Transcript IMMUNOPHARMACOLOGY
ينلاديصلا دادعا مشاه نسحم يلع
IMMUNOPHARMACOLOGY
Major Steps in Immune Responses
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1- Antigen recognition
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2- IL-1 production
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3- IL-2 and other cytokine expression
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4- lymphocyte proliferation & differentiation
MAJOR STEPS IN IMMUNE RESPONSES Antigen 1 2 IL-1 antigen presenting cell (macrophage, dendritic cell) IL-2 CD8 T cell 4 3 IL-2 CD4 T helper cell IL-2 primed CD4 T helper cell 4 B cell cytotoxic T cells plasma cells
SITES OF ACTION OF IMMUNOSUPPRESSIVE DRUGS Antigen A X 1 antigen presenting cell B 2 X IL-1 IL-2 CD8 T cell 4 X E X C D 3 X IL-2 CD4 T helper cell D cytokines primed CD4 T helper cell X 4 cytotoxic T cells plasma cells
Inhibitors of Immune Response (site of action)
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A Immune Globulin (antigen recognition)
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B Corticosteroids (IL-1 production, cell proliferation)
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C OKT3 , ATG (T cell receptors/surface prot.)
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D Cyclosporine, Tacrolimus , ( 1L-2 gene expr.
), Sirolimus ( IL-2 signal transduction)
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E Rapamycin, Mycophenolate ( T cell prolif.
), Azathioprine,Cyclophosphamide (all cell prolif.)
Major Classes of Immunosuppressant Drugs
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Glucocorticoids
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Calcineurin inhibitors
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Cytotoxic agents: include azathioprine , cyclophosphamide ,leflunomide ,hydroxychloroquine, other cytotoxic agents vincristine, MTX,cytarabine
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Biologics (Antibodies)
Clinical uses of immunosuppressive agents
-Autoimmune disease: Idiopathic thrombocytopenic purpura (ITP) : Prednisone, vincristine, occasionally cyclophosphamide, mercaptopurine, or azathioprine; commonly high-dose gamma globulin Autoimmune hemolytic anemia chlorambucil, mercaptopurine, azathioprine, high-dose gamma globulin . : Prednisone, cyclophosphamide, Acute glomerulonephritis : Prednisone,mercaptopurine , cyclophosphamide .
Acquired factor XIII antibodies : Cyclophosphamide plus factor XIII Autoreactive tissue disorders (autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, scleroderma, dermatomyositis, mixed tissue disorder, multiple sclerosis, Wegener's granulomatosis, chronic active hepatitis, lipoid nephrosis, inflammatory bowel disease.): Prednisone, cyclophosphamide, methotrexate, interferon-α and -β, azathioprine, cyclosporine, infliximab, etanercept, adalimumab .
-Isoimmune disease ( Hemolytic disease of the newborn): Rh o (D) immune globulin .
-Organ transplantation Renal & heart : Cyclosporine, azathioprine, prednisone, ALG, OKT3, tacrolimus, basiliximab, daclizumab, sirolimus . Liver :Cyclosporine, prednisone, azathioprine, tacrolimus, sirolimus bone marrow :Cyclosporine, cyclophosphamide, prednisone, methotrexate, ALG . Prevention of cell proliferation (Coronary stents) : sirolimus .
Cyclosporine (Neoral, Gengraf)
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Structure
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lipophilic cyclic peptide
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Mechanism
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inhibits transcription of IL-2 gene plus other lymphokine genes (IL-3, gamma interferon)
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site of action is a binding protein that inhibits calcineurin (a phosphatase) which is necessary for the activation of a T-cell-specific transcription factor
Cyclosporine (Neoral)
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Pharmacokinetics
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variable, incomplete oral absorption
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extensive hepatic metabolism, excreted in bile
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used alone or in combination with prednisone and azathioprine (or other antineoplastic drugs)
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Adverse Effects
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nephrotoxicity, hepatotoxicity, hirsutism,HTN , hyperglycemia, hyperK,convulsion,gum hypertrophy.
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Drug interactions due to induction and inhibition of hepatic cytochrome P450
_ Cyclosporine may be used alone or in combination with other immunosuppressants, particularly glucocorticoids. _ Used successfully as the sole immunosuppressant for cadaveric transplants of the kidney, pancreas, and liver, and cardiac transplants as well. _ In combination with methotrexate, cyclosporine is a standard prophylactic regimen to prevent graft – versus-host disease .
