Help
Options
Didn't know it?
click below
click below
Knew it?
click below
click below
Don't Know
Remaining cards (0)
Know
retry
shuffle
restart
0:00
Embed Code - If you would like this activity on your web page, copy the script below and paste it into your web page.
Normal Size Small Size show me how
Normal Size Small Size show me how
Med Micro Y2S1B2
Immunopharmacology
| Question | Answer |
|---|---|
| Innate Immunity: Onset, mechanism of antigen recognition | onset is immediate; antigen recognition via receptors for microbe/viral molecules; |
| Innate Immunity: Cell types/factors | Macrophages, Neutrophils, Mast cells, NK cells, complement, interferon |
| Acquired Immunity: Cell-Mediated and Humoral: Onset, Mechanism of antigen recognition | days to weeks, unique antigen specific receptors (Tcell/Bcell receptors) |
| Acquired Immunity: Cell-mediated, Humoral: Cell Types/factors | APCs, T-lymphocytes, B-lymphocytes |
| Normal Immune Response | designed to protect host/eliminate disease; can recognize "self" antigens; innate/adaptive responses |
| Innate Immune System: First line of defense against antigenic insult | Physical (biochemical: complement/lysozyme/interferons); cellular (neutrophils/monocytes/MQs); Inflammatory response triggered by infxn (neutrophils/monocytes from peripheral circulation enter tissues) |
| Innate Immune System: First line of defense when barrier is breached | comlement and lysozymes are activated, destroys/lyses cell wall of bacteria; ingest/degrade/eliminate pathogens; disease is prevented or duration is decreased |
| Acquired Immunity | takes over when innate can't cope; mobilized by cues from innate; responds to variety of Ag; know's "self;" memory response; divided into Humoral & Cell-Mediated; involves activation of naive T cells |
| Acquired Immunity: mechanisms of recognition | requires APC (dendritic/MQs/Bcells) to process Ag into peptide frags; Peptides bind MHC class II molec w/in APC; MHC presented to CD4+ Tcells w/specific receptor for peptide-MHC complex |
| Acquired Immunity: Tcells require 2 signals to become fully active: | 1. peptide receptor binding; 2. APC T-cell interaction; 1 w/o 2 leads to tolerance |
| Acquired Immunity: Fully activated T cells | differentiate/proliferate into T-helpers (Th1, Th2); Th cells produce cytokines |
| Acquired Immunity: Cell-mediated | involves Th1-mediated activation of MQs and CD8+ cytotoxic lymphocytes (CTLs); Th1 cells secrete cytokines to recruit MQs; local inflam response by MQs can kill intracellular bacteria; CTLs mediate Ag-specific lysis |
| Examples of CTL mediated antigen specific lysis | tumor cells; graft/transplant cells; virally infected cells |
| pCTLs (naive precursor CTLs) require activation by 2 signals: | 1. binding of peptide Ag to APC which binds to TCR on CD* pCTLs; 2. Receptor-ligand interaction of co-stimulaotry molecules |
| Th1 cells produce: | cytokines which stimulate dendritic cells to upregulate co-stimulatory molecules and activate Ag-stimulated CD8 cells |
| Activated CTLs produce: | IL-2 |
| In some cases, APCs containing high levels of co-stimulatory molecules can: | activate CD8 cells without Th1 cells present |
| Activated CTLs cause: | Ag-recognition and binding which results in cell lysis |
| Humoral Immunity: Th2 cells | secrete cytokines which stimulate differentiation/proliferation of B cells that become Ab-secreting plasma cells or long-lived memory cells |
| Antigen-specific antibodies | can remove harmful foreign bugs by binding and neutralizing antigens; Ag-Ab complexes activate complement |
| Complement elicits: | a local inflammatory reaction that facilitates Ag removal by phagocytes |
| Fc region of Ab | binds to foreign protein/bacteria before binding to receptors on phagocytic cells for internalization of pathogen |
| Abnormal Immune Response leads to the inability to: | neutralize toxins, inactivate viruses, destroy transformed cells, eliminate pathogens |
| Inappropriate immune responses can result in: | tissue damate (hypersensitivity), reactivity against self (autoimmunity), impaired reactivity to appropriate targets (immunodeficiency) |
