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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