_ Cyclosporine has also proved useful in a variety of autoimmune disorders, including uveitis, rheumatoid arthritis, psoriasis, and asthma.
Tacrolimus (
FK506
)
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Structure
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macrolide (structure like erythromycin)
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Mechanism
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similiar to cyclosporine except binds to different protein that inhibits calcineurin (a phosphatase enzyme involved in gene transcription of IL-2, gamma interferon and other cytokines)
Tacrolimus(
FK506)
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Bioavailability
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given by IV infusion or orally
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used concomitantly with corticosteroids Adverse Effects
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nephrotoxicity, increased risk of lymphomas, hypersensitivity, hyperglycemia, GI complaints, hypertension, neurotoxicity (tremor, headache, motor disturbances, seizures)
Sirolimus (Rapamune)
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Structure
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macrolide similiar to tacrolimus
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Mechanism
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binds to immunophilin protein that binds to a key regulatory kinase required for T cell activation
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(new unique mechanism to inhibit T lymphocyte activation by IL-2)
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different site of action than cyclosporine and tacrolimus
Sirolimus (Rapamune)
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Inhibits mammalian target of rapamycin (mTOR)
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mTOR is a protein kinase that plays pivotal role in IL-2 receptor responses
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IL-2 binds to its receptor on T cells and leads to mTOR activation
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mTOR initiates cascade of events (including cyclin dependent kinases) that promote T lymphocyte proliferation and differentiation
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Inhibition of mTOR blocks IL-2 dependent cell-cycle progression at G1→S phase transition
Consequences of TOR Action
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Lymphocyte cell proliferation & differentiation
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T cells
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B cells
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Antibody production
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Mesenchymal cell proliferation
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Vascular smooth muscle cells
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Endothelial cells
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Fibroblasts
Properties of TOR Inhibitors such as Sirolimus (Rapamune)
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Selective blockade of cytokine signal transduction
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Inhibition of T cell division and proliferation
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Potent and effective immunosuppression
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Potential for synergy with other immunosuppressants
Sirolimus (Rapamune)
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other theoretical actions include
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blockade of B cell Ig synthesis
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inhibition of antibody-dependent cellular toxicity
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inhibition of lymphocyte activated killer cells
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inhibition of natural killer cells
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inhibition of immune and nonimmune cell proliferation (via inhibition of growth factor signaling) (may explain antitumor actions)
Sirolimus (Rapamune)
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Bioavailability
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low oral absorption
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hepatic metabolism by CYP4503A4 (drug interactions may occur)
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long half-life (60 hours)
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Adverse Effects
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thrombocytopenia, hyperlipidemia, rash
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lacks direct end organ toxicity but increased incidence impaired renal function when combined with cyclosporine
Mycophenolate Mofetil (CellCept)
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Structure
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derivative of mycophenolic acid
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Mechanism
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inhibits inosine monophosphate dehydrogenase involved in de novo synthesis of purines
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selectively suppressess T- and B-cell proliferation
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Also suppresses some macrophage functions (may explain anti-inflammatory actions)
Mycophenolate Mofetil
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Pharmacokinetics
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oral absorption and hepatic metabolism
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Adverse Effects
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diarrhea, leukopenia and CMV infections
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increased incidence of lymphomas and other malignancies
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Thalidomide inhibits TNFα,reduces phagocytosis by neutrophils,↑production of IL 10,alters adhesion mol. expression &enhances cell mediated immunity via interaction with T cell
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Indications for leprosy and multiple myeloma
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Side effects: teratogenicity, neuropathy, fatigue, constipation, deep vein thrombosis
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Thalidomide analogs have been obtained based on its antiangiogenic and immunomodulatory properties.( Immunomodulatory derivatives of thalidomide are termed IMiDs.)
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Lenalidomide (Revlimid) - as the first commercially derivative.It is only available in a restricted distribution to avoid its use during preg.
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CC-4047 (Actimid) is another IMiD that is being investigated for the treatment of myelodysplastic syndrome, myeloma, and prostate cancer.
