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Dr. Ahmed M. Alafeefy
The Immune Response - why and how ?Discriminate: Self / Non selfDestroy:
Infectious invadersDysregulated self (cancers)
Immunity:Innate, NaturalAdaptive, Learned
• Innate immune response – first line of defense against an antigenic
insult. Includesdefenses like physical (skin), Biochemical (complement, lysozyme,
interferons)cellular components (neutrophils, monocytes,macrophages).
• Adaptive immune responsea) Humoral immunity - Antibody production –killing extracellular organisms.b) Cell mediated immunity – cytotoxic / killer Tcells – killing virus and tumour cells.
Who are involved ?Innate
ComplementGranulocytesMonocytes/macrophages
NK cellsMast cellsBasophils
Adaptive: B and T lymphocytes
B: antibodiesT : helper, cytolytic, suppressor.
ABNORMAL IMMUNERESPONSE
• Hypersensitivity reactionsType 1 – Anaphylactic shockType 2 – mismatched blood transfusionType 3 – Serum Sickness,
glomerulonephritis and arthritis.Type 4 – TB, leishmaniasis.
Autoimmunity – Autoimmune diseases arisewhen the body mounts an immune responseagainst itself as a result of failure to
distinguish self tissues and cells from foreign antigens.
Rheumatoid Arthritis, S.L.E, Type 1 Diabetes Mellitus, Multiple Sclerosis etc….
• Immunodeficiency Diseasesa) Congenital – Di George’s syndrome, SCID
due to ADA deficiency.b) Extrinsic – HIV causing AIDS.
DEFINITIONImmunomodulators are drugs whicheither suppress the immune system – Immunosuppressants
orstimulate the immune system – Immunostimulants
ImmunosuppressantsGlucocorticoids - Prednisolone.Calcineurin inhibitors
CyclosporineTacrolimus
Antiproliferative / antimetabolic agentsSirolimusEverolimusAzathioprineMycophenolate MofetilOthers – methotrexate, cyclophosphamide,
thalidomide and chlorambucil , Interferon
AntibodiesAntithymocyte globulinAnti CD3 monoclonal antibody
Muromonab Anti IL-2 receptor antibody –
Daclizumab, basiliximabAnti TNF alpha – infliximab, etanercept
ImmunosuppressantsOrgan transplantationAutoimmune diseases Problem Life long use Infection, cancers Nephrotoxicity Diabetogenic
GlucocorticoidsInduce redistribution of lymphocytes –
decrease in peripheral blood lymphocyte counts
Intracellular receptors – regulate gene transcription
Down regulation of IL-1, IL-6Inhibition of T cell proliferation Neutrophils, Monocytes display poor
chemotaxisBroad anti-inflammatory effects on
multiple components of cellular immunity
USES - GlucocorticoidsTransplant rejection GVH – BM transplantationAutoimmune diseases – RA, SLE,
Hematological conditionsPsoriasisInflammatory Bowel Disease, Eye
conditions
ToxicityGrowth retardationAvascular Necrosis of BoneRisk of InfectionPoor wound healingCataractHyperglycemiaHypertension
CALCINEURIN INHIBITORS• Calcineurin (CN) is a protein phosphatase
activates the T cells of the immune system and can be blocked by drugs.
Cyclosporine –
– bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophilin inhibits the phosphatase calcineurin, which under normal circumstances induces the transcription of interleukin-2.
The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.
UsesOrgan transplantation: Kidney, Liver, Heart
Rheumatoid arthritis, IBD, uveitis
PsoriasisAplastic anemiaSkin Conditions- Atopic dermatitis, Alopecia Areata, Pemphigus vulgaris, Lichen planus, Pyoderma gangrenosum
Toxicity : CyclosporineRenal dysfunctionTremorHirsuitismHypertensionHyperlipidemiaGum hyperplasiaHyperuricemia – worsens goutCalcineurin inhibitors +
Glucocorticoids = Diabetogenic
Tacrolimus ( FK 506, Prograf )– It binds to the immunophilin FKBP1A,
followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than ciclosporin and has less pronounced side-effects.
Use-Prophylaxis of solid-organ allograft
rejection –Topical preparation available for use in
atopic dermatitis and psoriasis.
Toxicity - TacrolimusNephrotoxicityNeurotoxicity-Tremor, headache,
motor disturbances, seizuresGI ComplaintsHypertensionHyperglycemiaRisk of tumors, infections
Sirolimus (rapamycin, trade name Rapamune) Contrary to ciclosporin and tacrolimus,
drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second one( namely signal transduction and lymphocyte clonal proliferation).
It binds to FKBP1A like tacrolimus, however the complex does not inhibit calcineurin but another protein, mTOR (mammalian target of rapamycin ).
