Immunosuppressive Agents
- Azathioprine
- Corticosteroids
- Cyclosporine
- Tacrolimus
- Sirolimus
- Mycophenolate mofetil
- Polyclonal antithymocyte globulin
- Anti-CD3 monoclonal antibodies
Azathioprine (AZA)
- imidazole derivative of 6-mercaptopurine
- blocks DNA synthesis
- decreases the migration of leukocytes into grafts and inhibits the proliferation of premyelocytes within the bone marrow
- useful for blocking the 1o response
- NOT USEFUL for blocking the 2o immune response or for the reversal of the incidence of acute allograft rejection
- Side effects: severe: leukopenia &/or thrombocytopenia, GI disturbances, fever, hepatotoxicity, and an increased risk of Neoplasia
- Notice that it is not nephrotoxic
Corticosteroids – prednisone, prednisolone, & methylprednisolone
- block expression of several cytokine genes (IL-1, IL-2, IL-3, IL-6, TNF-a, INF-g)
- use to be used in high doses with AZA, but now with CsA low levels are used
- Side effects: osteoporosis, avascular necrosis, cataracts, obesity, hyperglycemia, susceptibility to infection
- Associated with an incidence of: GI hemorrhages, cataracts, obesity, & post-transplant diabetes mellitus
Cyclosporine (CsA)
- inhibits cytokine production by activated T cells
- T cell receptor signaling blocker
- Side effects: nephrotoxicity, HTN, neurotoxicity, diabetogenicity, hirsuitism, gingival hyperplasia, gynecomastia, and hypomagnesia, susceptibility to infection
- Association with: lymphomas
Tacrolimus (FK506)
- binds to FX506 binding protein which binds and blocks calcineurin
- prevents the NF-Atc entrance into the nucleus
- blocks cytokine production
- works like cyclosporine
- inhibits T cell activation
- Side effects: nephrotoxicity, NEUROTOXICITY, and diabetogenicity
- No hirsuitism, gingival hyperplasia, gynecomastia, or decreased magnesium
Sirolimus (SRL)
- new immunosuppressive agent
- structure similar to FK506 (Tacrolimus)
- binds to mTOR and forms complex which inhibits biochemical pathways – these pathways are required for cell progression through the late G1 phase or entry into S phase
- DOES NOT inhibit cytokine production (like Tacrolimus and CsA)
- Blocks cytokine signal transduction
- Side effects: reversible thrombocytopenia and leukocytopenia, increase in cholesterol levels
- Synergistic with CsA
Mycophenolate Mofetil
- inhibits inosine monophosphate dehydrogenase —- depletes GMP, GTP, and dGTP
- inhibits T and B cell proliferation
- used in combo with CsA
- Side effects: mild bone marrow suppression
- Notice that there is no Nephrotoxicity or hepatotoxicity
Polyclonal antithymocyte globulin (ATGAM)
- used to reverse acute allograft rejection
- eliminates lymphocytes from the circulation
- bind to T cells and activate the classical complement pathway and T-cell lysis results
- causes profound lymphopenia — reversible
- Side effects: dependent on batch of ATGAM; thrombocytopenia, granulocytopenia, serum sickness, glomerulonephritis
- Opportunistic infections
- To prevent oversuppression T cells should not be lower than 10% of pretreatment levels in the blood
OKT3 monoclonal antibodies
- bind to the delta protein on T cells and thereby eliminate the activated T cells from the circulation
- limited use because of the development of anti-mouse antibodies
- reverses kidney allograft rejection at the rate of 94%
- Side effects: flu-like symptoms (shaking, chills, N&V, diarrhea, headache, and weakness.
- Monitor level of T cells (10% rule in effect here also)
Tags: 1. Azathioprine, Anti-CD3 monoclonal antibodies, Avascular Necrosis, cataracts, Corticosteroids, Cyclosporine, hemorrhages, hyperglycemia, methylprednisolone, Mycophenolate mofetil, obesity, osteoporosis, Polyclonal antithymocyte globulin, prednisolone, rednisone, Sirolimus, Tacrolimus
