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Immuno Pharmacology

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    IMMUNOPHARMACOLOGY

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    Protection from infection and disease is

    provided by: *the innate immune system :

    -a physical component: skin, mucosa;

    - a biochemical component: thecomplement;

    -a cellular component: neutrophils.

    *the adaptative immune system(cellularand humoral immunity).

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    1. Immunosuppressant agents:

    =drugs which inhibit cellular or humoral

    immunity or both immune responses

    and have their major use in organtransplantation and autoimmune

    diseases.

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    a) CORTICOSTEROIDS

    MECHANISM OF ACTION-at biochemical level: decrease the synthesis of

    PG, leukotrienes, limphokins: they inhibitmajor histocompatibility complex expression

    and IL-1,IL-2, IL-6 production so that helper T-cells are not activated;

    -at the cellular level: they inhibit theproliferation of T ly but B ly are less affected;

    at doses used for immunosuppression, theyare cytotoxic to certain subsets of T cells.

    Continuous therapy IgG level by increasingcatabolism of this class of immunoglobulins.

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    CLINICAL USES

    Prednisone:-several autoimmune diseases:

    *autoimmune hemolytic anemia;

    *idiophatic thrombocytopenicpurpura;

    *acute glomerulonephritis;

    -organ transplantation(in combination).SIDE EFFECTS

    *adrenal suppression, *growth inhibition,

    *osteoporosis, *salt retention.

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    b)CYCLOSPORINE

    It is a peptide antibioticMechanism of action:

    -it inhibits T lymphocytes proliferation, IL-

    2 and other cytokine production.it enhances expression of an inhibitor of

    IL-2 which attenuates IL-2 stimulated T-

    cell proliferation and production of killerlymphocytes.

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    Clinical uses:

    -prevention and treatment ofgraft rejectionreaction(! the most effective drug);It is

    routinely used in renal, hepatic, cardiac, bone

    marrow and other transplantations.

    *It is given orally but therapy may be started

    with i.v. infusion.

    - autoimmune diseases (early treatment of type

    I diabetes, asthma, severe rheumathoid

    arthritis, inflammatory bowel diseases,

    dermatomyositis)

    *it is often used alon with corticosteroids.

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    c)TACROLIMUS(FK 506)

    Mechanism of action:

    -it interferes with the synthesis of interleukins in

    activated T cells.

    ~ 100 times more potent than cyclosporine

    Clinical uses:

    - liver, kidney, pancreas, heart transplantations.( orally as well as by i.v infusion)

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    d) CYTOTOXIC

    IMMUNOSUPPRESSANTS

    1.AZATHOPRINE

    It is a purine antimetabolite which has more

    marked immunosuppressant than antitumor

    action. It is a prodrug and it is transformed inthe body into 6- mercaptopurine which then

    undergoes further transformations to inhibit

    de novo purine synthesis and damage to DNA.Mechanism of action:

    -It inhibits early phases of T cells proliferation ; it

    has less effects on B cells.

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    Clinical uses:

    -prevention of renal and other graft rejection ;

    -it is used in several autoimmune

    diseases(progressive rheumatoid arthritis )

    Side effects:

    -bone marrow suppression;

    -GI rash, skin rashes, liver dysfunction.

    -it increases the risk of neoplasms

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    2.METHOTREXATE- folate antagonist

    - it markedly depresses cytokine production

    and cellular immunity and has anti-

    inflammatory properties.

    -autoimmune diseases, like rapidly

    progressing rheumatoid arthritis.

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    3.CHLORAMBUCIL

    -weak immunosuppressant

    -sometimes utilized in autoimmune diseases

    and transplant maintenance regimens.

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    4.CYCLOPHOSPHAMIDE

    - It has more marked effect on B cells andhumoral immunity

    Clinical uses:

    -bone marrow transplantation, autoimmunediseases (lupus erythematosus,thrombocytopenic purpura, hemolyticanemia).

    Side effects:- pancytopenia, GI distress, hemorrhagic cystitis,

    alopecia.

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    e)ANTIBODIES AS IMMUNOSUPPRESSANTS

    1. Antithymocyte globulin (ATG)

    * It is a policlonal antibody purified from horse or rabbitimmunized with human thymic lymphocytes.It binds toT lymphocytes initiating their distruction by serumcomplement.

    Uses :*bone marrow transplantation to prevent the graft-versus host reaction.

    *in combination with cyclosporine or cytotoxic drugs(or both) for maintenance following bone marrow,heart, renal transplantations.

    Adverse effects:

    *HS reactions, (anaphylaxia and serum sickness.)

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    2)Muromonab CD3

    * It is a murine monoclonal antibody to the T3

    (CD3) antigen on the surface of human

    thymocytes and mature T cells; it blocks the

    killing action of cytotoxic T cells and probably

    interferes with other T cell functions.