It indirectly inhibits several T lymphocyte-specific kinases and phosphatases, hence preventing their transition from G1 to S phase of the cell cycle.
Sirolimus prevents B cell differentiation into plasma cells,
reducing production of IgM, IgG, and IgA antibodies.
CELL CYCLE
SirolimusUsesProphylaxis of organ transplant
rejection with other drugs
ToxicityIncrease in serum cholesterol,
TriglyceridesAnemiaThrombocytopeniaHypokalemiaFeverGI effects Risk of infection, tumors
Azathioprine (Imuran )the main immunosuppressive cytotoxic
substance. It is nonenzymatically cleaved to mercaptopurine, that acts as a purine analogue and an inhibitor of DNA synthesis.
By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity.
UsesPrevention of organ transplant rejectionRheumatoid arthritis
Toxicity - Azathioprine Bone marrow suppression-
leukopenia, thrombocytopenia, anemiaIncreased susceptibility to infectionHepatotoxicityAlopeciaGI toxicity
Drug interaction: Allopurinol
Mycophenolate MofetilProdrug Mycophenolic acid Inhibits IMPDH – enzyme in guanine
synthesis (Inosine monophosphate dehydrogenase (IMPDH) is a major target for both antitumor and immunosuppresive drug design.)
T, B cells are highly dependent on this pathway for cell proliferation
Selectively inhibits lymphocyte proliferation, function , Antibody formation, cellular adhesion, migration
Uses - Mycophenolate MofetilProphylaxis of transplant rejectionCombination: Glucocorticoids
Calcineurin Inhibitors
ToxicityGI, Hematological
Diarrhea, Leucopenia Risk of Infection
Drug InteractionDecreased absorption when co-administered with antacids
Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion
AntibodiesAgainst
lymphocyte cell-surface antigens
Polyclonal / Monoclonal
AntibodiesAntithymocyte GlobulinMonoclonal antibodies
Anti-CD3 Monoclonal antibody (Muromonab-CD3)
Anti-IL-2 Receptor antibody (Daclizumab, Basiliximab)
Campath-1H (Alemtuzumab) Anti-TNF Agents
InfliximabEtanerceptAdalimumab
LFA-1 Inhibitor (lymphocyte function associated)Efalizumab
Anti-thymocyte GlobulinPurified gamma globulin from serum
of rabbits immunized with human thymocytes
Cytotoxic to lymphocytes & block lymphocyte function
UsesInduction of immunosuppression –
transplantationTreatment of acute transplant
rejection
ToxicityHypersensitivity Risk of infection, Malignancy
Anti-CD3 Monoclonal Antibody(Muromonab-CD3 )Binds to CD3, a component of T-cell receptor complex involved inantigen recognitioncell signaling & proliferation
UsesTreatment of acute organ transplant rejection
Toxicity“Cytokine release syndrome” High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness
Prevention: Steroids
Cytokine release syndromeis a common immediate complication
occurring with the use of anti-T cell antibody infusions such as ATG, OKT3
The pathogenesis is that the antibodies bind to the T cell receptor, activating the T cells before they are destroyed. The cytokines released by the activated T cells produce a type of systemic inflammatory response similar to that found in severe infection characterised by hypotension, pyrexia and rigors.
the cytokine release syndrome is effectively a type of non-infective fever.
Anti-IL-2 Receptor Antibodies (Daclizumab and Basiliximab )
Bind to IL-2 receptor on surface of activated T cells Block IL-2 mediated T-cell activation
UsesProphylaxis of Acute organ rejection
ToxicityAnaphylaxis, Opportunistic Infections
Anti-TNF AgentsTNF – Cytokine at site of inflammation
InfliximabEtanerceptAdalimumab
InfliximabUsesRheumatoid arthritisChron’s disease – fistulaePsoriasisPsoriatic arthritis Ankylosing spondylosis
ToxicityInfusion reaction – fever, urticaria,
hypotension, dyspnoeaOpportunistic infections – TB, RTI, UTI
EtanerceptFusion protein produced through
expression of recombinant DNA.Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1
UsesRheumatoid arthritis
Uses :moderate to severely active crohn’s disease
Adalimumab Adalimumab
Recombinant human anti-TNF mAbRecombinant human anti-TNF mAb
LFA-1 Inhibitor - EfalizumabMonoclonal Ab Targeting Lymphocyte Function Associated Antigen
Blocks T-cell Adhesion, Activation, Trafficking
UsesOrgan transplantationPsoriasis
Glucocorticoids – Lympholytic activity,
antiinflammatory property.• Used as 1st line immunosuppressive
therapy in solid and heamatopoietic stem cell transplant, ITP, RA etc….
