated gene transcription –> inhibit T cell maturation and proliferation
4) form complex with another compound
What step of the immune response do proliferation signal inhibitors (RAPAMYCIN/SIROLIMUS) target? Which specific pathway does it inhibit? What does this pathway signal for? Describe the mechanism of RAPAMYCIN?
target step: downstream signals of IL2 receptor activation
pathway: mTOR (mammalian target of rapamycin) pathway
- signals for cell growth and proliferation
RAPAMYCIN mechanism:
inhibit mTOR by FKBP:sirolimus complex –> suppress cellular responses to IL2 receptor activation
What is another name for rapamycin?
sirolimus
Rapamycin/sirolimus binds to __________. (hint: same as Tacrolimus)
FKBP
What is the mechanism of cytotoxic agents/azathioprine? (hint: precursor for 6-mercaptopurine used in chemotherapy)
- alkylating agent
- mechanism: azathioprine metabolized to 6-mercaptopurine (fraudulent nucleotide)
- lead to cross-linking of neighbouring bases –> interfere with DNA replication
- inhibit synthesis of nucleotides and interfere with cell division
______________ is the precursor for 6-mercaptopurine.
a) cyclosporine
b) basiliximab
c) rapamycin
d) azathioprine
d) azathioprine
describe the structure of an atibody.
- 2 heavy chains
- 2 light chains
- Fab region
- Fc region
The ____ region of an antibody determines antigen specificity.
Fab
The ____ region of an antibody determines the antibody class (e.g. IgG, IgA, IgM, etc.)
Fc
Humans use antibodies that are raised in other animals. Why might this be a problem? What is the solution?
problem: they are flagged by our immune system and rapidly degraded
solution: use chimeric or humanized versions of murine (mouse) monoclonal antibodies
What does murine mean?
mouse
“-umab” or “-zumab” indicates __________ antibodies.
a) humanized
b) chimeric
humanized
hint: Umab and hUmanized
“-imab” and “-ximab” indicate _________ antibodies.
a) humanized
b) chimeric
b) chimeric
Is Alemtuzumab a humanized or chimeric antibody? What is its mechanism?
- humanized
mechanism:
- IgG1 Fc domain recognized by phagocytic immune cells, complement and NK cells
- leads to cell death by LYSIS or PHAGOCYTOSIS
- KEY POINT: healthy and destructive T and B cells are destroyed
Is Basiliximab a humanized or chimeric antibody? What is its mechanism?
- chimeric
mechanism: IL2 antagonist