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Another group of thalidomide analogs , selective cytokine inhibitory drugs (SelCIDs) , are phosphodiesterase type 4 inhibitors with potent anti-TNF- activity but no T-cell co-stimulatory activity. Several SelCIDs are currently under investigation for clinical use.
Corticosteroid
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Prednisone used most often orally
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Methylprednisolone used parenterally
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Numerous available preparations
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Corticosteroid action Inhibition of IL-1 and TNF gene expression and synthesis Decreased activation of T lymphocytes by decreasing IL-1 release Decreased neutrophil functions esp chemotaxis Decreased antibody production (high doses) Decreased release of kinins and proinflammatory eicosanoids (prostaglandins and leukotrienes)
Corticosteroid Immunosuppression
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Decreased cell-mediated immune reactions that mediate rejection of organ transplants
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Mechanisms:
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decreased activation of T lymphocytes by inhibition of IL-1 synthesis by macrophages
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decreased lymphocyte mobilization out of lymphoid organs (lymphopenia)
New Immunosuppressants
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Mizoribine (investigational)
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Inhibitor of purine nucleotide synthesis Brequinar (investigational)
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Inhibitor of de novo pyrimidine synthesis 15-Deoxyspergualin (investigational)
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Antimonocytic that decreases MHC antigen expression Pimecrolimus (Elidel)
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Calcineurin inhibitor like cyclosporine Approved for topical treatment of eczema
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New Class of Immunosuppressant
FTY720 (prodrug: requires phosphorylation)
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Sphingosine 1-phosphate receptor (S1P-R) agonist
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Reduces recirculation of lymphocytes from lymphatic system to the blood
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Lymphocyte homing action which reversibly sequesters host lymphocytes into lymph nodes
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Useful in combination therapy but not alone
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Toxicity: lymphopenia, decreased heart rate
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Biologics(antibodies):-
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Antilymphocyte & Antithymocyte Antibodies
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Immune Globulin Intravenous (IGIV)
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Rh O (D) Immune Globulin Micro-Dose
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Hyperimmune Immunoglobulins
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Monoclonal Antibodies (MABS)
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Antibodies Used for Acute Rejection of Organ Transplants -Antilymphocyte & Antithymocyte Antibodies Antisera directed against lymphocytes. ALG and antithymocyte globulin (ATG) are now in clinical use in many medical centers, especially in transplantation programs. The antiserum is usually obtained by immunization of large animals such as horses or sheep with human lymphoid cells.
ALG and ATG are useful for suppressing certain major compartments (ie, T cells) of the immune system and play a definite role in the management of solid organ and bone marrow transplantation -OKT3 (Muromonab-CD3)
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Murine monoclonal antibody to CD3 on T cell & thymocytes
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inhibits cytotoxic T killer cell function
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opsonizes circulating T lymphocytes and enhances their removal
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used to prevent or reverse acute graft rejection
Antithymocyte Globulin-Rabbit (Thymoglobulin)
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Rabbit gamma immune globulin preparation
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Composed of antibodies to variety of T cell markers
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Mechanisms
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removal of T cells from circulation
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modulation of T cell activation, homing and cytotoxicity
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decreases cytokine induced reactions
Adverse Effects of Antibody Preps
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Hypersensitivity reactions may occur with nonhuman antibodies resulting in chills, fever, thrombocytopenia, erythema, pruritis
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Problem with murine MAB OKT3 is formation of anti-OKT3 antibodies limit its action so only given by IV infusion for 7-14 days
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Immune Globulin Intravenous (IGIV)
This immunoglobulin preparation (usually IgG) is prepared from pools of thousands of healthy donors, and no specific antigen is the target of the "therapeutic antibody“& have a normalizing effect upon the patient's immune networks IGIV in high doses (2 g/kg) has proved effective in a variety of different conditions ranging from immunoglobulin deficiencies to autoimmune disorders to HIV disease to bone marrow transplants It is used in Kawasaki's disease, reducing systemic inflammation and preventing coronary artery aneurysms. it also used in SLE & refractory ITP Possible mechanisms of action of IGIV include a reduction of T helper cells, increase of suppressor T cells, decreased spontaneous immunoglobulin production, Fc receptor blockade, increased antibody catabolism, and idiotypic-anti-idiotypic interactions with "pathologic antibodies."
