Immunomodulation Therapy; L2 (11-11-15) Flashcards
Glucocorticoids (Prednisone, Prednisolone) - Indications
- __
- To prevent __ rejection
- To prevent __
- Tx of __-release syndrome
- Tx of a wide variety of ___ and __ diseases, e.g., RA, SLE, asthma, etc.
Glucocorticoids (Prednisone, Prednisolone) - Indications
- Immunosuppression
- To prevent graft rejection
- To prevent GvHD
- Tx of cytokine-release syndrome
- Tx of a wide variety of autoimmune and inflammatory diseases, e.g., RA, SLE, asthma, etc.
Glucocorticoids (Prednisone, Prednisolone) - MOA
- Activates the __ receptor transcription factor
- Modifies expression of __ and other __regulatory genes
- Suppresses active __ responses
Glucocorticoids (Prednisone, Prednisolone) - MOA
- Activates the glucocorticoid receptor transcription factor
- Modifies expression of cytokine and other immunoregulatory genes
- Suppresses active immune responses
Glucocorticoids (Prednisone, Prednisolone) - Adverse Effects
- MANY adverse effects
- __glycemia
- __tension
- __lipidemia
- Obesity
- Diabetes
- Poor __ healing
- Mania and psychosis
- Increased risk of __
Glucocorticoids (Prednisone, Prednisolone) - Adverse Effects
- MANY adverse effects
- Hyperglycemia
- Hypertension
- Hyperlipidemia
- Obesity
- Diabetes
- Poor wound healing
- Mania and psychosis
- Increased risk of infections
Glucocorticoids (Prednisone, Prednisolone) - Misc
- Glucocorticoid dose should be __ reduced to minimize adverse effects
- Glucocorticoids should NOT be __ __
Glucocorticoids (Prednisone, Prednisolone) - Misc
- Glucocorticoid dose should be gradually reduced to minimize adverse effects
- Glucocorticoids should NOT be withdrawn abruptly
Azathioprine - Indications
- __
- To prevent __ rejection
- To prevent __
- Tx of __ diseases
Azathioprine - Indications
- Immunosuppression
- To prevent graft rejection
- To prevent GvHD
- Tx of autoimmune diseases
Azathioprine - MOA
- __
- Converted to _-__ by __
- Inhibits de novo __ synthesis
- Incorporated into DNA and causes __ base mispairing -> apoptosis
- Inhibits __ co-stimulation
Azathioprine - MOA
- Prodrug
- Converted to 6-MP by HGPRT
- Inhibits de novo purine synthesis
- Incorporated into DNA and causes SS base mispairing -> apoptosis
- Inhibits CD28 co-stimulation
Azathioprine - Adverse Effects
- __penia/__penia
- __toxicity
- Increased risk of __
- Increased risk of __
Azathioprine - Adverse Effects
- Leukopenia/thrombocytopenia
- Hepatotoxicity
- Increased risk of infections
- Increased risk of malignancy
Azathioprine - Misc
-Interacts with __-__ drugs (__ and __) -> __ [azathioprine] -> increased __
Azathioprine - Misc
-Interacts with anti-gout drugs (allopurinol and febuxostat) -> increased [azathioprine] -> increased toxicity
Mycophenolate Mofetil - Indications
- __
- To prevent __ rejection
- To prevent __
- Tx of __ diseases
Mycophenolate Mofetil - Indications
- Immunosuppression
- To prevent graft rejection
- To prevent GvHD
- Tx of autoimmune diseases
Mycophenolate Mofetil - MOA
- __
- Converted to __ __
- Inhibits __ __ (IMPDH) type II (selectively expressed in __) -> inhibition of __ nucleotide synthesis - no __ pathway in lymphocytes
Mycophenolate Mofetil - MOA
- Prodrug
- Converted to mycophenolic acid
- Inhibits inosine monophosphatedehydrogenase (IMPDH) type II (selectively expressed in lymphocytes) -> inhibition of purine nucleotide synthesis - no salvage pathway in lymphocytes
Mycophenolate Mofetil - Adverse Effects
- __penia/anemia
- __ (male/female)
- Increased risk of __
- Increased risk of __
-RARE - __ __ __ __ __ (PML) - fatal viral disease caused by reactivation of JC virus
Mycophenolate Mofetil - Adverse Effects
- Leukopenia/anemia
- Teratogenic (male/female)
- Increased risk of infections
- Increased risk of malignancy
-RARE - Risk of Progressive Multifocal Leukoencephalopathy (PML) - fatal viral disease caused by reactivation of JC virus