| Hypersensitivity | classified as immediate or delayed responses (depends on time to manifest clinical Sx) |
| Immediate hypersensitivity | Ab-mediated; Sx occur w/in min-hrs; Hypersensitivity types I, II, III |
| Delayed hypersensitivity | cell mediated; response can occur 2-3 days following the initial exposure; hypersensitivity type IV |
| Hypersensitivity Type I | dt x-linking of membrane bound IgE (basophils in blood/mast cells in tissue); degranulation (histamine/leukotrienes/eosinophil chemotactic factor); asthma/hay fever/urticaria; severe rxns = anaphylaxis (requires immed med intervention) |
| Hypersensitivity Type II | results from Ag-Ab complexes (IgG or IgM); ex: blood transfusion rxn; can be drug-induced (PCN administered to allergic pt causes anaphylaxis) |
| Hypersensitivity Type III | dt high levels of Ag-Ab complexes; complex deposition and action of lytic enzymes; causes skin rashes/glomerulonephritis/arthritis |
| Hypersensitivity Type IV | delayed-type (DTH); cell-mediated; local inflam response (influx of Ag-nonspecific inflam cells: MQ/neutrophils); cells recruited by Th1 (extravasation/chemotaxis); phagocytic/microbicidal/APC/digestive enzymes; deleterious; intracellular pathogens!! |
| Autoimmunity | body mounts immune response to itself; dt inability to distinguish self from antigen (nonself); activation of self-reactive T/B lymphocytes; diseases are complex dt MHC genetics/environmental conditions/infectious entities/dysfxnl immune regulation |
| 3 Proposed mechanisms for autoimmunity | 1. exposure of self-reactive Tlymphocytes to Ag previously sequestered from immune system; 2. Inappropriate MHC-II expression (inc presentation of self peptide to Thelper cells); 3. Molecular mimicry of invading pathogens |
| Immunodeficiency Diseases | dt abnml immune system; inc susceptibility to infxns; inc duration/severity of disease; can arise from drug Tx; Congenital acquisition (X-linked aggamaglobulinemia/DiGeorge/SCID); or Extrinsic factors (AIDS) |
| Test of Immunocompetence | tests immunologic competence and drug-induced immune dysfxn; used to detect effect of immunosuppressive/immunostimulating agents; seven tests in pathology departments |
| Immunocompetence Test I | DTH testing w/skin antigens used to detect the ability to respond to a recall antigen |
| Immunocompetence Test II | measure of serum immunoglobulins, serum complement, and specific antibodies to natural and acquired antigens |
| Immunocompetence Test III | serial measurements of antibody response after primary immunization or secondary booster injection |
| Immunocompetence Test IV | total circulating lymphocyte count |
| Immunocompetence Test V | measurement of B cells, T cells and subsets (CD4, CD8, CD11a and CD56) |
| Immunocompetence Test VI | In vitro lymphocyte proliferative responses to mitogens or specific antigens of interest; response can be measured by cytokine production of titrated thymidine incorporation |
| Immunocompetence Test VII | mixed lymphocyte reaction, where lymphocytes from one individual are mixed with and proliferated in response to a allogenic lymphocyte from another individual |
| Glucocorticoids | hormonal agents w/lympholytic properties that reduce size and lymphoid content of lymph nodes and spleen; interferes w/cell cycle of activated lymphoid cells; can be cytotoxic to subsets of T cells |
| Glucocorticoids: immunologic effects | no direct cytotoxicity (incl proliferating myeloid/erythroid stem cells in bone marrow); Inhibits production of inflam mediators (PAF/leukotrienes/prostaglandins/histamine/bradykinin); dec chemotaxis & bacter-/fungicidal activity of neutrophils/monocytes |
| Glucocorticoids: leukocyte distribution | causes lymphopenia and neutropenia; dec production of IL-2 and IFN-g vi IL-1 inhibition; dec Ab response (affects cellular immunity > humoral); continued use can dec previously established Ab response |
| Continuous administration of prednisone increases | the fractional catabolic rate of IgG, thus lowering the effective concentration of specific antibodies |
