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General principles of immunosuppresion

primary immune response can be more easily and effectively and affected than secondary immune responses

immunosuppressive agents do not affect all immune responses in the same manner

therapy works best if used before, rather than after, exposure to the immunogen

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Clinical uses

organ transplantation

selective immunosuppression - decreased Rh hemolytic disease in newborns

autoimmune disorders

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limitations to therapy

increased risk for infection: usual plus opportunistic organisms

increased risk of lymphomas and related cancers

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cyclosporine (sandimmune) MoA

calcineurin inhibitor

MoA: binds to cyclophilin (also called an immunophilin) in T cells to form a complex which binds to and inhibits calcineurin and calcineurin mediated events including: the dephosphorylation of Nuclear Factor of Activated T cells (NFAT), the synthesis of cytokines (IL-2) proctooncogenes (c-myc and H-ras) and cytokine receptors (IL-2R). Can also increase production of transforming growth factor (TGF beta). Selective for T cells



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cyclosporine (sandimmune) Uses and Toxicity

Uses: Prevent rejction of kiddney, liver, and cardiac transplants (with or without corticosteroids). Autoimmune disorders (rheumatoid arthritis, Chrohn's disease, nephritic syndrome)

Toxicity: Nephrotoxicity (25-40%), hypertension (50% of renal transplant and nearly all cardiac transplant patients), and Hepatotoxicity (4-7%)

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Tacrolimus (FK506)

Calcineurin inhibitor

MoA: Binds FK506 binding protein-12 (FKBP) (also called an immunophilin). This complex inhibits calcineurin and calcineurin mediated events. Approximately 100 times more potent than cyclosporine. Uses similar to cyclosprine. Nephortoxicity.

SX: Nephortoxicity, Neurotixicity (tremor, headache, motor distrbance). Hypertension, and diabetes

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Sirolimus (rapamycin) and everolimus

MoA: binds to FKBP, but does not inhibit calcineurin like tacrolimus. Instead inhibition mTOR. mTOR is a kinase important for T cell proliferation. Blocks T cell cycle at the G1 to S transition.

Uses are similar to the uses of calcineurin inhibitors. Sirolimus-eluting stents are used to inhibit resenosis of blood vessels.

Toxicities: Hyperlipidemia (increases in serum cholesterol and triglycerides), delay graft function and delayed wound healing. Anemia, leukopenia, thrombocytopenia

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glucocorticoids (prednisone and methylprednisolone)

MoA: Unclear: glucocorticoids inhibit T cell proliferation, T cell dependent immunity and the expression of genes ecoding cytokines. T cells > B Cells.

Uses: Prevent organ rejection; autoimmune diseases.

Autoinflammatory properties.

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Azathioprine

Produrg that is converted to 6 mercaptopurine (6-MP) in vivo.

MoA: Ultiately, 6-MP and 6-MP metabolites can be incorporated into DNA, and they can also block the de novo pathway of purine synthesis. This makes them relatively selective for lympcytes due to their lack of a salvage pathway.

Uses: adjunct for prevention of organ transplant rejection. Also rheumatoid arthritis.

Drug interactions: If allopurinol is given, then azathioprine dose should be reduced. Allopurinol inhibits xanthine oxidase. Xanthine oxidase catabolizes azathioprine metabolites.

Toxcitiy: bone marrow sppression, inclduing leukopenia (common), thromocytopenia, and or anemia, increased risk for infection

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Mycophenolate mofetil

MoA: Prodrug converted to mycophenolic acid (MPA) in the gut. PA is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). INhibition of IMPDH inhibits de novo synthesis of guanine nucleotide. B and T cells are highly dependent on this pathway, because they lack the salvage pathway for purin synthesis.

Used to prevent transplant rejection.

Toxicity incldues GI effects, leukopenia,

Antacids (Mg and Al) decrease absorption

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Other immunosuppressive agents

methotrexate, cyclophosphamid, chlorambucil, vincristine, vinblastine, dactinomycin.

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Antibodies and fusion proteins

polyclonal and monoclonal antibodies against lymphocyte cell surface antigens

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Antithymocyte globulin (ATGAM)

Polyclonal antibody for serum of horses or rabbits immunized with human thymus lymphocytes

MoA: Binds to circulating T lymphocytes which induces lymphopenia (complement-mediated) and decreases T cell function

Prevent organ transplant rejection

toxicity: serum sickness, nephritis, chills, fever, and rashes

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Muromonab-CD3 (orthoclone)

*withdrawn from FDA but may come back in different form

mouse monoclonal antibody against CD3 glycoprotein. CD3 is adjacent to the T cell eceptor complex.

MoA: induces internalization of the T cell receptor complex.

prevent organ transplant rejection

SX: Cytokine release syndrome (due to initial activaition of T cells), anaphylactic reactions, CNS toxicity increased risk for infections and malignancy

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Daclizumab and basiliximab

bind the alpha subunit of the IL-2 receptor (CD25) on T cells. This inhibits T cell proliferation, which inhibits antigen induced T cell responses. Daclizumab used for relapsing mutliple sclerosis. Basiliximab used to prevent organ transplant rejection.