Mycophenolate Mofetil - Misc
-Contraindicated in __, women who wish to __ __, and men who wish to __ __
Mycophenolate Mofetil - Misc
-Contraindicated in pregnancy, women who wish to become pregnant, and men who wish to become fathers
Calcineurin Inhibitors (Cyclosporine, Tacrolimus) - Indications
- __
- To prevent __ rejection
- To prevent __
- Tx of __ diseases
Calcineurin Inhibitors (Cyclosporine, Tacrolimus) - Indications
- Immunosuppression
- To prevent graft rejection
- To prevent GvHD
- Tx of autoimmune diseases
Calcineurin Inhibitors (Cyclosporin, Tacrolimus) - MOA
- Cyclosporin and tacrolimus bind __ and __, respectively, to form inhibitory complexes
- __/cyclosporin and __/tacrolimus complexes inhibit the Ca2+-regulated phosphatase, __
- Inhibition of __ inhibits the activation of the __ transcription factor, which is involved in regulating the expression of IL-__ and multiple other immunoregulatory genes
- Potently inhibit the T-cell immune response by inhibiting signal __
Calcineurin Inhibitors (Cyclosporin, Tacrolimus) - MOA
- Cyclosporin and tacrolimus bind cyclophilin and FKBP, respectively, to form inhibitory complexes
- Cyclophilin/cyclosporin and FKBP/tacrolimus complexes inhibit the Ca2+-regulated phosphatase, calcineurin
- Inhibition of calcineurin inhibits the activation of the NFAT transcription factor, which is involved in regulating the expression of IL-2 and multiple other immunoregulatory genes
- Potently inhibit the T-cell immune response by inhibiting signal 1
Calcineurin Inhibitors (Cyclosporine, Tacrolimus) - Adverse Effects
- **__**
- __tension
- __toxicity/tremor
- Glucose intolerance ( __ > __ )
- Hyperlipidemia ( __ > __ )
- Hypertrichosis (__)
- Alopecia (__)
- Increased risk of __
- Increased risk of __
Calcineurin Inhibitors (Cyclosporine, Tacrolimus) - Adverse Effects
- **Nephrotoxicity**
- Hypertension
- Neurotoxicity/tremor
- Glucose intolerance ( T > C )
- Hyperlipidemia ( C > T )
- Hypertrichosis (C)
- Alopecia (T)
- Increased risk of infections
- Increased risk of malignancy
Calcineurin Inhibitors (Cyclosporine, Tacrolimus) - Misc
- Metabolized by CYP3A4 -> MANY drug interactions
- 3A4 inhibitors promote __ drug levels -> increased risk of __
- 3A4 inducers promote __ drug levels -> increased risk of __ rejection
Calcineurin Inhibitors (Cyclosporine, Tacrolimus) - Misc
- Metabolized by CYP3A4 -> MANY drug interactions
- 3A4 inhibitors promote increased drug levels -> increased risk of toxicity
- 3A4 inducers promote decreased drug levels -> increased risk of graft rejection
mTor Inhibitors (Sirolimus, Everolimus) - Indications
- __
- To prevent __ rejection (but NOT __, NOT __)
- To prevent __
- Included in __ stents to inhibit re__
mTor Inhibitors (Sirolimus, Everolimus) - Indications
- Immunosuppression
- To prevent graft rejection (NOT lung, NOT liver)
- To prevent GvHD
- Included in arterial stents to inhibit restenosis
mTor Inhibitors (Sirolimus, Everolimus) - MOA
- Drugs form complex with __
- __/drug complex inhibits IL-__ mediated activation of mTor kinase (T-cell signal __)
- Inhibits IL-__ stimulated protein synthesis, cell proliferation, and survival
mTor Inhibitors (Sirolimus, Everolimus) - MOA
- Drugs form complex with FKBP
- FKBP/drug complex inhibits IL-2 mediated activation of mTor kinase (T-cell signal 2)
- Inhibits IL-2 stimulated protein synthesis, cell proliferation, and survival
mTor Inhibitors (Sirolimus, Everolimus) - Adverse Effects
- __triglyceridemia
- __cholesterolemia
- Increased __ disease
- Increased risk of __
- Anemia, thrombocytopenia, and leukopenia
- Decreased __ healing
- Teratogenic
- Increased risk of __
- Increased risk of __
mTor Inhibitors (Sirolimus, Everolimus) - Adverse Effects
- Hypertriglyceridemia
- Hypercholesterolemia
- Increased lung disease
- Increased risk of diabetes
- Anemia, thrombocytopenia, and leukopenia