| Corticosteroids used in the treatment of | many conditions dt immunosuppressive/anti-inflammatory properties (idiopathic thrombocytopenia pupura, RA, allergies, bronchial asthma, premedication for transplant recipients) |
| Cyclosporine (gengraf) | fat-soluble peptide antibiotic; used for organ transplant; Tx of graft-v-host dx and some autoimmune disorders |
| Cyclosporine MOA | blocks activation of Tcells in early stage of Ag receptor-induced differentiation; complexes w/cyclophilin & inhibits cytoplasmic phophatase for (calciperuin) Tcell transcription factor (NF-AT)involved in IL-2 synthesis |
| Studies of Cyclosporine have shown | inhibition of gene transcription of IL-2, IL-3, IFN-g, and other factors stimulated by antigen-stimulated Tcells; does not block interaction with antigen or factors on primed T cells |
| Tacrolimus (FK506, Prograf) | macrolide antibiotic produced by Strep tsukubaensis; 10x more potent than cyclosporine; used for organ transplant (solid recipients and standard rejection therapy); atopic dermatitis and psoriasis |
| Tacrolimus (FK506, Prograf) MOA | IV, Oral, Topical; similar to cyclosporine; binds cyclophilin and immunophilin FK-binding ptn (FKBP); inhibits cacineurin (needed for activation of Tcell specific transcription factor (NF-AT) |
| Tacrolimus (FK506, Prograf) Pharmokinetics | dosage determined by trough levels at steady state; Peak [oral] at 1-4hrs; Half-life 9-12hrs (IV); metabolized by CYP450 |
| Tacrolimus (FK506, Prograf) Toxic Effects | nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, GI symptoms |
| Sirolimus (Rapamune) | derived from Strep hygroscopicus; used alone or in combo (cyclosporine/tacrolimus/mycophenolate mofetil); solid organ transplant; uveoretinitis; steroid-refractory acute/chronic graft-v-host in stem cell transplants |
| Sirolimus (Rapamune) MOA | similar to cyclosporine/tacrolimus; binds immunophilins, inhibits calcineurin, blocks Tcell respone to cytokines, inhibits Bcell/mononuclear cell prolif & immunoglobulin production; inhibits HEMATOPOIETIC recovery after Tx |
| Sirolimus (Rapamune) Pharmokinetics | antagonizes tacrolimus-induced Tcell response; synergistic response w/cyclosporine; **does NOT block IL production by Tcells** |
| Sirolimus (Rapamune) Toxicities | myelosuppression (esp thrombocytopenia); hepatotoxicity; diarrhea; hypertriglyceridemia; HA |
| Interferons | grouped into three families: INF-a, INF-b, INF-g; interact w/cell receptors to produce a variety of different effects |
| INF-a and INF-b | contain type I INFs; acid stable proteins that act on same receptors on target cells; usu induced by viral antigens; more potent than INF-g |
| INF-g | type II INFs; acid-labile protein that acts on a separate receptor target cell; usu produced by activated T-lymphocytes |
| INF immune enhancing properties | esp INF-g; inc APC, MQ, NKC, and cytotoxic Tcell activation; Inhibits cell proliferation; inc expression of MHC-I molecules on cell surfaces (INF-g induces MHC-II, also) |
| INF indications: Hepatitis C | combo therapy; INF-a + Rivabirin |
| INF indications: Cancers | melanoma, renal cell carcinoma, chronic myelogenous leukemia |
| INF indications: Relapsing-remitting multiple sclerosis | INF-b; reduced rate of exacerbation and less severe disease w/minimal side effects |
| INF Toxicities | fever, chills, malaise, myalgia, myelosuppression, HA, depression |
| Mycophenolate mofetil (CellCept) | semisynthetic derivative of mycophenolic acid isolated from Penicillium glaucum; solid organ refractory rejection (cadaver allografts); steroid refractory graft-v-host (bone marrow); lupus, RA, derm |
| Mycophenolate mofetil (CellCept): MOA | Oral, IV; inhibits mitogen and mixed lymphocyte responses; inhibits de novo synthesis of purines; hydrolyzed to mycophenolic acid (active immunosuppressant) |
| Mycophenolate mofetil (CellCept): Toxicity | GI disturbances (N/V/D, abdominal pain); myelosuppression (primary neutropenia) |
| Thalidomide (Thalomid) | sedative drug previously removed from market dt teratogenic effects; useful as immunosuppressant for >40 conditions |
| Thalidomide (Thalomid) MOA | inhibits TNF-a & angiogenesis; dec phagocytosis by neutrophils; inc IL-10 production; alters adhesion molec expression; enhances cell-mediated immunity by Tcell interaction; anti-inflammatory/immunomodulatory |
