-
What are the characteristics of the innate immune response?
- Early, rapid recognition
- No antigen specificity
- <100% immune response
- Limited specificity
- Limited antigen recognition
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What are the components of the innate immune response?
- Granulocytes (Eosinophils, Basophils, Neutrophils)
- Monocytes/Macrophages
- Dendritic cells
- Natural killer cells
- C-reactive protein
- Lysozymes
- Complement
- Interferons
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What are the characteristics of the adaptive immune response?
- Slower response (days)
- Memory a key component
- 100% immune response
- Very specific response
- Recognizes wide array of antigens
-
What are the components of the adaptive immune response?
- Antibodies
- Cytokines
- B cells
- T cells
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What is the process for producing the adaptive immune response?
- Antigen presenting cells (APC) (dendritic cells, monocytes/macrophages) present the antigen to T-helper cells
- Resting T-helper cells with the appropriate receptor (TCR) and CD4 recognize the antigen and MHC II on the APC (Signal 1)
- CD80 and CD86 on the APC interact with CD28 on the T-cell (Signal 2)
- The signal is then passed into the cell through TCR/CD3 complex and the activated T-cell starts expressing IL-2 receptors
- IL-2 binds to the IL-2 receptor which includes CD25, while IL-15 binds to the IL-15 receptor
- mTOR and CDK/cyclins are activated
- Mitosis begins and cell divides and differentiates into TH1, TH2, TH17, etc.
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What are the effects of T-cell activation and differentiation on the immune response and autoimmune diseases?
- TH1 cells secrete IL-2, Interferon gamma, and CD8+ cytotoxic cells, and target intracellular bacteria; viruses; and fungi
- TH2 cells secrete IL-4, IL-5, and stimulate conversion of B cells to plasma cells which produce lots of antibody, and target parasites
- TH17 cells probably cause autoimmune diseases, and target extracellular bacteria and fungi
- APC are also activated, maximizing macrophage activity, increasing conversion of B cells to plasma cells, and releasing inflammatory cytokines
-
What is the MOA of corticosteroids in immunosuppression?
- Inhibition of phospholipase A2 conversion of phospholipids to arachidonic acid causing:
- anti-inflammation
- anti-proliferation
- immunosuppression
- glucocorticoid activity (glucose retention)
- mineralocorticoid activity (sodium retention)
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What are the SE of corticosteroids?
- GI ulceration
- Appetite changes
- Indigestion
- Glucose intolerance
- Insomnia, nervousness, psychosis (high dose)
- Cushion's syndrome (taper off)
- Osteoporosis
- Cataracts, glaucoma
- Fluid and electrolyte disturbance
- Skin atrophy
- Telangiectasia
- Hypopigmentation
- Steroid acne
- Rosacea-like eruptions
-
What are the most widely used corticosteroids?
- Prednisone
- Methylprednisolone
-
What corticosteroid is used in kids and the renally impaired?
Prednisolone
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What are the special considerations for corticosteroids?
- Response may be seen in 2 wks, but maximal effectiveness may take 6-8 wks
- Use least potent agent that is effective (esp. in kids and elderly, or for large or thin-skinned areas)
- Use topical agents 2-4 times daily
- Only use high-potency agents on thick, chronic lesions over small areas and no longer than 2 wks
- Tachyphylaxis can occur with prolonged use (requiring higher doses/strength to get same effect)
-
What is the MOA of methotrexate in immunosuppression?
Inibition of dihydrofolate reductase, disrupting T-cell purine and thymidylic acid metabolism = disruption of cytokine production
-
What are the SE of methotrexate?
- Liver toxicity
- Stomatitis
- NV
- Abdominal pain
- Myelosuppression
- Renal toxicity
- Pneumonitis
- Pulmonary fibrosis
-
What are the special considerations of methotrexate?
- Always dose with folic acid (reduces stomatitis)
- Leucovorin is used to reverse MTX effects
- Doses over 15mg/wk should be given parenterally
- Pregnancy category X
-
What are the DI of methotrexate?
- Penicillin
- TMP/SMX
- Live vaccines
- NSAIDs
- Warfarin
- Immunosuppressants (Cyclosporine, Leflunomide)
- Oral retinoids (additive hepatotoxicity)
-
What is the MOA of leflunomide in immunosuppression?