• Sirolimus – inhibits protein kinase and inhibits T
cell response to IL-2.– Blocks cell cycle progression
SUMMARY
Thalidomide – inhibits angiogenesis, reducesphagocytosis, enhances cell mediated
immunity
– Increases levels of IL-10.
– Used in multiple myeloma, graft versus hostdisease, myelodysplastic syndrome, colon and prostrate Cancer.• Mycophenolate Mofetil – mycophenolic acid– Inhibits inosine monophosphatedehydrogenase which is a key enzyme inguanine nucleotide synthesis.– Used in steroid refractory GVHD, RA, SLE.
Leflunomide – it inhibits pyrimidine synthesis.Used in RA.• Cyclophosphamide – alkylating agent whichdestroys proliferating lymphoid cells. Used in
SLE, autoimmune haemolytic anaemia, multiple sclerosis, Wegener’s granulomatosis.
• Muromonab CD3 – T cell receptor complex( blocks Ag recognition ).– Used in steroid resistant rejection.• Daclizumab, Basiliximab – IL-2 receptor
(blocks IL-2 mediated T cell activation ).– Used in acute organ rejection in renal
transplant patients.
Azathioprine ( Mercaptopurine )– interferes with purine nucleic acid
metabolism and incorporates false nucleotide.
–Used in Renal allograft, RA, SLE, ITP, Crohn’s disease, glomerulonephritis
Interferons - IFN alpha- immune enhancing action
- melanoma.– IFN beta - multiple sclerosis– IFN gamma - chronic granulomatous
disease.
Immunostimulants
USES:
immunodeficiency disorders
Chronic infections cancer
specific ImmunostimulantsLevamisoleThalidomideBCGRecombinant Cytokines
Interferons Interleukin-2
Other drugs – inosiplex, azimexon, imexon, thymosin, methylinosine monophosphateImmunization Vaccines , Immune Globulin , Rho (D) Immune
Globulin
LevamisoleAntihelminthicRestores depressed immune function of
B, T cells, Monocytes, Macrophages USES:Adjuvant therapy with 5FU in colon
cancer Used to treat immunodeficiency
associated with Hodgkins disease.Toxicity
Agranulocytosis
ThalidomideBirth defectContraindicated in women with
childbearing potentialEnhanced T-cell production of
cytokines – IL-2, IFN-γ NK cell-mediated cytotoxicity
against tumor cells
USE:Multiple myeloma
Bacillus Calmette-GuerinLive, attenuated culture of BCG strain
of Mycobacterium BovisIt causes activation of macrophages to
make them more effective killer cells.used as intravesical therapy for
superficial bladder cancer.Adverse Effects HypersensitivityShockChills
InterferonsAntiviralImmunomodulatory activityBind to cell surface receptors –
initiate intracellular eventsEnzyme inductionInhibition of cell proliferationEnhancement of immune activitiesIncreased Phagocytosis
Interferon alfa-2bHairy cell leukemiaMalignant melanomaKaposi sarcomaHepatitis B
Adverse reactionsFlu-like symptoms – fever, chills,
headacheCVS- hypotension, ArrhythmiaCNS- depression, confusion
Interleukin-2 (aldesleukin)Proliferation of cellular immunity –
Lymphocytosis, eosinophilia, release of multiple cytokines – TNF, IL-1, IFN-γ
UsesMetastatic renal cell carcinomaMelanoma ToxicityCardiovascular: capillary leak
syndrome, Hypotension
Capillary leak syndrome(systemic capillary leak syndrome or
Clarkson syndrome) A rare medical condition where the
number and size of the pores in the capillaries are increased which leads to a leakage of fluid from the blood to the interstitial fluid, resulting in dangerously low blood pressure (hypotension), edema and multiple organ failure due to limited perfusion.
Immunization
Active – Stimulation with an Antigen
Passive – Preformed antibody
Active immunization
VaccinesAdministration of antigen as a whole,
killed organism, or a specific protein or peptide constituent of an organism
Booster dosesAnticancer vaccines: Vaccinating patients with autologous
antigen presenting cells (APC) expressing tumor-associated antigens (TAA)
Immune GlobulinIndicationsIndividual is deficient in antibodies –
immunodeficiencyIndividual is exposed to an agent,
inadequate time for active immunizationRabiesHepatitis B
Nonspecific immunoglobulinsAntibody-deficiency disorders
Specific immune globulinsHigh titers of desired antibody
Hepatitis B, Rabies, Tetanus
Rho (D) Immune GlobulinAntibodies against Rh(D)
antigen on the surface of RBC
prevent the immunological condition known as Rhesus disease (or hemolytic disease of newborn).
treating chronic idiopathic thrombocytopenic purpura in Rh-positive patients who have not been splenectomized