- Decreased wound healing
- Teratogenic
- Increased risk of infections
- Increased risk of malignancy
mTor Inhibitors (Sirolimus, Everolimus) - Misc
- Metabolized by __
- Many drug interactions
- Contraindicated in __
- NOT RECOMMENDED in __ transplantation (risk anastomotic dehiscence), __ transplantation (risk __ artery thrombosis)
mTor Inhibitors (Sirolimus, Everolimus) - Misc
- Metabolized by CYP3A4
- Many drug interactions
- Contraindicated in pregnancy
- NOT RECOMMENDED in lung transplantation (risk anastomotic dehiscence), liver transplantation (risk hepatic artery thrombosis)
Rabbit anti-thymocyte globulin - Indications
-Induction __therapy
Rabbit anti-thymocyte globulin - Indications
-Induction immunotherapy
Rabbit anti-thymocyte globulin - MOA
- Rabbit __clonal antibodies specific for human __
- Depletes __ from the blood
Rabbit anti-thymocyte globulin - MOA
- Rabbit polyclonal antibodies specific for human lymphocytes
- Depletes lymphocytes from the blood
Rabbit anti-thymocyte globulin - Adverse Effects
- __ release syndrome
- __penia
Rabbit anti-thymocyte globulin - Adverse Effects
- Cytokine release syndrome
- Leukopenia
Alemtuzumab - Indications
-Induction __therapy
Alemtuzumab - Indications
-Induction immunotherapy
Alemtuzumab - MOA
- Binds to CD__ expressed on t-cells, b-cells, macrophages, NK cells, and granulocytes
- Depletes cells from the blood by __-__ lysis
Alemtuzumab - MOA
- Binds to CD52 expressed on t-cells, b-cells, macrophages, NK cells, and granulocytes
- Depletes cells from the blood by Ab-mediated lysis
Alemtuzumab - Adverse Effects
- __ release syndrome
- __penia
- Can take over ____ for immune system to recover
Alemtuzumab - Adverse Effects
- Cytokine release syndrome
- Leukopenia
- Can take over 1 yr for immune system to recover
Basiliximab - Indications
-Induction __therapy
Basiliximab - Indications
-Induction immunotherapy
Basiliximab - MOA
- Antagonist of the IL-__
- Blocks __ proliferation
Basiliximab - MOA
- Antagonist of the IL-2R
- Blocks t-cell proliferation
IVIG - Indications
-Provide short-lived __ immunity to patients with deficiency in __ immune system (e.g., hypogammaglobinemia)
IVIG - Indications
-Provide short-lived humoral immunity to patients with deficiency in humoral immune system (e.g., hypogammaglobinemia)
IVIG - MOA
- Pooled __ from healthy individuals
- Provides patient with __ from healthy immunized donors to provide immunity to common pathogens
IVIG - MOA
- Pooled Ig from healthy individuals
- Provides patient with Ig from healthy immunized donors to provide immunity to common pathogens
Rho (D) - Indications
-Prevention of __ disease of the newborn in newborns born to __ females
Rho (D) - Indications
-Prevention of hemolytic disease of the newborn in newborns born to Rh- females
Rho (D) - MOA
- Purified Ig to ____ antigen
- Given to __ mother at 28 weeks and 72 hours post-pregnancy to deplete any fetal __ in maternal blood, to prevent the mother from generating an __ response to fetal __
Rho (D) - MOA
- Purified Ig to Rh (D) antigen
- Given to Rh- mother at 28 weeks and 72 hours post-pregnancy to deplete any fetal RBC in maternal blood, to prevent the mother from generating an immune response to fetal RBC
Hyperimmune Ig - Indications
-To provide rapid specific __ immunity to specific viruses and/or toxins
Hyperimmune Ig - Indications
-To provide rapid specific antibody immunity to specific viruses and/or toxins
Hyperimmune Ig - MOA
- Purified __ to specific antigens purified from healthy volunteers
- Given __ to patients in order to promote clearance of virus/toxin
Hyperimmune Ig - MOA
- Purified Ig to specific antigens purified from healthy volunteers
- Given IV to patients in order to promote clearance of virus/toxin
Ipilimumab - Indications
-Tx of late-stage __
Ipilimumab - Indications
-Tx of late-stage melanoma
Ipilimumab - MOA