    * It is used i.v. to reverse the renal allograft

    rejection crisis.

    *fever, chills, dyspnea, HS reactions.

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    3)AntiD immune globulin:

    *It is a human Ig G preparation that contains a

    high titer of antibodies against Rh (D) antigen. Itbinds to Rh0 antigens and does not allow them toinduce antibody formation in Rh negativeindividuals.

    *for prevention of postpartum formation ofantibodies in Rh0-D negative women who havedelivered an Rh0- D positive baby.maternalantibodies to Rh-positive cells are not producedin subsequent pregnancies and hemolytic disease

    of the neonate is thus averted. !! It should be administered within 72 hours of

    delivery.

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    4)I.v. Ig

    *a polyclonal human Ig from a pool of

    thounsands of healthy donors and no specific

    antigen is the target of the inoculated

    antibody.

    Mechanism of action:* diminuation of helper T

    cells, increase in suppressor T cells, decrease

    in spontaneous Ig production.

    Clinical uses: *autoimmune diseases.

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    2.Immunomodulating

    agents(immunostimulating agents):

    =stimulators of immune responses.They are

    used in the treatment of immune deficiency

    diseases, chronic infectious diseases and

    cancer.

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    a)Natural immunomodulating agents

    1)THYMOSIN-is a protein hormone from thethymus gland that stimulates the maturationof pre-T cells and promotes the formation ofT

    cells from ordinary lymphoid stem cells.Thymosin containing preparations have been

    used in thymic aplasia (DiGeorges syndrome).

    2)THYMOPOIETIN and THYMIC HUMORALFACTORare other two thymus-relatedpeptides with T cell stimulating properties.

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    3)CYTOKINES:

    * INTERFERONS:,, :

    -they interact with cell receptors and increase antigen

    presentation ;

    -they increase macrophage, NK and cytotoxic T ly

    activation;

    -they inhibit cell proliferation .Interferon -1b hasgreater immune- enhancing actions .

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    They are useful in:

    * Interferon alfa-2a : hairy cell leukemia,chronic myelogenous leukemia, malignant

    melanoma;* interferon beta-1b : relapsing multiple

    sclerosis ;

    * interferon gamma-1b :patients with chronicgranulomatous disease.They also are used inhepatitis.

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    *INTERLEUKINS: -they stimulate T and B cells

    proliferation and differentiation.

    *TUMOR NECROSIS FACTORit is

    oncostatic,proinflammatory, chemotactic ()

    and macrophage activator().It may be useful

    in malignant melanoma.

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    *COLONY-STIMULATING FACTORS: FILGASTRIMand SARGRAMOSTIN are recombinant formsof the human colonystimulating factors G-

    CSF and GM-CSF : they stimulategranulocyte,eosinophil production,macrophage activation.

    They are indicated for acceleration of marrowrecovery in patients undergoing cytotoxictherapy.

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    4) BCG (Bacille Calmette-Gurin):it has been

    used for immunization against tuberculosis

    and as immunostimulant in cancer( bladder

    cancer-it activates macrophages, lymphoidcells inclusively NK lymphocytes).

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    5) IMMUNOGLOBULINS(IG)

    Ig administered in humans confer passiveimmunization.

    They are human or animal Ig (fromhyperimmune donors) in varying degrees ofpurity.They may contain relatively high titers ofantibodies directed against a specific antigen or

    may simply contain antibodies from all classesformed in most of the population.

    They are admistered i.m. or i.v.

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    Clinical uses:

    -individuals unable to formantibodies(congenital agammaglobulinemia,hipogammaglobulinemia etc);

    -prevention of infectious diseases (hepatitis,

    rubella etc.)-treatment of certain diseases normally

    prevented by immuniZation(tetanus).

    -various conditions for which active

    immunization is not possible (eg. Snake bite).Side effects:-pain at the site of injection;-HSreactions;-transient hypotension and pruritus.

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    6) NONSPECIFIC VACCINESACTIVEIMMUNIZATION

    Active immunization: administration of antigen tothe host to induce formation of antibodies andcell- mediated immunity.An disadvantage ofactive immunization is that it requires time todevelop and is generally inactive at the time ofspecific exposure.

    Clinical uses: it is used to induce protection against

    many infectious agents.For example: protectionagainst hepatitis B virus by administration ofinactive viral antigen (i.m.).

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    b)Synthetic immunostimulating

    agents

    LEVAMISOLE( antiparasitic drug). It also

    stimulates the maturation and

    proliferation of T cells.It enhances T cell-

    mediated immune responses and

    restores delayed hypersensitivity. It may

    be useful in the immunodeficiency ofHodgkins disease and adjunctively in

    cancer chemotherapy.


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