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Rh o (D) Immune Globulin
Rh human IgG containing a higher titer of antibodies against the Rh o o (D) immune globulin is a concentrated (15%) solution of (D) antigen of the red cell .
used to suppress immune response of Rh(neg.) mother after delivery of Rh (pos.) baby
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Given within 24-72 hours after birth of Rh(pos.) baby,
the mother's own antibody response to the foreign Rh o (D) positive cells is suppressed because the infant's red cells are cleared from circulation before the mother can generate a B-cell response against Rh o (D)
,
to prevent hemolytic anemia of the newborn that may occur in subsequent preg.
The usual dose of Rh anti-Rh o (D) IgG. o (D) immune globulin is 2 mL intramuscularly, containing approximately 300 mcg Adverse reactions are infrequent,local discomfort at the injection site or, rarely, a slight temperature elevation.
Hyperimmune Immunoglobulins
_ _ _ Hyperimmune immunoglobulin preparations are IGIV preparations made from pools of selected human or animal donors with high titers of antibodies against particular agents of interest such as viruses or toxins.
Various hyperimmune IGIVs are available for treatment of respiratory syncytial virus, cytomegalovirus, varicella zoster, human herpesvirus 3, hepatitis B virus, rabies, tetanus, and digoxin overdose.
Intravenous administration of the hyperimmune globulins is a passive transfer of high titer antibodies that either reduces risk or reduces the severity of infection
MONOCLONAL ANTIBODYS
NOMENCLATURE
Murine Chimeric
Ritu
x i
mab
Muro
monab
Monoclonal Antibody
Dacli
z u
mab
Humanized
MONOCLONAL ANTIBODY STRUTURE
Mouse Human Chimeric Humanized
Advantages of Chimeric and Humanized Antibodies
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Reduce immunogenicity without sacrificing affinity Allow complement fixation to occur by using the human Fc region instead of murine Fc
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Resulting in ADCC and activation of phagocytic cells
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Humanization of Fab fragment may decrease binding affinity compared to initial murine antibody
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Baciliximab has higher affinity for IL-2 receptor than Daclizumab
Antitumor MABs 1.Alemtuzumab
humanized MAB binds to CD52 found on normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and granuloctes Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and have failed fludarabine therapy,it deplete leukemic and normal cells by direct antibody-dependent lysis S.E:lymphopenia and neutropenia, anemia, and thrombocytopenia
2.
Bevacizumab
binds to vascular endothelial growth factor (VEGF) and inhibits VEGF from binding to its receptor, especially on endothelial cells. It is an antiangiogenic drug inhibit growth of blood vessels (angiogenesis) in tumors. It is approved for first-line treatment of patients with metastatic colorectal cancer alone or in combination with 5-FU-based chemotherapy.
S.E: hemorrhage, GI perforations, and wound healing problems
3.Cetuximab
chimeric MAB binds to epidermal growth factor receptor (EGFR) & inhibits tumor cell growth by a variety of mechanisms, including decreases in kinase activity, matrix metalloproteinase activity, and growth factor production, and increased apoptosis. It is indicated for use in patients with
4.
metastatic colorectal cancer whose tumors overexpress EGFR.
Gemtuzumab
is a humanized MAB specific for CD33 found on leukemic blast cells in 80 –90% of patients with acute myelogenous leukemia (AML).In the clinical formulation, gemtuzumab is coupled to the cytotoxic agent, ozogamicin, which is an antibiotic with antitumor activity.
types of cytotoxic chemotherapy Gemtuzumab is approved for the treatment of patients 60 years and older in first relapse with CD33 acute myelogenous leukemia who are not considered candidates for other S.E: severe myelosuppression,especially neutropenia,others hepatotoxicity and various hypersensitivity reactions.
5.Rituximab binds to CD20
molecule on normal and malignant B lymphocytes and is approved for the therapy of patients with relapsed or refractory low-grade or follicular, B-cell non Hodgkin's lymphoma.