| Thalidomide Indications | multiple myeloma (initial diagnosis & relapsed-refractory disease; combo w/dexamethasone?); erythema nodosum leprosum (leprosy); skin manifestations of SLE; better response w/combo therapy |
| Thalidomide Toxicity | teratogenesis, peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, inc risk of DVT (thrombosis is particularly frequent in myeloma pts --> use warfarin therapy) |
| Azathioprine (Imuran) | prototype for antimetabolite cytotoxic immunosuppressants; derivative of mercaptopurine; action is mediated by its conversion to an active structural metabolite; |
| Azathioprine: MOA | can block cellular immunity and secondary serum antibody response; kills proliferative cells; interferes w/purine nucleic acid metabolism and lymphocyte prolif following antigenic stimulation; less activity in proliferating cells; |
| Azathioprine: Pharmokinetics | absorbed in GI tract; metabolized to mercaptopurine; excreted in urine; small amts of unchaged drug are excreted renally |
| Azathioprine: Indications | renal allografts/other transplant tissues; acute glomerulonephritis; renal component of SLE, RA, Chron's disease, MS, prednisone-resistant Ab-mediated idiopathic thrombycytopenia purpura and autoimmune hemolytic anemia |
| Azathioprine: Caution and Toxicity | pts taking allopurinol should reduce dose to 1/3-1/4 of normal; bone marrow suppression (usu leukopenia), anemia, thrombocytopenia, skin rask, fever, N/V/D, hepatic dysfxn (inc alk phos/mild jaundice); can be 2x higher in anephric or anuric pts |
| Leflunomide (Arava) | inhibitor of purine synthesis; only FDA drug approved for RA; being studied in combo w/mycophenolate mofetil to treat autoimmune/inflamm skin disorders |
| Leflunomide (Arava): Pharmokinetics | should be started with a loading dose; prodrug; orally active w/an active metabolite (active metabolite half-life is several wks); can be taken every day after SS?? |
| Leflunomide (Arava): Toxicity | elevated LFTs; dec risk of liver damage; renal impairment; CV effects (angina, tachycardia), teratogenic |
| Cyclophosphamide (Cytoxan) | ankylating agent; one of most efficacious immunosuppressants for SLE, MS, autoimmune hemolytic anemia, Ab-induced pure red cell aplasia, Wegener's granulomatosis |
| Cyclophosphamide (Cytoxan): MOA | destroys proliferating lymphoid cells, alkylates some resting cells |
| Cyclophosphamide (Cytoxan): Concerns and Toxicity | at high doses it can induce apparent specific tolerance to new antigen; usu combined w/stem cell rescue (transplant) procedures; does NOT prevent graft v. host; Pancytopenia, hemorrhagic cystitis; N/V, cardio-toxic, electrolyte abnormalities |
| Vincristine (oncovin) | vinca alkaloid; idiopathic TP refractory to prednisone |
| Vincristine (oncovin): MOA | though to prevent mast cell degranulation; binds to microtubule units w/in cell; prevents release of histamine and other vasoactive compounds |
| Methotrexate (rheumatrex) | extensive use in RA and graft v. host disease; used in pts w/idiosyncratic rxns to purine antagonists; oral administration |
| Cytarabine (cytosar) | inhibits DNA synthesis; hepatic metabolism; used for bone marrow transplantation, solid organ tumors, leukemia, lymphoma |
| Dactinomycin (cosmegen) | antibiotic, used in renal transplant recipients w/impending rejection |
| Immunosuppressant sites of action: Antigen recognition | Antilymphotyic globulin, monoclonal anti-Tcell antibodies; Rho (D) immune globulin |
| Immunosuppressant sites of action: Proliferation | Prednisone; Cyclosporine; Tacrolimus; Azathioprine; Methotrexate; Dactinomycin; Cyclophosphamide; Antilymphotyic globulin, monoclonal anti-Tcell antibodies |
| Immunosuppressant sites of action: Differentiation/synthesis | Cyclosporine; Tacrolimus; Dactinomycin; Antilymphotyic globulin, monoclonal anti-Tcell antibodies |
| Immunosuppressant sites of action: Tissue injury | Prednisone |
| Other immunosuppressant sites of action | interaction, complement |
