Therapeutics Rheumat Witt Flashcard

Autograft
From one area of the body to another on the same individual
Isograft

AKA synograft

 

  • transplantation of cells, tissue, or organ
  • from one individual to another that is genetically identical

 

Allograft

  • graft or transplant from one individual to another that is genetically dissimilar and of the same species
  • family (non-identical — includes fraternal twins), friends, strangers, etc.
  • rejection occurs — this is what immunosuppressants are used for

Xenograft

  • between donor an recipient of different species
  • rejection occurs

Hyperacute Rejection

  • Occurs within minutes to hours of transplantation
  • Destruction of transplant is caused by preformed antibodies:

-Antibody dependent cellular toxicity

-Complemet

  • may be due to previous pregnancies or transplantations
  • may be due to blood type mismatch

No Pharmacological treatments — remove the organ

 

Acute Rejection

  • Cell mediated immunity caused by T-lymphocytes
  • Key initiating event in graft rejection is the direct activation of recipient’s CD4+ T cells with non-self MHC Class II molecules
  • Common type of rejection experienced by those for whom the tissue is a mismatch and do not receive adequate immunosupressive therapy
  • Begins after two days, leading to loss of the transplant function within weeks to months

Humoral Rejection

  • Antibody mediated against HLA (MHC) antigens on the donor vascular epithelium (IgG, complement)
  • Generally occurs during first 3 months
  • Increased fatality rate

Chronic Rejection

  • Occurs months or years after transplanted tissue has assumed normal function (major cause of late graft loss)
  • Caused by both antibody and cell-mediated immunity
  • Not reversible

Which cell-mediated pathway is critical in acute rejections?

The Th1 pathway

  • The Th1 pathway activates macrophages and leads to further proliferation of CD4+ T-cells
  • It also results in the release of pro-inflammatory cytokines such as IL-2
  • Release of IL-2 stimulates CD8+ T-cells, leading to proliferation of cytotoxic T-cells

;

Biochemical Pathway of CD4+ T-cell activation

Binding of MHC II to alpha and beta chain of CD4+ T cell receptor complex

;

Signal transduction by the CD3 molecule

;

[Ca2+]i increases

;

Calcineurin becomes activated

;

Calcineurin dephosphorylates NFAT

;

NFAT influences the transcription of IL-2 genes

;

IL-2 is produced and binds to mTOR, activating it

;

mTOR activation results in the transition of G1 to S

;

S to G2, then mitosis, resulting in proliferation of T-cells

Antilymphocyte Globulin (ATG)

  • A polyclonal antibody
  • Prepared by incoluating rabbits or horses with human lymphocytes
  • The horses and rabbits produce antibodies (IgG) against these lymphocytes and eventually are collected and purified
  • The purified IgG fraction contains antibodies directed against many cell surface molecules expressed on T-lymphocytes (CD2, CD3, CD4, CD8, etc.)

;

Antilymphocyte Serum (ALS)

  • A polyclonal antibody
  • Prepared by incoluating rabbits or horses with human lymphocytes
  • The horses and rabbits produce antibodies (IgG) against these lymphocytes and eventually are collected and purified
  • The purified IgG fraction contains antibodies directed against many cell surface molecules expressed on T-lymphocytes (CD2, CD3, CD4, CD8, etc.)

;

Problematic Effects of Polyclonal Antibodies

  • First dose reaction (febrile)
  • Antibodies can be made against polyclonal antibodies — this prohibits multiple dosing
  • There is variability from batch to batch in preparation potency and product properties

Monoclonal Antibody Nomenclature

Target

  • Tu = tumors
  • Li = immune system

Source

  • O = mouse
  • A = rat
  • Zu = human
  • Xi = chimeric

Mab = denotes monoclonal antibody

CD3

  • Part of the T-cell receptor complex
  • Transduces intracellular signals that result from engagement of TCR with antigen — results in increased [Ca2+]
  • Composed of δ, γ, and ε polypeptides
  • Does NOT bind to the antigen

