Pharm-Immunosupressants

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T Cell Suppressants

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Mechanism: either block the calcineurin (NFAT) pathway or the PKC pathway of gene expression

Cyclosporine A(Sandimmune)
Tacrolimus (Prograf)
Sirolimus (Rapamune/rapamycin)
Abatacept (Orencia)

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Cyclosporine A
(Sandimmune)

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T cell suppressant

calcineurin inhibitor (at an intracellular receptor cyclophilin)- blocks the activation of T cells via blocking NFAT gene expression

Side Effects- renal, HTN, overgrowth of gum tissues

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Tacrolimus (Prograf)- FK506

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T cell Suppressant

calcineurin inhibitor (by binding a different intracellular receptor FKBP12)- blocks the activation of T cells via blocking NFAT gene expression

Side Effects- renal, HTN, overgrowth of gum tissues

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Sirolimus (Rapamune/ rapamycin)

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T-Cell Suppressant

binds FKBP12 (like Tacrolimus) but acts as an mTOR inhibitor to decreases DNA synthesis and cell proliferation in response to cytokines binding their receptors-interrupts cytokine signaling in B- and T-cells.

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Abatacept (Orencia)

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T- cell suppressor- but used for rheumatoid arthritis, not for organ transplantation

a homologue of CD28- binds CD80 or CD86 to interrupt the costimulatory signal and block T-cell activation- results in T-cell Anergy

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Antibody Reagents

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Uses-
1. Prior to transplantation to deplete certain cell populations that could mount a rejection response to a transplanted organ (Atgam, OKT3)
2. Acute rejection in somebody already immunosuppressed on the triple regimen (Daclizumab)
3. To prevent hemolytic disease of the newborn (RhoGAM)


Antithymocyte globulin (Atgam)
Muromonab-CD3 (OKT3)
Daclizumab (Zenapax)
Rho(D)Ig (RhoGAM)

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Antithymocyte globulin (Atgam)

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Antibody derived from horses injected with human lymphocytes- purified IgG is isolated and injected into the patient to deplete T cells very rapidly

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Muromonab-CD3 (OKT3)

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Mouse monoclonal antibody that specifically targets the CD3 molecule on the helper T cell- as a big molecule, it can prevent interaction between helper T cells and APCs, but most importantly induces lysis of helper T cells

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Daclizumab (Zenapax)

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Antibody against the IL-2 receptor thereby blocking IL-2 from meeting its target on the CD8 cell- blocks downstream signaling.

Used for acute rejection episodes

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Rho(D)Ig (RhoGAM)

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Human product isolated from the serum of people with antibodies against the Rh antigen- given to Rh- women during pregnancy to prevent sensitization- does not cause lysis of those cells, just coats them to block their interaction with APCs

Used to prevent Hemolytic disease of newborn (+ kid with - mom)

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Cytotoxic Drugs

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interfere with the metabolism of nucleic acids- prevents clonal expansion of T and B cells

Mycophenolate mofetil (Celicept)
Azathioprine(Imuran)

also used (at higher doses) in cancer chemotherapy to kill rapidly dividing cells

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Azathioprine (Imuran)

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Cytotoxic

a pro-drug and is metabolized to mercaptopurine- Its metabolite is incorporated into the DNA strand during replication- it is bulky and stalls the DNA polymerase to interrupt chain elongation

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Mycophenolate mofetil (Celicept)

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Cytotoxic

a pro-drug that is metabolized to mycophenolic acid- the enzyme (IMP dehydrogenase) inhibitor that prevents the production of one of the nucleotides vital to DNA synthesis.
*Lymphocytes are more reliant on the de novo pathway than they are on the salvage pathway- drug specificity for immune cells over other rapidly proliferating cells

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Glucocorticoids

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multiple sites of action via binding of steroid receptors to initiate transcription of I_B (the inhibitory subunit of NF-_B):
1. Prevent lymphocyte trafficking by blocking adhesion
2. Inhibit T cell proliferation
3. Inhibit expression of cytokines
4. Inhibit macrophage and lymphocyte function

Prednisone(Prednisolone)
Methylprednisolone

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Methylprednisolone

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Glucocorticoid

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Prednisone (Prednisolone)

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Glucocorticoid

prevents lymphocyte tracking by blocking the adhesion of lymphocytes to the endothelium in order to leave the circulatory system

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Risks of long term immunosupression

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Immediate risk of infection

Long-term risk of malignancy

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Organ transplants regimen

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triple regimen:
T-cell suppressant
a cytotoxic drug
a glucocorticoid

antibody agents are used pre-transplant to prepare the immune system