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Alemtuzumab (campath-1H)

Humanized anti-CD25 antibody. Induces cytolysis upon binding CD52 on the surface of B and T lymphocytes, monocytes, macrophages, and NK cells. used for relapsing remitting multiple sclerosis and chronic lymphoid leukemia.

Major toxicity: depletion of normal neutrophils and T cells. Serious myelosuppression

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Efalizumab

Withdrawn from market due to increased risk of progressive multifocal leukoencephalopathy. BInds CD11a subunit of leukocyte function associated 1 (LFA-1) protein on T and B cells. was used to treat Atopic dermatitis (sever)

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Tocilizumab

Humanized anti IL6 antibody that neutralizes IL6. This suppresses inflammation associated with rheumatoid arthritis. Therapeutic uses include: juvenile rheumatoid arthritis, rheumatoid arthritis

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Rituximab

chimeric anti CD20 antibody. Induces B lymphocyte apoptosis by binding to C20 on malignant B lymphocytes. used to treat chronic lymphoid leukemia, non Hodgkin's lymphoma and rheumatoid arthritis.

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Infliximab

chimeric anti TNF alpha antibody

AntiTNF agent bind to and neutralize TNF alpha

used for rheumatoid rathritis, psoriasis, ulcertaive colitis, crohn's disease

toxicity: increased risk for infection, lymphomas and other cancers

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Certolizuman pegol

humanized PEGylated anti TNFalpha antibody\

AntiTNF agent bind to and neutralize TNF alpha

used for rheumatoid rathritis, psoriasis, ulcertaive colitis, crohn's disease

toxicity: increased risk for infection, lymphomas and other cancers

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Adalimumab

Human anti TFA alpha antibody

AntiTNF agent bind to and neutralize TNF alpha

used for rheumatoid rathritis, psoriasis, ulcertaive colitis, crohn's disease

toxicity: increased risk for infection, lymphomas and other cancers

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Etanercept

Decoy tnf alpha receptor. Fusion protein made of two extra cellular domains of the TNF alpha receptor linked by the constant FC portion of human immunoglobulin 1 (IgG1)

AntiTNF agent bind to and neutralize TNF alpha

used for rheumatoid rathritis, psoriasis, ulcertaive colitis, crohn's disease

toxicity: increased risk for infection, lymphomas and other cancers

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Alefacept (discontinued)

fusion of LFA-3 with IgG1. Interefered with lymphocyte activation by specficially binding to the lymphocyte antigen, CD2, and inhibiting LFA-3/CD2 interaction (costimulatory interaction)

was used to treat psoriasis

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Abatacept and Belatacept

fusion proteins (cytotoxic T lymphocyte antigen immunoglobulin fused to human IgG1 (CTLA-4 IgG1).

Belatacept is more potent than Abatacept.

CTLA-4 IgG1 binds CD80 and CD86 on APCs and by doing so prevents their bidning with CD28 on T cells. INhibition of CD28 activation inhibits the second costimulatory signal needed for optimal activation of T cells.

Abatacept uses included juvenile arthritis and rheumatoid arthritis.

Belatacept used to prevent organ transplant rejection

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Immunostimulants

treat conditions of immunodeficiency (AIDS) or to bolster immunity against specific targets.

Can act through cellular or humoral immunity or both.

magnitude of stimulation can be highly variable

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Immune globulins (pooled human plasma)

immune globulin contains all immunogobulin subclasses (IgG > IgM) to provide passive immunity

used in various immunodeficiency states, to prevent measles, Hep A, and tetanus. Many types of immune globulins available

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bacillus calmette- guerin (BCG) vaccine

a viable attenuated strain of mycobacterim bovis; muramyl dipeptide is the active component.

stimulates NK cells and T cell activity

TX: Bladder cancer

Toxicity: severe hypersensitivity reactions and shock can develop

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Levamisole

Drug normally used as an anthelminic agent. Inhibits T suppressor cells.

Used as an imnunostimulant in colon cancer

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Thalidomide

Indications: erythema nodusum leprosum (ENL), multiple myeloma. Has been shown to reduce TNF levels in patients with ENL

Contraindicated in women who are pregnant or who may become pregnant due to teratogenic properties. Pregnancy catagory of X

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Interferon alpha

glycoprotein that is part of our natural antiviral defense.

activates macrophages, t lympcytes and NK t cells

used to treat cancers and Hep B and C

Currently human recombinant interferon alpha is used clincially

toxicities: flue like symptoms and boxed warning regarding development of pulmonary hypertension

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Interleukin-2 (IL2) (proleukin)

MoA: activates cellular immunity

indicated for metastatic melanoma, renal cell carcinoma and in AIDS patients.

toxicity: IL2 can induce severe hypotension and life threatening cardiovascular toxicity

pulmonary edema (capillary leak syndrome) is dose limiting

available as natural or recombinant forms

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granulocyte colony stimulating factors (myeloid growth factor0

glycoproteins produced by monocytes, fibroblasts and endothelial cells. Stimulate increases in the number of granlocytes and monocytes

used to reduce neutropenia in several instances