| Antibody agents | began w/hybridoma technology; used clinically and diagnostically; development of monoclonal antibody fragments w/specificity and high affinity for antigen; hu |
| Antibody agents and hybridomas | consist of antibody forming cells fused to immortal plasmacytoma cells; stable hybrid cells produce the required amount of cloned antibody in mass culture |
| Humanization of murine monoclonal antibodies | increases half-life; decreased risk of producing antimouse antibodies |
| Antilymphocyte and Antithymocyte Antibodies | heterologous antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) |
| ALG | acts on small, long-lived lymphocytes; w/long use "thymus-dep" lymphocytes depleted; destruction/inactivation of Tcells impairs DTH & cellular immunity; used in combo w/monoclonal Ab for immunosuppression, initial rejection, steroid-resistant rejection |
| ALG: Toxicity | local pain and redness around injection site; anaphylaxis and serum sickness; histocytic lymphomas in buttock; increased risk of cancer |
| ALG and ATG: Indications | suppresses compartments of immune system; manages organ/bone marrow transplants; can be used in combo w/cyclosporine for bone marrow transplant prep (treat high dose 7-10d prior; residual ALG destroys Tcells in donor marrow and dec risk of graft v. host) |
| Immune Globulin (IGIV) | prepared from thousands of healthy donors; no specific antigen targeted; pooling "normalizes" effect on pts immune network |
| Immune Globulin (IGIV): MOA | reduces production of Th cells; Increases suppression of Tcells; causes dec in spontaneous immunogobulin production |
| Immune Globulin (IGIV): Indications | asthma, autoimmune disorders (Kawasaki's disease, subacute SLE, refractory idiopathic TP) |
| Rho (D) Immune Globulin Micro-dose | 15% human IgG w/a higher titer of Ab against Rho (D) antigens on RBCs; Rh+ cells are transferred in 3rd trimester leading to development of erythroblastosis fetalis |
| Sensitization of mother to D-antigen (Rh) occurs at: | time of birth, from miscarriage or from ectopic pregnancies |
| Rho (D) Immune Globulin Micro-dose: Indications | used to treat Rh hemolytic disease of the newborn; Prophylaxis of Rho (D)-negative mothers that have not been immunized to the Rho factor; Treatment for Rh-negative others that have had an abortion, miscarriage or ectopic pregnancy |
| Rho (D) Immune Globulin Micro-dose: Toxicity | usu infrequent, but may cause local discomfort at injection site and rarely a slight temperature increase |
| Hyperimmune Immunoglobulins | preparations of IVIG made from pools of select human or animal donors (they have high-titer antibodies against a SPECIFIC antigen like virus or toxin) |
| Hyperimmune Immunoglobulins: Indications | respiratory syncytial virus, varicella-zoster virus, human herpes virus 3, hepatitis B virus; rabies, tetanus, digoxin overdose; given as antivenom for rattlesnake or coral snake bites |
| Hyperimmune Immunoglobulins: Pharmokinetics | IV administration conveys passive transfer of high-titer antibodies; reduces the risk or severity of the infection |
| Monoclonal Antibodies | gene manipulation of immunoglobulins resulted in humanized and chimeric monoclonal antibodies; several engineered Abs are available on market |
| The murine element remains in the human monoclonal antibodies | complementarity-determining region (CDRs) in heavy and light chains); CDR loops are responsible for Ag-binding capacity of antibodies |
| Chimeric antibodies contain | the antigen-binding murine variable regions and human constant regions |
| Trastuzumab (Herceptin) | recombinant DNA-derived humanized monoclonal antibody; Used for metastatic breast cancer (tumors overexpressing HER-2/neu); induces remission in 15-20% of pts; can be used in combo w/chemotherapy (inc response rate/duration and 1-yr survival) |
| Trastuzumab (Herceptin): MOA | binds to extracellular domain of human epidermal growth factor receptor (HER-2/neu); blocks the natural ligand from binding and down-regulates the receptor |
| Trastuzumab (Herceptin): Pharmokinetics | IV infusion, dosage adjustment for renal impairment; under investigation for use in other tumors that express HER-2 |
