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BCG (ImmuCyst)
- Adjuvant - live attenuated bacillus calmette-guerin
- surface antigens interact directly with PAMPs on APCs to increase APC activity
- useful in some cancer therapies (bladder cancer)
- direct activation of leukocytes (principally macrophages) can produce a systemic inflammatory response and septic shock
- BCG related to pathogen that causes TB - will test + for TB test if used BCG
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interleukin-2 (IL-2, Aldesleukin, Proleukin)
- cytokine
- increase proliferation of activated T cells, production of IFN-γ, and cytotoxic killer cell activity
- treatment of metastatic melanoma and renal cell carcinoma
- assoc. with serious cap. leak syndrome, hypotension, and reduced organ perfusion. Can be fatal
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IFN-γ (Actimmune)
- cytokine - interferons
- stimulates cell mediated cytotoxic immune response
- used to treat severe recurrent infections
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ipilimumab (Yervoy)
- immune checkpoint inhibitor: fully human antibody to CTLA-4
- experimentally shown to promote regression of a variety of tumor types
- approved in 2011 for treatment of metastatic melanoma
- can cause severe and fatal immune-mediated rxns caused by T-cell activation and proliferation (enterocolitis, dermatitis, neuropathy, endocrinopathy, hepatitis)
- runs can occur weeks to months after treatment
- requires permanent discontinued treatment and high dose corticosteroid treatment to suppress immune-mediated rxns
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nivolumab (Opdivo) and pembrolizumab (Keytruda)
- immune checkpoint inhibitor - fully human antibody to PD-1
- experimentally shown to promote regression of a variety of tumor types
- increased survival rates compared to conventional chemotherapy for melanoma or non-small cell lung cancer (approved for both)
- assoc. with severe immune-mediated colitis, hepatitis, nephritis, pneumonitis, and thyroid disfunction
- combination drug synergistically increases tumor regression and survival in melanoma clinical trials
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cyclophosphamide (Cytoxan)
- immunosuppressive - crosslinks DNA and kills proliferating cells, preventing expansion of antigen-specific lymphocytes
- used in many auto-immune diseases and bone marrow transplants
- adverse effects: myelosuppression, nausea, vomiting, infertility
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azathioprine (Imuran)
- immunosuppressive - metabolized to 6-mercaptopurine and further metabolized to 6-thioguanine
- products inhibit purine synthesis and become incorporated into DNA as thio-guanine nucleotides (causes DNA damage)
- inactivated by xanthine oxidase (decreased when combined with allopurinol)
- uses: renal and other tissue transplantation, some auto-immune disorders (lupus, RA)
- adverse effects: myelosuppression, nausea, vomiting
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mycophenolate mofetil (Cell-Cept)
- hydrolyzed to mycophenolic acid
- inhibits inosine monophosphate dehydrogenase, preventing purine synthesis
- used for solid organ transplant as an alternative to cyclosporine, and some auto-immune diseases
- adverse effets: myelosuppression, nausea, vomiting
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methotrexate
- inhibits DHFR - direct inhibition and accumulated inhibitory intermediates prevent synthesis of thymidine and purine nucleotides
- used as drug of choice in RA, some auto-immune diseases
- adverse effects: nausea, mucosal ulcers, modest hepatotoxicity, myelosuppression
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leflunomide (Arava)
- metabolized to A77-1726 (active form)
- inhibits dihydroorotate dehydrogenase, leading to decreased pyrimidine synthesis
- A77-1726 is subject to enterohepatic recirculation and has a half-life of 19 days
- used for RA and some autoimmune diseases
- adverse effects: diarrhea, modest hepatotoxicity, myelosuppression
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prednisone
- glucocorticosteroid - combined immuno-suppresive and anti-inflammatory effect (focus now on immunosuppressive)
- affect gene txn as ligands for glucocorticoid receptors
- primary immunosuppressive effect is in inhibition of cytokine (IL-2, IFN-γ) gene expression from antigen-activated T cells
- orally available for systemic immunosuppression and reduced inflammation - can apply topically for localized effects and inhaled as aerosol for asthma therapy
- first line immunosuppressant for solid organ and hematopoietic stem cell transplant
- useful in management of various immune-based disorders (certain autoimmune diseases, asthma, allergic rxns, systemic inflammation)
