Cytokines as Therapeutics Flashcards
IL-2 role
T-cell growth factor
Binds IL-2 receptor on lymphocytes
Pro-inflammatory cytokine
Secreted by CD4 lymphocytes; expansion and proliferation of lymphoid cells (B-cells, NK cells); induce secretion of other pro-inflammatory cytokines (e.g., TNF) and immunoglobulins
Main physiological roles of IL-2
Anti-viral/anti-bacterial immune response, select regulatory T-cells, suppress self anti-self recognition
Both immunostimulatory and immunosuppressive effects
Therapeutic uses for IL-2
Metastatic renal carcinoma, acute myeloid leukemia
Limited overall use due to toxicity (auto-immune disorders, capillary leak syndrome, cardiac, CNS, renal/liver toxicity
Main function of interferons
Interfere with viral replication
Type I and Type II interferoms
Type I = INF-alpha, INF-beta
Type II = INF-gamma
Immunostimulatory and immunosuppressive functions of Type I INF
Immunostimulatory: Promote Th1 repsonse, induce IL-15 secretion (promote differentiation of NK cells memory T-cells); induce INF-gamma secretion; induce chemokine secretion
Immunosuppressive: Increase IL-10, decrease IL-12 (pro-inflammatory cytokine)
Type II INF immunostimulatory functions
Activate APCs, increase proliferation of other cells involved in Th1 response
Therapeutic INF uses?
Treat infectious diseases, cancer, autoimmune disease (hep. B and C; hairy cell leukaemia)
Can also precipitate autoimmune diseases
INF-alpha2a indications
Acute and chronic hep C, chronic hep B, leukemias, lymphona
INF-alpha2a mechanism of action
Decreases cell proliferation and differentiation; decrease replication of virally infected cells
Major adverse effects of INF-alpha2a
Immunosuppression, myelosuppression, auto-immune diseases, headache, fatigue, fever
Advantages of a PEGylated formulation of cytokine therapeutics?
Longer half-life
Indications and mechanism of action of INF-alpha2b?
Same as INF-alpha2a
Major adverse effects of INF-alpha2b?
Allergic and hypersensitivity reactions Chest pain Fatigue, fever Headache Myelosuppression
INF-beta indication?
Relapsing MS
Mechanism of action of INF-beta?
Anti-viral and immunoregulatory properties; action in MS not fully understood
Major adverse effects of INF-beta?
Cardiovascular issues (HTN, tachycardia), myelosuppression, allergy/hypersensitivity
G-CSF and GM-CSF indications
Neutropenia (decreased neutrophils - chemo, AIDS, bone marrow transplant), harvesting of peripheral blood cells
Mechanism of action of G-CSF and GM-CSF
Bind receptors (CD114, CD116), stimulate granulocytes and macrophage proliferation
Common adverse effects of G-CSF and GM-CSF?
Nausea, vomiting (questionable), bone pain, allergy, hypersensitivity
What is erythropoietin?
Type of colony stimulating factor - stimulates RBC production
Indications for erythropoietin?
Anemia (from chemo or chronic renal failure)
Mechanism of action of erythropoietin?
Bind erythropoietin receptor, stimulate erythroid cells (RBCs) proliferation
Major adverse effects of erythropoietin?
Pure RBC aplasia, thickened blood due to increase RBCs (CHF, MI, DVT, pulmonary embolism, stroke), seizures
Anti-cytokine therapy?
Inhibit pro-inflammatory cytokines (e.g., TNF) by binding cytokine/cytokine receptor
Anti-TNF, anti-IL-2, etc.
Etanercept
Fusion protein (soluble portion of TNF receptor linked to Fc portion of immunoglobulin) Binds circulating TNF, decreases its serum concentration
Infliximab and adalimumab
Binds circulating TNF-alpha, decreases its concentration
Daclizumab
Binds IL-2 receptor on activated lymphocytes, prevents binding of IL-2
Basiliximab
Binds IL-2 receptor and blocks IL-2 from binding
