IP 850-Solid Organ Transplantation Flashcards
An antigen-presenting cell binds to the T-cell receptor and triggers the T cell at signal
- Costimulator molecules and ligands bind at signal
- The activation of both signals 1 and 2 are needed to result in the expression of interleukin-2 (IL-2) and other factors. At signal 3, stimulation of the IL-2 receptor on the T-cell surface triggers T-cell proliferation.
Mechanisms of action of the available immunosuppressive medications include:
- blocking the production and release of cytokines from activated T cells
- downregulating and inhibiting T-cell surface receptors
- inhibiting T-cell proliferation
- and causing T-cell depletion
Cylcosporine and tacrolimus inhibit
calcineurin
The monoclonal antibody basiliximab bind and inhibits
the IL-2 receptor
Azathioprine acts as
an antimetabolite to prevent T-cell proliferation
Mycophenolate mofentil (MMF) and Mycophenolic acid (MPA) inhibit
purine synthesis, which prevents proliferation of T and B cells
Sirolimus and everolimus inhibit
cytokine-stimulated T-cell proliferation
Belatacept binds to
cluster of differentiation 80 (CD80) and cluster of differentiation 86 (CD86) receptors on the antigen-presenting cells, which prevents binding to cluster of differentiation 28 (CD28) on the T cell
Alemtuzumab binds to
cluster of differentiation 52 (CD52), which is present on the surface of T and B cells.
The goals of immunosuppression are to
- prevent gait rejection
- improve graft and patient survival
- reduce complications
- minimize medication adverse effects
- improve overall patient quality of life
- minimize the number of immunosuppressants that the patient receives for the duration of their life
What are the 3 phases of immunosuppression?
Induction, Maintenance, and treatment of rejection
MOA: Antithymocyte globulin
Blocks T-cell membrane proteins
MOA: Alemtuzumab
Monoclonal antibody directed against the CD52 cell surface antigen
MOA: Basiliximab
Chimeric monoclonal antibody against CD25
MOA: Cyclosporine
Binds to cylophilin and forms complex that inhibits calcineurin
MOA: Tacrolimus
Binds to FKBP12 and forms complex that inhibits calcineurin
MOA: Azathioprine
Inhibits protein synthesis
MOA: Mycophenolate
Inhibits inosine monophosphate dehydrogenase
MOA: Sirolimus and Everolimus
Binds and forms complex with FKBP12 complex that inhibits mammalian target of rapamycin (mTOR)
MOA: Belatacept
Selective T-cell costimulation blocker binds to CD80 and CD86 receptors on the antigen-presenting cell and prevents them from binding to CD28 on the T lymphocyte
MOA: Corticosteroids
Block T-cell-derived and antigen-presenting cell-derived cytokine expression
Antibody therapy includes
- T-cell-depleting (used for the treatment of rejection)
2. Non-depleting agents (divided into polyclonal and monoclonal agents)
Polyclonal antithymocyte antibodies are
rabbit antithymocyte globulin (rATG) and horse antithymocyte globulin (hATG)
Alemtuzumab is a
humanized monoclonal anti-CD52 antibody
Induction with antibody therapy includes:
Antithymocyte Globulin, Alemtuzumab, and Basiliximab
Maintenance Immunosuppression includes:
Calcineurin Inhibitiors, Antiproliferatives, Corticosteroids, mTOR inhibitors, and Belatacept
AEs: Antithymocyte globulin
- Cytokine-release syndrome
- Thrombocytopenia, leukopenia
- Headache, dizziness
- Abdominal pain, diarrhea, nausea
- Dyspnea
- Hypertension, peripheral edema
- Hyperkalemia
AEs: Alemtuzumab
- Anemia, neutropenia, thrombocytopenia
- Infusion reactions
- Infections (cytomegalovirus, Pneumocystis jiroveci pneumonia, herpes virus
- Diarrhea, nausea, vomiting
- Insomnia
AEs: Basiliximab
- Comparable to placebo
- Constipation, nausea, abdominal pain, vomiting, diarrhea, dyspepsia
AEs: Cyclosporine
- Nephrotoxicity
- Hypertension
- Hyperlipidemia
- Neurotoxicity
- Post Transplant diabetes
- Hyperkalemia
- Hypomagnesemia
- Hirsutism
- Gingival hyperplasia
AEs: Tacrolimus
- Similar to cyclosporin except:
1. Fewer cardiovascular issues
2. Fewer cosmetic problems such as hirsutism and gingival hyperplasia
3. More post transplant diabetes
4. More neurotoxicity than cyclosporine
AEs: Azathioprine
- Anemia, neutropenia, thrombocytopenia
- Hepatotoxicity
- Pancreatitis
AEs: Mycophenolate
- Diarrhea, nausea, vomiting
- Leukopenia, thrombocytopenia, anemia
AEs: Sirolimus and Everolimus
- Hypertension
- Perpipheral edema
- Hyperlipidemia
- Anemia, thrombocytopenia
- Headache
- Proteinuria
- Delayed wound healing
- Interstitial lung disease
- Mouth ulcers
AEs: Belatacept
- Hypertension
- Peripheral edema
- Hyperkalemia, hypokalemia
- Constipation, diarrhea, nausea, vomiting
- Headache
- Cough, fever
- Post transplant lymphoproliferactive disease
- Progressive multifocal leukoencephalopathy
- Tuberculosis
AEs: Corticosteroids
- Hyperglycemia
- Hypertension
- Hyperlipidemia
- Increased risk of gastric ulcers
- Risk of fungal and bacterial infections
- Osteoporosis
- Suppression of HPA axis
- Psychosis
Calcineurin inhibitor concentrations are increased with concomitant administration of:
- Calcium Channel Blockers (eg, diltiazem)
- Triazole antifungals (eg, ketoconazole, itraconazole, voriconazole)
- Macrolide antibiotics (eg, erythromycin)
- Prokinetic agents (eg, metoclopramide)
- Other medications such as amiodarone, cimetidine, omeprazole, and protease inhibitors
Calcineurin inhibitor concentrations are decreased with concomitant administration of:
- Anticonvulsant (eg, carbamazepine, phenytoin, and phenobarbital)
- Rifampin
- St. John’s wort
Cyclosporine and Tacrolimus can also result in increased renal toxicity with concomitant use of
- aminoglycoside
- amphotericin B
- diuretics
- non-steroidal anti-inflammatory drugs
Mycophenolate concentrations are decreased with the use of
- antacids
- iron
- cholestyramine
- rifamycins
- sevelamer
Mycophenolate concentrations are increased with use of
- acyclovir
- ganciclovir
- valacyclovir
- probenecid
Black Box Warnings for both Sirolimus and Everolimus
-Increased risk of infections and malignancies
Sirolimus cautions against use in liver and lung transplant recipients due to safety and efficacy issues