Disrupts T cell pyrimidine metabolism and cytokine production
-
What are the SE of leflunomide?
- Liver toxicity
- Drug-induced hepatitis
- GI distress
- Myelosuppression
- Alopecia
-
What are the special considerations for leflunomide?
- Loading dose necessary d/t long half-life
- Pregnancy category X
-
What are the DI of leflunomide?
- MTX (additive hepatotoxicity)
- Warfarin
- Live vaccines
-
What is the MOA of the thiopurines (Azathioprine and 6-Mercaptopurine) in immunosuppression?
- Interfere with purine metabolism
- Induce T-cell apoptosis
-
What are the SE of the thiopurines (Azthioprine and 6-Mercaptopurine)?
- Myelosuppression
- Hepatotoxicity
- NV
- Pancreatitis
- Hyperuricemia
-
What are the special considerations for the thiopurines (Azathioprine and 6-Mercaptopurine)?
- Pregnancy category D
- Take with food
- Adjust dose in renal failure (hyperuricemia)
-
What are the DI of the thiopurines (Azathioprine and 6-Mercaptopurine)?
- 5-ASA and related compounds (myelosuppression)
- Allopurinol
-
What is the MOA of mycophenolate in immunosuppression?
Non-competitive inhibition of inosine monophosphate dehydrogenase, interfering with purine synthesis
-
What is are the SE of mycophenolate?
- Myelosuppression
- N, D (dose-related)
-
What are the DI of mycophenolate?
- Aluminum/Magnesium Antacids (absorption)
- Cholestyramine (absorption)
-
What are the special considerations for mycophenolate?
- Pregnancy category D
- Adjust dose in renal failure
-
What is the MOA of cyclophosphamide in immunosuppression?
- Cross-linking and breaks in DNA, decreasing DNA synthesis
- Cell apoptosis
-
What are the SE of cyclophosphamide?
- Myelosuppression
- Alopecia
- Infections
- Cancer
- Hemorrhagic cystitis
- Pneumonitis
- Pulmonary fibrosis
- Reproductive toxicities
-
What are the special considerations for cyclophosphamide?
- Lower doses used in immunosuppression than in oncology
- Use MESNA to prevent bladder toxicity
- Pregnancy category X
- Mainly used for Lupus nephritis
-
What is the MOA for calcineurin inhibitors?
Inhibition of calcineurin causes inhibition of T-cell activation and decreases expression of IL-2 and other cytokines that disrupt T-cell proliferation
-
What are the SE of systemic calcineurin inhibitors?
- Nephrotoxicity
- Increase blood glucose (Tacrolimus more)
- Drug-induced hyperlipidemia (Cyclosporine more)
- Electrolyte disturbances (hyperkalemia)
- Drug-induced hypertension (Cyclosporine more)
- Hirsutism (Cyclosporine)
- Alopecia (Tacrolimus)
- Tremors, disorientation, HA (Tacrolimus more)
- Gingival hyperplasia (Cyclosporine)
-
What are the special considerations for calcineurin inhibitors?
- All three oral formulations are different
- Standard (Sandimmune) and Modified formulations (Neoral, Gengraf) are not interchangeable
- Sandimmune absorption is highly variable d/t reliance on bile salt emulsification
- Narrow therapeutic window = need monitoring
- Monitor trough for all formulations
- Monitor C2 for modified formulations
- Topical use for Psoriasis and Ecsema well tolerated
- Ophthalmic use for Sjogren syndrome reduces dry eye associated with this inflammation
-
What are the SE of topical calcineurin inhibitors?
- Stinging and burning of application site
- Black Box Warning: lymphoma and skin cancer risk in kids and adults
-
What are the calcineurin inhibitors used in immunosuppression?
- Cyclosporin
- Tacrolimus
- Pimecrolimus
-
What are the mTOR inhibitors used for immunosuppression?
-
What is the MOA of mTOR inhibitors in immunosuppression?
bind mTOR complex 1 and inhibit intracellular mTOR activities (continuation of cell growth and division)
-
What are the SE of mTOR inhibitors?
