AKA synograft

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

• 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

• between donor an recipient of different species
• rejection occurs

• 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

• 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

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

• 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

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

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

• 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.)

• 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.)

• 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

Target

• Tu = tumors
• Li = immune system

Source

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

Mab = denotes monoclonal antibody

• 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

• 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

• 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

• 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

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

- B cells

- T cells

- Macrophages

• 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

• 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

• 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

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

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

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

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

• 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

• 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