| Trastuzumab (Herceptin): Toxicity | pain, fever, chills, HA, N/V/D, abdominal discomfort, weakness, back pain, cough, dyspnea, rhinitis, pharyngitis; monitor for cardiac dysfunction during infusion |
| Rituximab (Rituxan) | murine-human monoclonal IgG1 (human Fc) antibody; used for relapse or refractory low-grade of follicular Bcell non-Hodgkin's lymphoma |
| Rituximab (Rituxan): MOA | binds CD20 molecule on normal and malignant Blymphocytes; complement-mediated lysis of cell; antibody-dependent cellular toxicity; induction of apoptosis of malignant lymphoma cells; used in combo w/chemotherapy (synergistic) |
| Rituximab (Rituxan): Toxicities | Bcell depletion (70-80%), fever, chills, asthenia, angioedema, HA, nausea, leukopenia |
| Ibritumomab tuxetan (Zevalin) | anti-CD20 murine monoclonal Ab labeled w/Indium-111 and Yttrium-90; Used for relapse/refractory low-grade, follicular or Bcell non-Hodgkin's lymphoma (NHL); Used in pts w/rituximab-refractory follicular NHL |
| Ibritumomab tuxetan (Zevalin): MOA | binds to and induces apoptosis of Blymphocytes; Tuxetan is a chelator used in specific chelation site of Indium-111 or Yttrium-90; Acts as delivery system to direct radioactive isotopes to target cells; Used in combo w/Rituximab in a 2-step regimen |
| Ibritumomab tuxetan (Zevalin): Toxicity | myelosuppressive (highly); thrombocytopenia, neutropenia, anemia (>60%); chills, fever, pain, HA, N/V, abdominal pain, weakness, dyspnea, infection |
| Daclizumab (Zenapax) | humanized (chimeric) IgG1 that binds to CD25; functions as an interleukin antagonist, Prophylaxis of acute organ rejection in renal transplants; administered 24hrs prior to transplant and 4 separate doses at 2wk intervals |
| Daclizumab (Zenapax): MOA | blocks IL-2 from binding to activated lymphocytes; used in combo w/glucocorticoids and cyclosporine |
| Daclizumab (Zenapax): Toxicity | diarrhea, vomiting, fever, pruritus, respiratory tract infections, UTI |
| Basiliximab (Simulect) | Chimeric human-mouse IgG1 monoclonal antibody; similar to Daclizumab; Used as prophylaxis of acute organ rejection in renal transplants |
| Basiliximab (Simulect): MOA | binds to IL-2 receptor alpha chain on activated lymphocytes; given in 2 IV bolus or IV infusions; Given no more than 2hrs bf transplant and the second dose 4 days after procedure |
| Basiliximab (Simulect): Toxicity | peripheral edema, HTN, atrial fibrillation, fever, HA, insomnia, pain, electrolyte imbalances, UTI, dyspnea, URTI, anemia, tremors |
| Abciximab (ReoPro) | Fab fragment of a murine-human monoclonal antibody; Used to prevent acute cardiac ischemic complications in pts at high risk for re-stenosis; Adjunct to heparin therapy to prevent cardiac ischemia in pts w/unstable angina |
| Abciximab (ReoPro): MOA | Binds to the GPIIb/IIIa receptor on activated platelets resulting in steric hinderance; Inhibits fibrinogen, Von-Wilebrand factor and other adhesive molecules from binding to activated platelets; Prevents platelet aggregation |
| Abciximab (ReoPro): Toxicity | Hypotension, chest pain, minor bleeding, back pain; Monitor CBC, PT, aPTT, platelet count, fibrinogen, guaiac stools |
| Palivizumab (Synagis) | monoclonal antibody; Used in prevention of RSV infection in neonates at risk; reduced frequency of infection and hospitalization by 50%; should be used during on set of RSV season (Oct-Dec) |
| Palivizumab (Synagis): MOA | binds to fusion protein of respiratory syncytial virus (RSV); exhibits neutralizing properties against RSV; Prevents infection in susceptible cells in the airways |
| Infliximab (Remicade) | human-mouse chimeric IgG1 monoclonal antibody (contains human Fc and murine variable regions); Used for Chron's disease of colon and RA (in combo w/Methotrexate) |
| Infliximab (Remicade): MOA | binds to TNF-a (pro-inflammatory cytokine); causes suppression of downstream inflammatory cytokines (IL-1, IL-6, adhesion molecules involved in leukocyte activation and migration) |
| Infliximab (Remicade): Toxicity | increased incidence of lymphoma; HA, fatigue, fever, rash, N/V/D, URTI, cough, infxn, development of antinuclear antibodies, development of new abscess (Chron's); Contraindicated in CHF pts; Monitor hypersensitivity reaction |