- Antibody specific for __
- Antagonizes the negative regulatory __ protein responsible for down-regulating activated __
- Enhances __ response
Ipilimumab - MOA
- Antibody specific for CTLA4
- Antagonizes the negative regulatory CTLA4 protein responsible for down-regulating activated T-cells
- Enhances T-cell response
Ipilimumab - Adverse Effects
-Potential for __ autoimmune response (can be fatal)
Ipilimumab - Adverse Effects
-Potential for RARE autoimmune response (can be fatal)
Pembrolizumab/Nivolumab - Indications
-Tx of late-stage __
Pembrolizumab/Nivolumab - Indications
-Tx of late-stage melanoma
Pembrolizumab/Nivolumab - MOA
- Antibody specific for the __ protein, which is a __ regulatory receptor expressed on activated __ that is responsible for down-regulating __ responses
- The __ ligand __ is expressed on __ cells - this is a mechanism for __ cells to avoid the immune response
- These antibody drugs block __/__ interactions, blocking the inhibitory signal and leading to enhanced __ immune responses
Pembrolizumab/Nivolumab - MOA
- Antibody specific for the PD1 protein, which is a negative regulatory receptor expressed on activated t-cells that is responsible for down-regulating t-cell responses
- The PD1 ligand PD-L1 is expressed on tumor cells - this is a mechanism for tumor cells to avoid the immune response
- These antibody drugs block PD1/PD1-L1 interactions, blocking the inhibitory signal and leading to enhanced tumor immune responses
Methotrexate - Indications
-Tx of autoimmune diseases - especially __ __
Methotrexate - Indications
-Tx of autoimmune diseases - especially rheumatoid arthritis
Methotrexate - MOA
- Inhibition of __ __ to inhibit __ proliferation
- __ mechanism of immunosuppression
Methotrexate - MOA
- Inhibition of dihydrofolate reductase to inhibit lymphocyte proliferation
- Indirect mechanism of immunosuppression
Methotrexate - Adverse Effects
- __ toxicity
- __ toxicity
- __ toxicity
- __ disease
- __ suppression
- __toxicity
- __genic
Methotrexate - Adverse Effects
- Renal toxicity
- Hepatic toxicity
- GI toxicity
- Lung disease
- BM suppression
- Neurotoxicity
- Teratogenic
Methotrexate - Misc
-Contraindicated in __
Methotrexate - Misc
-Contraindicated in pregnancy
Cyclophophamide - Indications
- To prevent __ rejection
- To prevent __
- Tx of __ cases of autoimmune disease
Cyclophophamide - Indications
- To prevent graft rejection
- To prevent GvHD
- Tx of severe cases of autoimmune disease
Cyclophophamide - MOA
- __ chemotherapeutic agent
- ____ DNA, RNA, and proteins
- Inhibits __ proliferation
- Promotes __
Cyclophophamide - MOA
- Alkylation chemotherapeutic agent
- Cross-links DNA, RNA, and proteins
- Inhibits cell proliferation
- Promotes apoptosis
Cyclophophamide - Adverse Effects
- __ suppression
- __ toxicity
- Increased risk of __
- Increased risk of __
- __genic (male/female)
Cyclophophamide - Adverse Effects
- BM suppression
- GI toxicity
- Increased risk of infections
- Increased risk of malignancy
- Teratogenic (male/female)
Cyclophophamide - Misc
-Contraindicated in __, women who wish to __ __, and men who wish to __ __
Cyclophophamide - Misc
-Contraindicated in pregnancy, women who wish to become pregnant, and men who wish to become fathers
Chlorambucil - Indications
-Sometimes used in the tx of __ diseases
Chlorambucil - Indications
-Sometimes used in the tx of autoimmune diseases
Chlorambucil - MOA
- __ chemotherapeutic agent
- ____ DNA, RNA, and proteins
- Inhibits __ proliferation
- Promotes __
Chlorambucil - MOA
- Alkylation chemotherapeutic agent
- Cross-links DNA, RNA, and proteins
- Inhibits cell proliferation
- Promotes apoptosis
Chlorambucil - Adverse Effects
- __ suppression
- __ toxicity
- Increased risk of __
- Increased risk of __
- __genic (male/female)
Chlorambucil - Adverse Effects
- BM suppression
- GI toxicity
- Increased risk of infections