- Hyperlipidemia
- Peripheral edema
- Delayed wound healing
- Mouth ulceration
- Bone marrow suppression (anemia, leukopenia, thrombocytopenia)
- Interstitial lung disease
- Pneumonitis
- Pneumonia
- UTI
- Post-transplant malignancy
- Comstipation (Everolimus)
- Teratogenic
-
What are the special considerations for mTOR inhibitors (Everolimus, Sirolimus)?
- Narrow therapeutic window = monitoring
- Monitor trough
-
What are the DI of mTOR inhibitors (Everolimus, Sirolimus)?
- 3A4 and p-glycoprotein interacions = many
- Calcineurin inhibitor SE enhanced
-
What is the MOA of Fingolimod in immunosuppression?
- Sphingosine 1-phosphate (S1P) receptor modulator
- Maybe - reduces migration of lymphocytes from nodes to peripheral circulation
-
What are the SE of Fingolimod?
- HA
- Influenza
- D
- Back pain
- Liver enzyme elevation
- Cough
-
What are the DI of Fingolimod?
- CI antiarrhythmics (Quinidine, Procainamide)
- CIII antiarrhythmics (Amiodarone, Sotalol)
- BBL
- Ketoconazole
- Live vaccines
-
What is the MOA of biologic therapy in immunosuppression?
Typically, through non-covalent binding, disrupt cell signaling and/or cause depletion of B-cells and T-cells
-
What are the SE of biologic therapies?
- Infusion/injection reactions (hypotension, injection site rxns, fever, chills, cytokine release)
- Hypersensitivity
- Flu-like syndromes
- Coughing
- Infections
- Skin reash (esp. with SQ dosing)
-
What are the special considerations for biologic therapies?
- Production of neutralizing antibodies by the host can reduce and eliminate effectiveness
- Very few drug interactions
- DO NOT combine biologic agents together
-
What are the types of biologic therapies used for immunosuppression?
- Polyclonal antibodies
- Monoclonal antibodies
- Intravenous Immune Globulin (IVIG)
-
What is the MOA of polyclonal antibodies (Atgam, Thymoglobulin)?
T-cell depletion by killing active T-cells Blocks CD25, CD3 to prevent T-cell activation)
-
What are the SE of polyclonal antibodies?
- Fever, chills, cytokine release (use diphenhydramine)
- Thrombocytopenia
- Leukopenia
- HA (first few doses)
-
What are the special considerations for polyclonal antibodies?
- Atgam (lymphocyte)(horse):
- Skin testing strongly recommended before administration
- Preferred route = central line over 4h
- Thymoglobulin (antithymocyte)(rabbit):
- Pre-medicate with APAP and diphenhydramine
- Infuse with an in-line filter through a central line
-
What is the MOA of IVIG in immunosuppression?
Disrupts immune system and tones it down
-
What are the SE of IVIG?
- Chills, nausea, HA, flushing during and after infusion (pre-medicate, slow down infusion, or temporarily stop infusion)
- Acute renal failure
- Transient neutropenia
- Risk of infection
- Hep B, Hep C, HIV
- Creutzfeldt-Jakob disease
-
What are the special considerations for IVIG?
Each preparation is different composition, salt content, and/or pH (Selected - specific IgGs, Unselected - lacks specificity)
-
What is the MOA of monoclonal antibodies in immunosuppression?
- Induction of apoptosis
- Antibody-dependent cell cytotoxicity (ADCC)
- Antibody-mediated cell death by other cells of the immune system
- Complement-mediated cell death (CDC)
-
What are the SE of infliximab?
- Reactivation of Hep B and TB
- Serious infection risk
- Heart failure exacerbation
- Lymphoma risk
- Demyelinating disease
-
What are the SE of adalimumab?
- Reactivation of Hep B and TB
- Serious infection risk
- Heart failure exacerbation
- Lymphoma risk
- Demyelinating disease
-
What are the SE of Certolizumab pegol?
- Reactivation of Hep B and TB
- Serious infection risk
- Heart failure exacerbation
- Lymphoma risk
- Demyelinating disease
-
What are the special considerations for Certolizumab pegol?
- It is a Fab fragment (no Fc region on the mab)
- No ADCC or CDC expected
-
What are the SE of golimumab?