The mechanism of action includes complement-mediated lysis, antibody-dependent cellular cytotoxicity, and induction of apoptosis in the malignant lymphoma cells. _ _ Adverse reactions: Serious adverse events include cardiac arrest, tumor lysis syndrome Infections:Hepatitis B reactivation,Other viral infections Progressive multifocal leukoencephalopathy (PML) _ _ _
Other anti CD20
monoclonal antibodies being developed:
Ocrelizumab ,
humanized B-cell depleting agent.
Ofatuzumab
a fully-human B-cell depleting agent.
6.Trastuzumab
humanized MAB binds to the extracellular domain of the human epidermal growth factor receptor HER-2/neu. This antibody blocks the natural ligand from binding and down-regulates the receptor. Trastuzumab is approved for the treatment of metastatic breast cancer in patients whose tumors overexpress HER-2/neu. As a single agent it induces remission in about 15 – 20% of patients; in combination with chemotherapy, it increases response rate and duration as well as 1-year survival.
MABs Used to Deliver Isotopes to Tumors 1.Arcitumomab
is a murine F(ab') with technetium 99m ( 99m gastrointestinal carcinomas.
2 fragment from an anti-carcinoembryonic antigen (CEA) antibody labeled Tc) that is used for imaging patients with metastatic colorectal carcinoma (immunoscintigraphy) to determine extent of disease. CEA is often upregulated on tumor in patients with
2.
.
Capromab pendetide
is a murine monoclonal antibody specific for prostate specific membrane antigen. It is coupled to isotopic indium ( determine extent of disease.
111 In) and is used in immunoscintigraphy for patients with biopsy confirmed prostate cancer and post-prostatectomy in patients with rising prostate specific antibody level to
3.Ibritumomab tiuxetan
is an anti-CD20 murine MAB labeled with isotopic yttrium ( 90 Y) or 111 radiation of the isotope provides the major antitumor activity. Ibritumomab is approved for use in patients with relapsed or refractory low-grade, follicular, or B cell non-Hodgkin's lymphoma, including patients with rituximab-refractory follicular disease.
In. The
4.Nofetumomab
is a mouse MAB coupled to cell types, but also on some normal cells. 99m Tc that is used for diagnostic purposes to determine extent of disease and to stage patients with small cell lung cancer. It binds a 40 kD antigen found on many tumor
5. Tositumomab
is another anti-CD20 MAB and is complexed with iodine 131 ( 131 I).It is used in two-step therapy in patients with CD20-positive, follicular non Hodgkin's lymphoma whose disease is refractory to rituximab and standard chemotherapy. Toxicities are severe thrombocytopenia and neutropenia.
MABs Used as Immunosuppressants and Anti Inflammatory Agents #ANTI-TNF α MABS
b lock TNF α(a proinflammatory cytokine) from binding to TNF receptors on inflammatory cell surfaces results in suppression of downstream inflammatory cytokines such as IL-1 and IL-6 and adhesion molecules involved in leukocyte activation and migration.They are includes _
Adalimumab
use in RA is a completely human MAB approved for ,administered as single doses subcutaneously, _ _ every other week.
Etanercept
is a dimeric fusion protein,it is approved for adult RA, polyarticular-course juvenile RA, and psoriatic arthritis. It may be used in combination with methotrexate.Administered
subcutaneously, twice weekly
Infliximab
is a chimeric MAB ,it is approved for use in Crohn's disease, ulcerative colitis,RA, ankylosing spondylitis, and psoriatic arthritis.It is given by i.v infusion every 8 weeks.
#Abatacept
is a fusion protein composed of the extracellular domain of CTLA-4 fused to human IgG Fc. CTLA-4 is a costimulatory molecule found on T cells that binds to CD80 and CD86 on APC.It blocks activation of T cells by binding to CD80 or 86 so that CD28 on T cells cannot bind and stimulate the T cell and lead to cytokine release. Abatacept is approved for patients with severe RA who have failed other DMARDS
#Alefacept
is an engineered protein consisting of the CD2-binding portion of LFA-3 fused to a human IgG 1 approved for the treatment of plaque psoriasis. It inhibits activation of T cells by binding to cell surface CD2, inhibiting the normal CD2/LFA-3 interaction.
Fc Treatment of patients with alefacept also results in a dose dependent reduction of the total number of circulating T cells and the drug discontinued if CD4 lymphocyte levels fall below 250 cells/μ L.