- Increased risk of malignancy
- Teratogenic (male/female)
Chlorambucil - Misc
-Contraindicated in __, women who wish to __ __, and men who wish to __ __
Chlorambucil - Misc
-Contraindicated in pregnancy, women who wish to become pregnant, and men who wish to become fathers
Fingolimod - Indications
-Tx of relapsing-remitting __ __
Fingolimod - Indications
-Tx of relapsing-remitting multiple sclerosis
Fingolimod - MOA
- __ analog
- Binds to 51P receptor to promote sequestration of __ in the lymph node, thereby preventing __ entry to CNS
Fingolimod - MOA
- Sphingosine analog
- Binds to 51P receptor to promote sequestration of lymphocytes in the lymph node, thereby preventing lymphocyte entry to CNS
Fingolimod - Adverse Effects
- __arrhythmia
- __ __
- Increased risk of __ __ __ infection (potentially fatal)
- Increased risk of __
Fingolimod - Adverse Effects
- Bradyarrhythmia
- AV block
- Increased risk of varicella zoster virus infection (potentially fatal)
- Increased risk of malignancy
Natalizumab - Indications
-Tx of relapsing-remitting __ __
Natalizumab - Indications
-Tx of relapsing-remitting multiple sclerosis
Natalizumab - MOA
- Binds __ __ adhesion molecule
- Prevents entry of __ into the CNS
Natalizumab - MOA
- Binds alpha4 integrin adhesion molecule
- Prevents entry of lymphocytes into the CNS
Natalizumab - Adverse Effects
-Increased risk of __ - especially if: a) prior use of immunosuppression, b) seropositive for __ virus, c) chronic treatment
Natalizumab - Adverse Effects
-Increased risk of PML - especially if: a) prior use of immunosuppression, b) seropositive for JC virus, c) chronic treatment
Interferon beta - Indications
-Tx of relapsing-remitting __ __
Interferon beta - Indications
-Tx of relapsing-remitting multiple sclerosis
Interferon beta - MOA
- Activates __ beta receptors
- Alters expression of __ gene expression
- Inhibits entry of __ cells into CNS
Interferon beta - MOA
- Activates IFN beta receptors
- Alters expression of pro-inflammatory gene expression
- Inhibits entry of inflammatory cells into CNS
Glatiramer acetate - Indications
-Tx of relapsing-remitting __ __
Glatiramer acetate - Indications
-Tx of relapsing-remitting multiple sclerosis
Glatiramer acetate - MOA
- Polymer of 4 amino acids found in __ __ __ (MBP)
- Production of specific suppressor __ that suppress inflammation in the __
Glatiramer acetate - MOA
- Polymer of 4 amino acids found in myelin basic protein (MBP)
- Production of specific suppressor T-cells that suppress inflammation in the CNS
Drugs covered in this lecture
- Glucocorticoids/steroids: __/__
- Proliferation inhibitors and anti-metabolites: __, __ __
- Immunophilin-binding drugs - inhibitors of t-cell signaling pathways: calcineurin inhibitors (__, __), mTOR inhibitors (__, __)
- Other anti-proliferative drugs used for immunosuppression: __, __, __
-Antibodies for induction immunosuppression: __ __ __-__ __, __, __
- Misc immunosuppressive drugs used in the tx of RR-multiple sclerosis: __, __, __, __
- Passive immunization IG: __, __, __
- Immune checkpoint inhibitors: __, __ and __
Drugs covered in this lecture
- Glucocorticoids/steroids: prednisone/prednisolone
- Proliferation inhibitors and anti-metabolites: azathioprine, mycophenolate mofetil
- Immunophilin-binding drugs - inhibitors of t-cell signaling pathways: calcineurin inhibitors (cyclosporin, tacrolimus), mTOR inhibitors (sirolimus, everolimus)
- Other anti-proliferative drugs used for immunosuppression: methotrexate, cyclophosphamide, chlorambucil
-Antibodies for induction immunosuppression: rabbit polyclonal anti-thymocyte globulin, alemetzumab, basiliximab
- Misc immunosuppressive drugs used in the tx of RR-multiple sclerosis: fingolimod, natalizumab, interferon, glatiramer
- Passive immunization IG: IVIG, Rho(D) Ig, Hyperimmune Ig
- Immune checkpoint inhibitors: ipilimumab, nivolumab and pembrozilmab
