Immunosuppressants Flashcards
List the Clinical use of Immunosupressants
(1)Organ Transplant Rejection
kidney, liver, pancreas, heart, ……
(2) Graft-versus-Host Disease
bone marrow transplant
(3) Autoimmune Disorders
rheumatoid arthritis :: systemic lupus erythematosus
multiple sclerosis :: Crohn’s disease :: psoriasis
idiopathic thrombocytopenic purpura
hemolytic anemia
(4) Recalcitrant Inflammatory Diseases
severe asthma :: severe atopic dermatitis
Mechanism of Organ Trasplant Rejection
When there is antigen presenting cell in the graf, their antigens are presented and the CD4 helpert T cells and CD8 cytokine t cell read them
after that, they undergo clonal expansion and releave a lot cytokines.
Cytokines would then attract the B lymphocytes and attract the macrophages, which would all attack the transplanted organ,
this results in the organ rejection
List the Immunosupressant Drugs
Corticosteroids(Immunosuppressants in Clinical Use)
Cortisone
Antilymphocyte Ab
Azathioprine
Ciclosporin
OKT3 mAbs
Sirolimus
Mycophenolic Acid
Antithymocyte Ab
Fingolimod
Calcineurin Inhibitors: T Cell-Selective Immunosuppressants
Ciclosporin
mechannism of action of Calcineurine inhibitors
normally,
foreign antigen binds
ca2+ increase
ca activate calmodulin
calmodulinform complex with calclineurine and dephosphorylate nuclear factor of activated t cells
dephospohorylated NFTAC formed heterodimer with NFTAN and activate DNA
however when the drug binds to the CYCLOPHILIN,
Cyclophilin is a peptidyl-prolyl cis-trans isomerase (PPIase) but functions as a
Chaperone in immunosuppression
Cyclophilin complex binds & inhibits Calcineurin, a Ca++/Calmodulin-
dependent Ser/Thr phosphatase (PP2B)
Prevent dephosphorylation and nuclear translocation of transcription Factors:
NF-AT (Nuclear Factor of Activated T Cells)
Inhibits cytokine gene transcription & synthesis (e.g. IL-2, 3, 4, 6, TNFα, IFNγ)
Inhibits primarily T Cell proliferation, and B cells & CTL proliferation as well
what is ciclosporin
polypeptide antibiotic
(Beauveria nivea)
Efficacy of Ciclosporin
Efficacy: First T-cell selective immunosuppressant
↓ Rate of acute rejection and ↑ allograft survival
Little bone marrow suppression
Uses of ciclosporin
Uses: kidney, pancreas, liver and cardiac transplants
uveitis, rheumatoid arthritis, psoriasis
Side effect of cuclosporine
SE: Nephrotoxicity / Hyperglycemia/ Gum hyperplasia
Hyperlipidemia / Hypertension / Neurotoxicity
What is a mTOR Inhibitors
Sirolimus (Rapamycin)
Mechanism of action of Sirolimus
Sirolimus:FKBP Complex
Sirolimus:FKBP Complex binds & inhibits mTOR (mammalian Target of Rapamycin), a
Ser/Thr kinase
this cokmplex :
(1) inhibits activity of 70 kDa S6 kinase (p70S6K)
(2) activates repressor activity of 4E-BP1
(3) growth Arrest from G1 phase
Inhibits IL-2 cytokine-mediated proliferation of T & B cells
advantages of Sirolimus
Anti-proliferative & anti-angiogenic activities
what happens when Sirolimus + Ciclosporine
Sirolimus + Ciclosporine : useful combination but may impair renal function
Side effects of sirolimus
Hyperlipidemia / thrombocytopenia / hyperglycemia/ hypertension
What are the Cytotoxic Immunosuppressant
Azathioprine
Mycophenolate Mofetil (MMF)
conversion of drug Azathioprine
Azathioprine is converted to 6-mercaptopurine (6-MP)
6-MP → 6-methyl-MP → 6-thioguanine (6TG)
Immunosuppressive actions of azathioprine:
(1) Structural analog/antimetabolite: 6TG impedes DNA and RNA synthesis
(2) Inhibits de novo purine synthesis → ↓proliferation of lymphocytes
Side effects of azathioprine
bone marrow depression: leukopenia, anemia, thrombocytopenia, bleeding, GI
toxicity, neoplasia
What else is it effective for
Effective in renal transplant and various autoimmune disorders using triple therapy
(e.g. calcineurin inhibitor + steroid + azathioprine)
What is the conversion of Mycophenolate Mofetil (MMF)
MMF is converted to mycophenolic acid, the active metabolite
what does MMF inhibit
Inhibitor of de novo pathway of purine (guanosine nucleotide) synthesis
MOA: inhibition of inosine 5’-monophosphate dehydrogenase (IMPDH)
MPA preferentially inhibits type II (inducible) more than type I (resting) of IMPDH
More selective anti-proliferative effects for T /B cells
Less bone marrow depression and GI toxicity than azathioprine
Suppresses antibody formation by B cells
Inhibits recruitment of leukocytes to graft sites
Side effects of MMF
diarrhea / neutropenia (viral/fungal infections) / anemia / hypertension
What is Fingolimod
Sphingosine 1-Phosphate Receptor Agonist
indiacated for multiple sclerosis
what is Fingolimod converted
phosphorylated to active metabolite FTY720-P
Mechanism of action of Fingolimod
Five S1PR on lymphoid tissues: FTY720-P activates S1P1, 3, 4 & 5R
S1P1R activation leads to receptor downregulation to prevent lymphocyte egress from lymph
nodes, and decreases circulating auto-aggressive lymphocytes infiltration into the CNS
Long T1/2: ~ 8 days
Newer S1P receptor agonists: Siponimod and Ozanimod – selective for S1P1 & 5R
Side effects of Fingolimod
first-dose” bradycardia/heart block effects due to S1P1 activation in sinoatrial cells,
hypertension, increased liver enzymes, GI upset
what is polyclonal antibodies
Antibodies raised against human lymphocytes or thymocytes
Non-selective purified IgG targeting T and B lymphocytes, NK cells, and MHC class I and II
antigens, co-stimulator molecules, etc.
Polyclonal antibodies drugs
Lymphocyte Immune Globulin, Anti-Thymocyte Globulin
mechanism of actions of polyclonal antibodies
(1) opsonization and complement-dependent cytotoxicity
(2) antibody-dependent cell-mediated cytotoxicity
(3) depletion of T lymphocytes
(4) cross-link TCR leading to T cell anergy induction
side effect of Polyclonal antibodies
first dose effect: cytokine storm (fever, chill, hypotension)
thrombocytopenia / leukopenia / serum sickness / development of anti-IgG antibodies
MOnoclonal Antibodies what are they
Muromonab-CD3 (OKT3, Ortho-Kung-T cells-clone 3)
Murine monoclonal antibody
Directed against CD3-TCR complex
First Most selective for T lymphocytes marketed in 1986
T cell depletion / ↓ T cell activity
Side effect of Monoclonal Antibodies
Development of HAMA: preclude continuous use
Anaphylaxis and serum sickness
First dose “flu-like” syndrome: fever, headache, cytokine storm
↑ Risk of infection / malignancies