# Anakinra
is a recombinant IL-1 receptor antagonist it is approved for use in adult rheumatoid arthritis patients who have failed treatment with one or more DMARDS.
#Basiliximab
is a chimeric MAB that binds to CD25, the IL-2 receptor alpha chain on activated lymphocytes. It functions as an IL-2 antagonist,and is therefore immunosuppressive. It is indicated for prophylaxis of acute organ rejection in renal transplant patients
#Daclizumab
is a humanized MAB similar basiliximab, but the mode of administration differs.
#Efalizumab
is humanized anti-CD11a MAB approved for the treatment of adult patients with severe psoriasis. Binding of efalizumab to CD11a (the alpha subunit of LFA-1) inhibits the interaction of LFA-1 on all lymphocytes with ICAM-1, thereby inhibiting the adhesion, activation, and migration of lymphocytes into skin.It is administered by S.C. injection.
#Omalizumab
is an anti-IgE humanized MAB that is approved for the treatment of allergic asthma in adult and adolescent patients refractory to inhaled steroids.It
blocks the binding of IgE to the high-affinity Fc as histamine and leukotrienes.
έ receptor on basophils and mast cells, which suppresses IgE-mediated release of type I allergy mediators such
Other MABs Abciximab
is a Fab fragment of MAB that binds to the GPIIb/IIIa receptor on activated platelets and inhibits fibrinogen, von Willebrand factor, and other adhesion molecules from binding to activated platelets, thus preventing their aggregation.
Palivizumab
is a MAB that binds to the fusion protein of respiratory syncytial virus, preventing infection in susceptible cells in the airways. It is used in neonates at risk for this viral infection.
Immunostimulatory Cytokines
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Interleukins IL-2 (enhance antitumor actions of cytotoxic T cells and NK cells)
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Colony Stimulating Factors
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G-CSF (Filgrastim)(Neupogen®) treat neutropenia
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GM-CSF (Sargramostim)(Leukine®) myeloid recovery after bone marrow transplant
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Interferon Alpha (Roferon®, Intron®) (prod. by leukocytes) (antiviral, antiproliferative) malignant melanoma, renal cell carcinoma, hairy cell leukemia, Kaposi’s sarcoma
_
Interferon Beta (Avonex®, Rebif®)
(
prod. by fibroblasts) (antiviral, antiproliferative
)
relapsing type MS
_
Interferon Gamma (Actimmunex®)
(
prod. by lymphocytes) (stimulates NK cells and macrophages
)
chronic granulomatous disease
Other Hematopoetic Growth Factors
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Erythropoietin alpha (Epoetin alpha) (Procrit®)
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Produced by recombinant DNA technology
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Stimulates division and differention of erythroid progenitor cells
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Used for anemia due to renal failure or cancer chemotherapy
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Adverse effects include hypertension, headache, hypersensitivity reactions are rare
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Darbopoetin alpha (Aranesp®)
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Recombinant long-acting erythropoetin (3X epoetin)
Other Immunostimulants
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Thymic Hormones
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Improve primary immune deficiency in children
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Synthetic Stimulants
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Levamisole stimulates phagocytosis and T cell production of cytokines
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Adjuvants of bacterial origin
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BCG is viable strain of Mycobacterium bovis that enhances macrophage activity
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BCG used for bladder cancer and melanomas
References
- Basic and Clinical Pharmacology. Bertram Katzung. 10 th ed.
-Clinical Immunology: Principles and Practice. Robert Rich et al. Second Edition.
-Rheumatology Secrets. Sterling West. Second Edition.
-Immunobiology. Charles Janeway. 5 th edition -Review of Immunology. Andrew Lichtman. 2005 -Genomic and non genomic effects of glucocorticoids. Stah and Buttgereit. Nature Clinical Practice. 2008 Vol4 no10; 525-533 -Therapeutic vaccination for chronic diseases: a new class of drugs in sight. Bachman and Dyer. Nature reviews. 2004 vol3 -Inflammatory resolution: new opportunities for drug discovery. Derek Gilroy et al. Nature reviews. 2004 vol3.
-Recognition of microorganisms and activation of the immune response. Ruslan Medzhitov. Nature 2007 vol449/18.
-Basic Immunology: Function and Disorders of the Immune System. Abul Abbas. 2 nd edition.