| Etanercept (Enbrel) | dimeric fusion protein composed of human IgG1; Used for RA, polyarticlar course juvenile RA, psoriatic arthritis; |
| Etanercept (Enbrel): MOA | binds to both TNF-a and TNF-b; similar effect to infliximab (TNF-a mediated inflam); |
| Etanercept (Enbrel): Pharmokinetics | SQ administration twice weekly; can be used in combo w/methotrexate |
| Etanercept (Enbrel): Toxicity | HA, injection site reaction, RTI, URTI; infection, positive ANA, positive dd-DNA autoantibodies |
| Adalimumab (Humira) | completely *Human IgG1 monoclonal antibody; generated using antibody-phage display technology |
| Adalimumab (Humira): MOA | blocks the interaction of TNF-a with TNF receptors on cell surfaces; does not bind TNF-b; lyses cells expressing TNF-a in presence of complement; reduced levels of CRP, ESR, serum IL-6, MMP-13 |
| Adalimumab (Humira): Pharmokinetics | half-life of 2wks; maybe increased by 29-44% in pts taking combo therapy w/methotrexate |
| Alefacept (Amevive) | engineered protein made of CD2-binding portion of LFA-3 fused to human IgG1 Fc region (hinge, Ch1 and Ch2); Used for plaque psoriasis |
| Alefacept (Amevive): MOA | Inhibits activation of T cells by binding to cell surface CD2; Inhibits normal CD2/LFA-3 interactions |
| Alefacept (Amevive): Pharmokinetics and Toxicity | dosed once weekly IV or IM bolus; Dose-dependent reduction in circulating Tcells overall and Tcells in psoriatic plaques; Monitor Tcell levels (*d/c medication if CD4 levels fall below 250cells/uL) |
| Alemtuzumab (Campath) | Humanized IgG1 w/a kappa chain that binds CD52; Used for B cell chronic lymphoyctic leukemia (in pts who fail treatment w/alkylating agents and fludarabine); partial response of 20-30% in clinical trials |
| CD52 | found on normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and small population of granulocytes |
| Alemtuzumab:Toxicity | lymphopenia, neutropenia, anemia, thrombocytopenia; Monitor opportunistic infxns and hematologic toxicity |
| Solid organ and bone marrow transplant | requires tissue typing (based on donor/recipient histocompatibility matching; HLA); close matching reduces graft rejection/intensive immunosuppressant therapy |
| Prior to transplant, pt receives | immunosuppressive therapy: ATG, Muromonab-CD3, Daclizumab, or Basiliximab |
| Four types of transplant rejection can occur: Hyperacute | preformed antibodies against donor organ, occurs w/in hrs of transplantation, cannot be stopped by immunosuppressive therapy |
| Four types of transplant rejection can occur: Accelerated | mediated by antibodies and Tcells; cannot be stopped by immunosuppressive therapy |
| Four types of transplant rejection can occur: Acute | involves cellular immunity; occurs w/in days-months of transplantation; can be treated w/general immunosuppressants (azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, glucocorticoids, cyclophosphamide, methotrexate, rapamycin) |
| Four types of transplant rejection can occur: Chronic | characterized by thickening/fibrosis of vasculature of transplanted organ; both cellular and humoral immunity; occurs w/in months-years after transplant; treated w/same meds used for acute rejecion |
| Allogenic hematopoietic stem cell transplantation is an established treatment for | malignant and non-malignant disease; HLA-matched donor is found; Pt treated w/high-dose chemo/radiation or both & donor's stem cells are transfused |
| A conditioning regimen for bone marrow transplant is used to: | kill cancer cells and suppress the immune system so the pt doesn't reject transplant; a new immune system develops from donor stem cells; rejection is uncommon and is treated by infusion of more stem cells |
| Graft v. host disease in bone marrow transplant | very common dt donor Tcells failing to recognize the pt's tissues as self; acute cases occur w/in 100 days (rash, severe diarrhea, hepatotoxicity); Chronic is after 100 days (requires more therapy) |
| Attempts to prevent Graft v. Host disease in bone marrow transplant | pts are immunosuppressed early in transplant course; usu able to discontinue immunosuppressive therapy w/in 1-2yrs post transplant (unlike solid organ transplant) |
