Immunosuppression lecture 6 Flashcards
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
Clinical uses
organ transplantation
selective immunosuppression - decreased Rh hemolytic disease in newborns
autoimmune disorders
limitations to therapy
increased risk for infection: usual plus opportunistic organisms
increased risk of lymphomas and related cancers
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
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%)
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
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
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.
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
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
Other immunosuppressive agents
methotrexate, cyclophosphamid, chlorambucil, vincristine, vinblastine, dactinomycin.
Antibodies and fusion proteins
polyclonal and monoclonal antibodies against lymphocyte cell surface antigens
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
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
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.