- Reactivation of Hep B and TB
- Serious infection risk
- Heart failure exacerbation
- Lymphoma risk
- Demyelinating disease
-
What are the SE of Tocilizumab?
- Serious infection risk (neutropenia)
- Liver toxicity
- GI perforation
- Lipid abnormalities
-
What are the SE of Ustekinumab?
- Mycobacterial and salmonella infection risk
- Malignancy risk
- Risk of Reversible Posterior Leukencephalopathy Syndrome (RPLS; 1 case)
-
What are the SE of natalizumab?
- Risk of demyelinating disease (Progressive Multifocal Leukencephalopathy PML; 5 cases)
- This is fatal, there is no treatment
-
What are the SE of Rituximab?
- Demyelinating disease
- Renal toxicity
- Infection (monitor CBC)
-
What are the SE of Daclizumab and Basiliximab?
generally well tolerated
-
What is the target of Infliximab, Adalimumab, Certolizumab pegol, and Golimumab?
TNF alpha
-
What drugs target TNF alpha?
- Infliximab
- Adalimumab
- Certolizumab pegol
- Golimumab
-
What is the target of Tocilizumab?
IL-6
-
What is the target of Ustekinumab?
-
What is the target of Natalizumab?
alpha-4-integrin (adhesion molecule)
-
What is the target of Rituximab?
CD20 (B cells)
-
What is the target of Daclizumab and Basiliximab?
CD25
-
-
What are the meanings of the first infix of monoclonal antibodies?
- -li-/-l-: immunomodulatory
- -ki(n)-/-k-: targets interleukins
- -tu-/-t-: targets tumors
- -ci-/-c-: targets cardiovascular system
- -so-/-s-: bone
-
What are the meanings of the second infix of monoclonal antibodies?
- -u-: fully human
- -zu-: humanized
- -xi-: chimeric
- -o-: fully mouse
- -i-: primate
-
What are the antibody-based fusion proteins used in immunosuppression?
- Etanercept (TNF alpha)
- Abatacept (CD80/CD86)
- Alefacept (LFA-3)
- Rilonacept (IL-1)
- Anakinra (IL-1)
-
What is the target for Etanercept?
TNF-alpha
-
What is the target for Abatacept?
CD80/CD86
-
What is the target for Alefacept?
LFA-3
-
What is the target for Rilonacept?
IL-1
-
What is the target for Anakinra?
IL-1
-
What are the SE of Etanercept?
- Reactivation of HepB and TB
- Heart failure exacerbation
- Lymphoma risk
- Demyelinating disease
- Serious infection risk
-
Why do TNF-alpha agents cause exacerbation of heart failure?
TNF-alpha keeps the heart in check
-
What are the SE of Abatacept?
- Relatively safe and well tolerated
- Contains CTLA-4 (endogenous co-stimulation signal blocker)
-
What are the special considerations for Alefacept?
- Monitor CD4 counts
- Mild effects and slow onset
-
What are the SE of Rilonacept?
- Injection site reactions
- URTIs
-
Which agents prevent T-cell activation?
- Abatacept (CD80/CD86)
- Cyclosporine (Calcineurin)
- Tacrolimus (Calcineurin)
- Pimecrolimus (Calcineurin)
-
Which agents decrease the inflammatory effects of cytokines?
- Corticosteroids
- Infliximab (TNF)
- Adalimumab (TNF)
- Certolizumab pegol (TNF)
- Golimumab (TNF)
- Etanercept (TNF)
- Tocilizumab (IL-6)
- Ustekinumab (IL-12, IL-23)
- Rilonacept (IL-1)
- Anakinra (IL-1)
-
Which agents interrupt the cell cycle and disrupt cell division/differentiation?
- Sirolimus (mTOR)
- Everolimus (mTOR)
-
Which agents prevent the release of IL-2 and activation of IL-2 receptors, halting the cell cycle and differentiation/division?
- Daclizumab (CD25)
- Basiliximab (CD25)
-
Which agents inhibit B-cells?
Rituximab (CD20)
-
What happens if T-cells are not activated?
- APCs are not activated and:
- cytokines are not released
- macrophages are not at full capacity
- B-cells do not become plasma cells
- Antibodies are not released
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