Muromonab CD3 (OKT3): Description, MOA

  • A murine monoclonal antibody directed against the ε polypeptide of CD3 on human T-cells
  • Inhibits intracellular signal transduction resulting from the TCR interacting with non-self antigen
  • Antibody treatment induces rapid internalization of the T-cell receptor and prevent subsequent antigen recognition
  • Reduces function of remaining T cells

Muromonab CD3 (OKT3): Mechanism of Side Effects

  • When Muromonab initially binds to the TCR complex, it activates the T-cell resulting in cytokine release (TNFα, IL-2, IL-6, IFNγ) — the antibody is recognized and a foreign antigen and the T-cell responds as it should
  • Elaboration of these cytokines can result in sequestration of neutrophils in the lungs, causing pulmonary edema and distress — can be life-threatening
  • The body also produces antibodies against the foreign drug, since the mouse portion is highly antigenic

Alemtuzumab: MOA

  • Humanized monoclonal antibody
  • Targets CD52 — found on the surface of mature lymphocytes, but not on the stem cells from which they are derived
  • Primarily an anti-cancer drug
  • Used for bone marrow and kidney transplants

CD52

  • Augments CD3 mediated responses on CD4+ and CD8+ cells
  • Antigen found on:

– B cells

– T cells

– Macrophages

Prednisone: MOA and Actions in the body

  • Binds to intracellular GR, activates the GR, and GR forms a homodimer
  • Has inhibitory influences on gene transcription by NFAT
  • Decreases transcription of pro-inflammatory cytokines

 

  • Suppresses prostaglandin synthesis
  • Impairs monocyte and lymphocyte function
  • Decreases the number of circulating CD4+ T cells
  • Decreases transcription of pro-inflammatory cytokines

Basiliximab: MOA

  • Chimeric (Human-Mouse)
  • Binds to CD25
  • Inhibits IL-2 mediated activation and proliferation of T lymphocyte
  • Because it is humanized, does not trigger a strong human anti-mouse antibody (HAMA) response and does not produce first-dose reaction/cytokine release syndrome

Daclizumab: MOA

  • Human
  • Binds to CD25
  • Inhibits IL-2 mediated activation and proliferation of T lymphocyte
  • Because it is humanized, does not trigger a strong human anti-mouse antibody (HAMA) response and does not produce first-dose reaction/cytokine release syndrome

CD25

  • alpha chain of IL-2 receptor
  • only expressed in activated T-cells
  • important in the clonal expansion of activated T-cells

Sirolimus: MOA

  • Binds to immunophillin FKBP-12
  • The Sirolimus/FKBP12 complex inhibits mTOR
  • Cellular proliferation in response to IL-2 is inhibited

Everolimus: MOA

  • Binds to immunophillin FKBP-12
  • The Sirolimus/FKBP12 complex inhibits mTOR
  • Cellular proliferation in response to IL-2 is inhibited

Sirolimus: Side Effects
Impairs fibroblast growth factor — results in wound healing problems
Everolimus: Side Effects
Impairs fibroblast growth factor — results in wound healing problems
mTOR

  • Involved in cell cycle progression (G1 to S)
  • Increases translation of selected mRNAs that promote transition from G1 to S

Azathioprine: MOA

  • Prodrug of 6-mercaptopurine
  • HGPRT is enzyme responsible for generating active metabolites

TIMP

  • blocks purine synthesis completely in T-lymphocytes and B cells

6-Thioguanine

  • incorporated into replicating DNA
  • Halts replication

Mycophenolate mofetil: MOA

  • Prodrug
  • Converted to mycophenolic acid (MPA)
  • MPA is a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH) — the rate limiting step in converting inosine monophosphate to guanosine monophosphate
  • MPA end results — lymphocyte proliferation, antibody formation

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