Imunofarmakologija - seminar - Prof. Zoran Todorović
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1 Imunofarmakologija - seminar - Prof. Zoran Todorović
2 Imunofarmakologija Specifična i nespecifična imunost (stečeni i urođeni imunitet) Lekovi imunosupresivi lekovi koji deluju na TNFalfa imunomodulatori (interferoni, interleukini) serumi i vakcine
3 Imunosupresivi Primena sprečavanje odbacivanja transplantata autoimune bolesti Problem slabija odbrana od infekcija razvoj maligniteta
4 Imunosupresivi GLUKORTIKOIDI Inhibitori kalcineurina - CIKLOSPORIN A, TAKROLIMUS Lekovi koji izazivaju prekid ćelijskog metabolizma sa inhibicijom proliferacije - citotoksični lekovi (AZATIOPRIN, METOTREKSAT, CIKLOFOSFAMID) i MIKOFENOLAT MOFETIL ANTITELA (IMUNOGLOBULINI)
5 Mesta delovanja imunosupresiva 1) Prepoznavanje antigena (monoklonska antitela, anti- Rh faktor globulin 2) Proliferacija limfocita (glukokortikoidi, inhibitori kalcineurina, citotoksični lekovi, antilimfocitni globulin i monoklonska antitela) 3) Diferencijacija limfocita (citotoksični lekovi, antilimfocitni globulin i monoklonska antitela) 4) Dejstvo T limfociti ili antitela + komplement 1) Oštećenje tkiva (glukokortikoidi)
6 Autoimunske bolesti i imunosupresivi Autoimuna hemolitička anemija Miastenija gravis Reumatoidni artritis Sistemski lupus Ulcerativni kolitis... TNF-alfa IL-1...
7 Opšti principi primene imunosupresiva Primarni imuni odgovor - lakše se blokira nego sekundarni (kada nastanu memorijske ćelije) najosetljiviji na dejstvo antigena: obrada antigena, proliferacija i diferencijacija ćelija lekovi manje efikasni kod zdravih Nisu svi oblici imunog odgovora jednako osetljivi na dejstvo imunosupresiva (npr. ćelijski i humoralni imunitet ili različita At) Neki imunosupresivi imaju i druga korisna dejstva (npr. glukokortikoidi - antiinflamatorno)
8 Inhibitori kalcineurina Ciklosporin i takrolimus sprečavaju stvaranje IL-2 inhibicijom kalcineurinskog signala transplantacija organa i kostne srži, Th reumatoidnog artritisa i psorijaze [Sirolimus različit mehanizam dejstva sprečava delovanje IL-2 na aktivaciju T i B limfocita primena u kardiologiji - stentovi]
9 Ciklosporin - T limfociti Ciklosporin+ciklofilin C kalcineurin (fosfataza) NF-AT IL-2 i mnoge antiapoptotičke proteine, TGFbeta odgovor T limf. na antigensku stimulaciju Toksičnost (doza!): nefro- (vazokonstrikcija!), hepato-, neuro- & hipertenzija, hiperglikemija, hiperlipidemija Interakcije!
10 Ciklosporin - T limfociti Farmakokinetika lipofilan - u ricinusovom ulju parenteralna primena - rastvara se prvo u FR (0,9% NaCl ili 5% Glc) oralna primena - želatinske kapsule ili rastvor - nisu bioekvivalentni!
