Immunomodulatros Flashcards
Cyclophosphamide
General Growth Inhibitor
- Prevent Clonal Expansion and Cell-mediated immunity
- Not specific to leukocytes/leukocytes
Effective immunosuppresant by cross-linking DNA and killing proliferating cells
- Prevent expansion of lymphocytes (antigen specific)
Uses:
- Autoimmune disease
- Bone marrow transplant
Adverse Effects:
- Myelosuppression
- Nausea
- Vomiting
- Infertility
Azathioprine
General growth inhibitor
- Prevent clonal expansion and cell-mediated immunity
Metabolized to 6-mercaptopurine then to 6-thioguanine
- Inhibit purine synthesis, becomes incorporated into DNA as thio-guanine nucleotide
Inactivated by Xanthine Oxidase
- Decreased inactivation when combined with allopurinol= NEED DECREASE DOSAGE
Use:
- Renal/tissue transplantation
- Autoimmune disease (lupus, Rh Art)
Adverse Effects:
- Myelosuppression
- Nausea
- Vomiting
Leflunomide
General Growth Inhibitor
Metabolized to A77-1726 (active)
Inhibits dihyrdoorate Dehydrogenase leading to decreased pyrimidine synthesis
- Subject to enterohepatic recirculation and has a half-life of 19 days
Uses:
- Rh Art
- Some autoimmune disease
Adverse Effects:
- Diarrhea
- Hepatotoxicity
- myelosuppression
- less pronounced than other anti-metabolites
Methotrexate
General Growth Inhibitor
Inhibits dihydrofolate reducatase
- Direct inhibition and accumulated intermediates prevents synthesis of thymidine as well as purine nucleotides
Uses:
- DRUG OF CHOICE: RH ART
- Some autoimmune diseases
Adverse Effects:
- Nausea
- Mucosal Ulcers
- Modest Hepatotoxicity
- Myleosuppression less pronounced than other anti-metabolites
Mycophenoate Mofetil
General Growth Inhibitor
Hydrolyzed to mycophenolic acid (active Form)
Inhibits inosine monophosphate dehydrogenase, preventing purine synthesis
USE:
- Solid Organ Transplant
- Alternative to Cyclosporine
- Some autoimmune diseases
Adverse Effects:
- Myelosuppression
- Nausea
- Vomiting
Prednisone
Glucocorticoid
Anti-inflammatory and immunosuppressive effects
Induces transcription of Annexins (lipocortins)
- Inhibit PLA2 and synthesis of lipid derived mediators
Repress transcription of
- IL-1, 2, 3, 5, TNF alpha, IFN gamma, GM-CSF
- Reduces Th mediated responses, B cell antibody production, cytotoxic response
Repress TF NFkB and AP-q
- Targets cyclooxygenase, nitric oxide synthase, phospholypase A to REDUCE mediator release
- Target IL-8 and other Chemotaxins: Reduce recruitment of leukocytes
FIRST Line immunosuppresant for Transplant
Combined anti-inflammatory/immunosuppressant activity useful in managing immune-based disorders
Adverse effects: ( greater than 2 week administration)
- CUSHINGS syndrome
- Glucose Intolerance
- Susceptibility to Infection
- Osteoporosis
- Hypertension
Sirolimus
mTOR Inhibitor
Prevent Cytokine Induced Growth due to mTOR inhibition
- Can be used alone or in combination with other therapies to preserve solid organ transplant
Useful in steroid resistant Graft-Vs-Host disease (hematopoietic stem cell transplants)
ANTAGONIZES tacrolimus effects
SYNERGIZES with cyclosporine (consistent with selective dependence on immunophilins)
Adverse Effects:
- Myelosuppression
- Hyperlipidemia, hypertension, edema
- Hepatotoxicity
Inhibits IL-2 receptor signal transduction
Cyclosporine
Calcineurin Inhibitor
Prevent TCR-induced cytokine expression by inhibiting Calcineurin Activity
- Binds with CYCLOPHILIN and endogenous protein
Can be effective without use of other immuno-suppressants in some patients
Commonly useful in kidney, liver, and cardiac transplants
Useful in a variety of autoimmune disorders and may have applications in some inflammatory diseases (asthma)
ADVERSE EFFECTS:
- Nephrotoxicity, hypertension, hyperglycemia, liver dysfunction
- Increased cancer incidence
Tacrolimus
Calcineurin Inhibitor
FK506 binds with FKBP12 to inhibit calcineurin activity when increased Ca in the cell
Uses:
- Kidney, liver, cardiac transplant
- Useful in variety of autoimmune disorders and may have some application in inflammatory diseases (asthma)
10-100 times more potent than cyclosporine
ANTAGONIZES sirolimus effects
Anti-T cell globulin
Antibody
Suppress immune activity by opsonizing and depleting critical immune cells
Alemtuzumab
Chimeric Antibody
Activate human complement leukocytes
Do NOT induce anti-antibody response
Few side effects
HUMANIZED anti-CD52 antibody
- Depletes a broad variety of cells involved in adaptive and innate immune
- ADVERSE EFFECTS:
- Myelosuppression, flu-like symptoms
- Effect: Produces prolonged depletion of T cell and other cells of
the immune system (ONE YEAR)
Basiliximab
Chimeric Antibody
Activates human complement leukocytes
Does NOT induce an anti-antibody response
Anti-IL-2 receptor (anti-CD25): humanized antibody
- Mechanism: Blocks and opsonizes the alpha-chain of IL-2 receptor (CD25) present on ACTIVE T cells
Well Tolerated
Effect: Depletes only antigen-activated T cells
- Moderate effect compared to ATG, more appropriate for patients with low - to moderate risk for rejections
- Reduced immune-depletion is associated with reduced incidence of infection (chronic CMV infection) and malignancy
Rh(D) immune Globulin
Human Antibody
Activate human complement leukocytes
DO NOT induce anti-antibody response
Treatment for RH HEMOLYTIC DISEASE
- Occurs when RH negative mothers sensitized to D antigen of RH positive fetus
- Subsequent pregnancies maternal antibodies against RH-positive cells can transfer to the fetus leading to Hemolytic Disease
Concentrated solution of human IgG with a high titer of Rh(D) antibodies. Maternal administration of Rh(D) immune globulin prevents initiation of a maternal immune response to the fetal Rh(D) antigen
Mechanisms immune suppression mediated through opsonization and clearance of D antigens
Dantigen/antibody complexes inhibit activation of maternal naive Rh(D) reactive B cells
T cell responses not specifically affected are not harmful to the fetus
Belatacept
New biologic immunosuppressant that is approved for kidney Transplant
Blocks Co-Stimulatory Receptors for Immunosuppression
Fusion Protein of a high-affinity B7 ligand (CTLA4) with IgG Fc domain
- Second generation abatacept, higher affinity for B7
Mechanism:
- Prevents interaction between B7 on APC and CD28 (T cell)
- T cells activated by antigen presentation and TCR activation become anergic in the absence of CD28 activation
- No proliferation
- NO cytokine production
- T cell dies
Adverse Effects:
- Anemia, neutropenia, peripheral edema
- Increase risk of infection and maliganancy
Interleukin-2
Cytokine
Activated T cells secrete this and express IL-2 receptor protein
Stimulate proliferation and clonal expansion of the antigen-specific T cell population
Increase Prolliferation of activated T cells, production of IFN gamma,
and cytotoxic killer cell activity
Use:
- Treatmenet of metastatic melanoma and renal cell carcinoma
Associated with serious capillary leak syndrome, hypotension, and reduced organ perfusion
CAN BE FATAL
