Immunomodulatory Drugs Flashcards
What are the three T cell activation signals that are modified with immune modulatory drugs?
- TCR/MHC Activation
- CD28 (Tcell)/B7 (APC) Costimulatin
- Cytokine signalling:
IL-2 from Tcells to Tcell IL-2R for cell activation
What is Graft vs Host Disease?
Undesired immune reaction to organ/cell allogeneic transplantation:
- T cell driven immune response –> Donor-derived T cells recognize recipient tissues as foreign and attack
Direct Allorecognition:
Donor APCs migrate to a local lymph node and stimulate alloreactive recipient T cells
Indirect Allorecognition:
Recipient APCs process proteins and present peptides derived from the graft
What is the signal cascade for TCR/MHC-II activation?
MHC-II (From APC)+Antigen binds to TCR (from Tcell) with CD3+CD4+ complex
–> Binding of TCR with MHC leads to an influx of Ca++
–> Calcium is necesssary for Calcineurin function
–> Calcineurin is typically used to dephosphorylate NFAT, allowing NFAT to enter the nucleus and complex to become a transcription factor of cytokines (i.e. IL-2)
What is Cyclosporine A?
Calcineurin inhibitor
- Binds to cyclophilin and inhibits calcineurin from dephosphorylating NFAT
- Used to prevent acute rejection of solid organs
(kidney, liver, heart, etc.) as well as acute GVHD - Usually used in conjunction with corticosteroids
- Used for treatment of severe rheumatoid arthritis and psoriasis
What are the side effects of Cyclosporine A?
- ***nephrotoxicity**** - most critical
- Renal hypperfusion
- Arteriopathy
- Tubular atrophy
- Interstitial fibrosis
HTN
Hepatotoxicity
Increased risk of:
lymphoma
Infections
Convulsions
What is tacrolimus?
Calcineurin inhibitor
- Binds to FK binding protein, preventing calcineurin activation
- More potent than CsA
- Superior performace in preventing acute rejection of renal, heart-lung, and liver allografts
What are the side effects of tacrolimus?
Nephrotoxicity
Neurotoxicity
HTN
diabetes
malignant lymphoma
What is Sirolimus (rapamycin)?
mTOR inhibitor –> blocks effects of IL-2 on Tcells
- MOA: Inhibits mTOR complex 1, blocks IL-2 induced proteins synthesis
- Used to prevent renal allograft rejection
- *(as effective as cyclosporine A w/o nephrotoxicity)**
- Contraindicated for liver/lung transplant
What are the toxicities of Sirolimus?
anemia
thrombocytopenia
hyperlipidemia
What is the IL-2R signal cascade?
IL-2 binds to IL-2R on the surface of the Tcell
–> TOR is activated
–> Cyclin/CDK is activated
–> Activates cell cycle progression from G1 phase to S phase
What are the immunemodulators that interfere with the TCR cascade?
Cyclosporine A: Calcineurin inhibitor that binds to cyclophilin
_Tacrolimus: _ Calcineurin inhibitor that binds to FK binding protein
What is Mycophenolate Mofetil (MMF)?
Inhibitor of inosine monophosphate dehydrogenase (required for purine biosynthesis)
–> blocks cell cycle progression
- Useful in kidney/liver transplants in combination with CsA or Tacrolimus
- Hydrolyzed by liver esterases to MPA (the active inhibitor of IMD)
What is Azathioprine?
- *Purine analog metabolized to 6-mercaptopurine**
- disrupts de novo purine synthesis and inhibits DNA transcription
- Used in combination therapy (prednisone +/- CsA/Tacrolimus)
Side Effects:
GI distress
leukopenia
increased infections
What are the “1st line” DMARDs for RA?
1. Methotrexate (Same rationale as MMF; stops cell cycle)
Folic acid analogue –> dihydrofolate reductase inhibitor
Blocks nucleoside biosynthesis
2. Leflunamide
Prodrug whose active metabolite inhibits dihydroorate dehydrongenase (an essential enzyme for pyrimidine synthesis)
- *Also:**
- *Chloroquine** (perturbs lysosomal processing and antigen presentation –> decreased Tcell activation)
Penicillamine (metal chelator prevents IL-1 production and collagen maturation)
Sulfasalazine (Scavenger of ROS produced by neutrophils)
What kind of Antibodies end in:
- omab
- ximab
- zumab
- umab
-omab: mouse antibodies
-ximab: chimeric antibodies
-zumab: humanized antibodies
-umab: human antibodies