11 Interferoni Familija od 23 proteina, Mr Oslobadjaju se iz skoro svih ćelija posle stimulacije virusima i drugim induktorima (npr. interleukini IL-1 i IL-2, kao i TNF) Transmembranski RR (receptori za citokine - enzimska aktivnost) - tip I i II indukcija enzima inhibicija ćelijske proliferacije potenciranje imunog odgovora ( fagocitne aktivnosti makrofaga, NK i citotoksičnih T limfocita, kao i ushodna regulacija molekula klasa I i II MHC1)
12 Interferoni Na antivirusno dejstvo interferona nisu jednako osetljivi svi virusi; npr. mnogi DNK virusi pokazuju veoma malu osetljivost Interferoni se dele u dve grupe: tip I - IFNα, IFNβ... (makrofagi, fibroblasti, limfoblasti, osteoblasti, endotelne ćelije...) tip II - IFNγ (aktivirani T limfociti) Indikacije IFNα hepatitisi b i c, maligni tumori IFβ multipla skleroza
13 Osobine bioloških lekova Antitela, hormoni... Stvaraju se u živim organizmima Rekombinantna tehnologija biotehnološki lekovi Složena struktura komplikovana proizvodnja teško je napraviti kopiju veoma su osetljivi na spoljašnje faktore temperatura i dr.) Imunogenost Visoka cena
14 Inhibicija TNFalfa Lekovi glukokortikoidi pentoksifilin, talidomid infliksimab, adalimumab (monoklonska IgG) etanercept (solubilni TNF-alfa receptori)
15 Inhibicija TNFalfa Sprečavaju vezivanje TNFalfa za receptore infliksimab - antitelo protiv TNFalfa (cirkulišući ili vezan za membranu) etanercept - receptori za TNFalfa - vezuju ga u cirkulaciji Inhibira dejstvo TNFalfa - talidomid
16 Imunizacija Aktivna - vakcine živi, atenuirani uzročnici (žive vakcine) - morbili, rubeola, BCG, polio ubijeni uzročnici (inaktivisane vakcine) - grip, besnilo toksoid - tetanus, difterija fragment uzročnika - tifus (kapsularni Vi polosaharid) Pasivna - imunoglobulini, serumi
17 Vakcine - kontraindikacije Opšte akutne bolesti febrilna stanja preosetljivost na sastojke vakcine oslabljen imunitet trudnoća (žive vakcine) Posebne AIDS (BCG) nekontrolisana epilepsija (veliki kašalj) trudnoća i 3 mes. posle porođaja, deca do 3 god. i stariji od 60 god. (tifus)
18 Vakcine - kontraindikacije Lažne (SZO) blage infekcije i prolivi (T < 38,5 o C) astma i alergijska stanja konvulzije u porodičnoj anamnezi Th antibioticima ili malim dozama steroida (< 2 mg/kg/dan prednizolona) dermatoze ili lokalne kožne infekcije hronične bolesti (srca, pluća, jetre, bubrega) stabilne neurološke smetnje i Daunov sindrom u anamnezi - žutica na rođenju, nedonoščad, neuhranjenost odojče...
19 Anti-Rh faktor globulin Rastvor humanih IgG protiv Rh(D) antigena Majka Rh-, a dete Rh+ Stvaranje At protiv Rh faktora - problem u sledećoj trudnoći sa Rh+ detetom Anti D globulini At protiv Er Rh+ ploda Tokom prva tri dana posle porođaja i.m. (oblažu Er ploda koji su dospeli u krv majke i tako sprečavaju senzibilizaciju)
20 Pitanje An Rh-negative mother gives birth to an Rhpositive baby.this is the mother s first child. Is immunotherapy necessary? (A) Yes.The mother should receive Rho(D) immune globulin to prevent hemolytic anemia in future neonates. (B) Yes.The mother s immune system reacted against the baby s T cells.thymosin should be given to augment the baby s cellular immunity. (C) Yes.The mother s immune system reacted against the baby s B cells. Fetal interferon should be given to augment the baby s humoral immunity. (D) No. Immunotherapy is not necessary, since this is the first child. (E) No. Immunotherapy would only have been necessary if the mother were Rh positive and baby Rh negative.
21 Odgovor A. An Rh-negative mother can develop antibodies against the Rh antigen if she is exposed to the blood of an Rh-positive baby during pregnancy or birth. If no therapy is given, hemolytic anemia can occur in future Rh-positive babies. Rho(D) immune globulin contains antibodies against the Rh antigen. Administered to the mother, it will destroy any red blood cells from the baby that entered her blood, preventing the mother from developing an immune response to the Rh antigen.
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