- adverse effects (generally with >2 weeks daily systemic administration): Cushing's syndrome effects, glucose intolerance, hypertension and fluid retention, osteoporosis, adrenal suppression, GI disturbances, ocular disturbance, psychiatric disturbances
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cyclosporine (Sandimmune)
- calcineurin inhibitor
- can be effective without other immunosuppressants, but often combined with other agents
- forms a complex with the immunophilin cyclophilin
- commonly useful in kidney, liver, and cardiac transplants
- can be useful in a variety of autoimmune disorders (RA) and may have applications in some inflammatory diseases (IBD, asthma)
- adverse effects: nephrotoxicity, HTN, hyperglycemia, liver dysfunction, increased cancer incidence documented although probably no greater than other immunosuppressants
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tacrolimus (Program, FK506)
- calcineurin inhibitor
- can be effective without other immunosuppressants, but often combined with other agents
- forms a complex with the immunophilin FKBP12
- commonly useful in kidney, liver, and cardiac transplants
- can be useful in a variety of autoimmune disorders (RA) and may have applications in some inflammatory diseases (IBD, asthma)
- adverse effects: nephrotoxicity, HTN, hyperglycemia, liver dysfunction, increased cancer incidence documented although probably no greater than other immunosuppressants
- 10-100x more potent than cyclosporine
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sirolimus (Rapamune, rapamycin) and everolimus (Afinitor)
- mTOR inhibitor
- can be used alone or in combination therapies to preserve solid organ transplants
- forms a complex with FKBP12
- may be useful in steroid-resistant GVHD in hematopoietic stem cell transplants
- antagonizes tacrolimus effects, but synergies with cyclosporine
- Adverse effects: myelosuppression, hyperlipidemia, hypertension, edema, hepatotoxicity
- everolimus more commonly used in cancer chemotherapy
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Rh(D) immune globulin (BayRho-D, WinRho SDF)
- antibody for RH hemolytic disease
- Rh negative mothers can be sensitized to foreign D antigen of an Rh+ fetus. Subsequent pregnancies, maternal antibodies against Rh+ cells can transfer to the fetus leading to hemolytic disease
- concentrated solution of human IgG with a high titer of Rh(D) antibodies.
- prevents initiation of a maternal immune response to fetal Rh(D) antigen
- mechanism is mediated by opsonization and clearance of fetal Rh+ cells before an effective immune response can develop
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belatacept (Nulojix)
- fusion protein of a high-affinity B7 ligand (CTLA4) with an IgG Fc domain
- second generation version of abatacept, with higher affinity for B7
- approved for kidney transplants
- prevents B7 (on APC) interacting with CD28 (TCell), causes T cells to become anergic, which prevents proliferation, cytokine production, and causes the TCell to die
- Adverse effects: anemia, neutropenia, peripheral edema, increase risk of infection and malignancy, post transplant lymphoproliferative disorder (possibly higher frequency than other immunosuppressive agents, contraindicated in EBV-negative patients)
- Effect: comparable to calcineurin inhibitors in preventing transplant rejection
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anti-T cell globulin (ATG)
- Immune-depleting agent
- product of repeated injection of human T cells into animals. Purified serum IgG
- blocks T cell surface receptors and opsonizes T cells
- Adverse effects: cytokine release syndrome (fever, chills, headache, nausea, malaise, etc) which is reduced with acetaminophen and antihistamine, serum sickness, anaphylaxis potential (mostly on repeated use)
- effect: produces prolonged T cell depletion (more than a year), but potential for late rejection as lymphoid system recovers
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alemtuzumab (Campath)
- immune-depleting agent
- humanized anti-CD52 antibody
- CD52: surface protein expressed on T and B cells, monocytes, macrophages, and NK cells
- mechanism: depletes a broad variety of cells involved in adaptive and innate immune rxns
- adverse effects: myelosuppression, flu-like symptoms
- effect: produces prolonged depletion of T cell and other cells of the immune system (up to a year)
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basiliximab (Simulect)
- immune-depleting agent
- humanized anti-IL-2 receptor (anti-CD25) antibody
- mechanism: blocks and opsonizes α-chain of IL2 receptor (CD25) that is present on ACTIVATED T cells
- adverse effects: well tolerated
- effect: depletes only antigen-activated T cells, moderate effect compared to ATG
- may be more appropriate for patients with low to moderate risk of rejection
- reduced immune-depletion is assoc with a reduced incidence of infection (particularly chronic CMV) and malignancy
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