| Effectiveness of immunosuppressive therapy in autoimmune disorders | variable; remission can be obtained and improvement has been shown |
| Plasma immunoabsorption using Protein A columns has been explored to: | remove the immunoreactive antibody, particularly in the formation of immune complexes |
| Immunomodulating Agents | BCG and Levamisole; modulate rather than suppress immune system; inc the immune responsiveness of pts w/immunodeficiency, chronic infections, or cancer; |
| Cytokines | large grp of ptns w/diverse fxns; part of immune system and regulators of hematopoiesis via receptors on target cells; antiproliferative, antimicrobial, antitumor effects; |
| Cytokines and vaccines | adjuvants in clinical trials; GM-CSF (sargrmostim) - thought to induce antitumor immune response resulting in tumor regression |
| INF-a | approved in treatment of several neoplasms (hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, Kaposi's sarcoma, Hep B/C) |
| INF-b | approved for treatment of relapsing-type MS |
| INF-g | approved for treatment of chronic granulomatous disease |
| IL-2 | used in metastatic renal cell carcinoma and malignant melanoma |
| Cytokine administration/toxicity | most have short serum half-life (minutes); usu administered SQ; fever, flu-like symptoms, anorexia, fatigue, malaise; being studied for inflammatory diseases and septic shock |
| Levamisole (Ergamisol) | 1st used for parasitic infxns; shown to inc magnitude of delayed hypersensitivity (Tcell-mediated immunity); used for Dukes class C colorectal cancer after surgery; when used for Hodgkin's disease it inc Tcells/enhances skin test reactivity; RA efficacy |
| Levamisole MOA | macrophage activation; kills residual tumor cells by activating MQs; May potentiate the effects of 5-FU in adjuvant therapy of colorectal cancer |
| Levamisole: Toxicity | severe agranulocytosis (stops when d/c); nausea, diarrhea, metallic taste; Monitor CBC w/platelets prior to treatment and LFTs every 3 months |
| Bacille Calmette-Guerin (BCG) | a viable strain of Mycobacterium bovis; Used for immunization against TB; non-specific adjuvant/immunostimulant in cancer therapy (esp bladder cancer) |
| Bacille Calmette-Guerin (BCG): MOA | activation of MQs to create more effective killer cells as well as lymphoid cells of immune response |
| Other Adjuvant Agents: Picibanil (OK432), Lentinan, Pachymaran | clinical trials have shown prolonged remission in studied pts; MOA - stimulates MQs to release cytokines including IL-1, CSF, TNF-a |
| Inosiplex (isoprinosine) | immunomodulator; increases NK cell cytotoxicity and Tcell/monocyte function; approved in Europe |
| Cyanoaziridine compounds (azimexon, ciamexon, imexon) | synthetic immunomodulating drugs; under investigation for treatment of AIDS and neoplasia |
| Methylinosin monophosphate | synthetic immunomodulating drug; under investigation of treatment of AIDS and neoplasia |
| Diethyl dithiocarbamate (DTC) | sulfur immunomodulating agent; reduces infxns and slows progression of disease in advanced HIV pts; not yet approved |
| Thymosin | ptn hormones from epithelioid of thymus (bovine/human); conveys Tcell specificity by inducing pre-Tcell maturation to uncommitted lymphoid stem cells and inc number of cells that manifest Tcell surface markers/fxn; Europe and Asia; Tx for HepB/C? |
| Immunologic Rxns to Drug Therapy and Drug Allergy: Type I | immediate drug allergy |
| Immunologic Rxns to Drug Therapy and Drug Allergy: Type II | autoimmune reaction to drugs |
| Immunologic Rxns to Drug Therapy and Drug Allergy: Type III | serum sickness and vasculitic reactions |
| Two groups of drugs that modulate immune function | 1. immune suppressants; 2. immune potentiators |
| Immune suppressants | 1. Antibodies and 2. Drugs [glucocorticoids (prednisone), immunophillin ligands (cyclosporine), cytotoxic (cyclophosphomide), Anti-TNF-a (etenercept), enzyme inhibitors (mycophenolate mofetil)] |
| Immune potentiators | Cytokines (IL-2, Interferon), BCG vaccine, Thymosin |
Created by:
bscaryp