L12. Immunosuppression Flashcards
glucocorticoid receptor agonists
prednisone, hydrocortisone, dexamethasone
prednisone. hydrocortisone, dexamethasone
Glucocorticoids leads to increased transcription of anti-inflammatory genes and decrease transcription of pro-inflammatory drugs (IL-1, IL-2, IL-6)
Net result of glucocorticoids:
- Decrease in immune cell signaling
- Decrease proliferation
- Immunosuppression
- Reduced inflammation
- Glucocorticoids are used when there is:
Adrenal insufficiency
Suppression of allergic
Inflammation
Autoimmune disorder
Asthma
To prevent acute transplant rejection and to treat graft vs host diseas
cytotoxic cells
> target cell proliferation (not selective)
- cyclophosphamide
- azathioprine
- mycophenolate motefil
- methotrexate
cyclophosphamide
> cytotoxic
- DNA alkylating agent
- Bivalent compound with 2 active chloroethyl groups that can cross link DNA → it is hard to repair these crosslinks
- Anti-cancer drug and immunosuppressant
Covalently binds DNA
- irreversible until NER
- produces INTERSTRAND DNA crosslinks
azathioprine
> cytotoxic
- Purine analog
- Gets metabolized into 6-mercaptopurine in the body
- 6-mercaptopurine resembles a purine except for its sulfhydryl group
- 6-mercaptopurine works by inhibiting purine synthesis in immune cells to block DNA or RNA synthesis
- 6-mercaptopurine ALONE is used as an anti-cancer drug
- Azathioprine is used as the precursor drug of 6-mercaptopurine for immunosuppression
mycophenolate motefil (MMF)
> cytotoxic
- More specific as an immunosuppressive drug
- Inhibits conversion of inosine phosphate to guanine phosphate IMP → GMP by inhibiting the enzyme that catalyzes this conversion which is inosine monophosphate dehydrogenase
- Blocks de novo synthesis of purine
- T and B cells depend on de novo synthesis rather than salvage pathways → that’s why we have a more specific effect against T and B cells in the body with MMF
methotrexate
- Folic acid is a methyl donor in thymidylate synthesis which exists in the form of THF inside the body
- Methotrexate is a folic acid analog and it blocks DHF reductase and thymidylate synthase which results in blocking THF production in the body
- Net result: starving cells from thymidine
T cell targets
- Cyclosporine
- Tacrolimus
- Sirolimus
cyclosporine and tacrolimus
> T- cell targets - Calcineurin inhibitors
- Large complex molecules
- In the T cell, an increase in Ca2+ activates calcineurin
- Calcineurin is a phosphatase that dephosphorylates transcription factor NFAT to allow it to translocate to the nucleus and bind DNA
- Activated NFAT increases transcription of cytokine genes especially IL-2
SO when blocking calcineurin we would reduce IL-2 transcription
- Cyclosporine binds cyclophilin and Tacrolimus binds FKBP which both bind calcineurin preventing it from activating NFAT and therefore preventing entry to the nucleus
Net response of calcineurin inhibitors: blocking T cell activation and blocking IL-2 synthesis
sirolimus
> T-cell targets
- Binds mTOR which has the effect of blocking cell cycle progression
- Blocking mTOR decreases the activity of Cdk2
- Decreasing the activity of Cdk2 blocks the progression of cells from G1 into S phase of the cell cycle
Sirolimus blocks action of IL-2
polyclonal antibody
- least selective approach
- anti-thymocyte globulin
- VERY helpful in organ transplantation bc it prevents graft rejection since it rapidly kills peripheral T cells/lymphocytes
monoclonal antibodies
- more specific
- CDR (complementarity determining region) of the antibody specifically recognizes a particular protein or molecule
4 types of mabs:
- human (-umab): lowest rejection risk
- murine (-momab): entirely human antibodies OR mouse antibodies / highest rejection risk
- chimeric (-ximab): both human and mouse antibody components
- humanized (-zumab): mouse CDR but the rest is human
muromonab (OTK3)
- murine Monoclonal antibody
- anti-CD3
- Binds T cell receptor CD3 which induces internalization
- Blocks antigen recognition
- Depletes Cd3+ cells
Used to reverse acute allograft rejection - No longer on the market because it’s a murine monoclonal antibody which causes side effects
basiliximab
- mAB
- Humanized anti-IL-2 receptor alpha (CD25)
- Specifically interacts with CD25 which is one of the protein components of the IL-2 receptor
- By targeting CD25, the interaction between IL-2 and IL-2 receptor will be blocked - SO blocks IL-2 mediated T cell activation and decreases proliferation
- Used with calcineurin inhibitors to prevent acute organ draft
belatacept
- fusion protein
- Binds CD80/86 on APCs to block co-stimulation of T cell and prevent T cell activation
infliximab
- Chimeric monoclonal antibody
Anti-TNF - Blocks signaling of tumor necrosis factor (TNF) which is involved in inflammatory responses + autoimmune disease like Crohn’s and Rheumatoid arthritis
- TNF interacts with TNF receptors causing a cascade of events that leads to apoptosis and inflammation
- Infliximab targets inflammatory responses
fingolimod
- Sphingosine 1 phosphate (S1P) receptor modulator
- Used to target Multiple Sclerosis
- Decreases sequestration of lymphocytes into lymph nodes pushing them away from circulation
- Prevents from amplifying the immune system
how to treat autoimmune diseases:
- first line: glucocorticoids such as prednisone and dexamethasone
- then use fewer doses of anti-proliferating drugs such as methotrexate and azathioprine than in cancer tx
- keep on low doses of methotrexate for a long time
- to have a more selective approach use mabs such as anti-TNF infliximab and IL-2 receptor antagonist basiliximab
how to treat isoimmune disease
Block initial immune response when the mother’s body first sees Rh+ cells by administering the antibody to the mother → antibody makes sure that the immune system does not see the Rh antigen
Give a high concentration to the mother at 28 weeks of gestation and/or within 72 hours of the birth of the 1st baby
organ transplantation treatment:
prednisone + tacrolimus + mycophenolate motefil (MMF)
prevention of cell proliferation in coronary infract
use stent with sirolimus
