Imunomodularea - mijloc de corectie a raspunsurilor imune anormale

1 Septembrie, 2010 - 23:00

In general imunomodularea este definita ca un ansamblu de interventii corective/reglatoare ale raspunsurilor imune aberante/anormale/patologice catre raspunsuri imune normale/fiziologice/echilibrate jogos casino online.

A. Imunomodularea in boli autoimune si in deficientele imunitare

Ca atare, imunomodularea poate include interventii stimulatorii sau represive/inhibitorii, dependente de nivelul, intensitatea si amploarea alterarii raspunsului imun fiziologic, situatie intalnita in afectiuni cu componenta disimunitara majora: boli autoimune, boli produse prin hipersensibilizare sau boli datorate imunodeficientelor primare si secundare Bonus Fara Depunere

Imunomodularea poate fi definita ca adaptativa sau intrinseca si fortuita.
Mijloacele de interventie adaptative includ o varietate de verigi de control la nivelul recunoasterii si activarii celulare, al secretiei de citokine si implicarii acestora in raspunsul imun, de control al reglarii interventiei moleculelor de adeziune celulara si intercelulara, precum si al retelei de reglaj idiotip - antiidiotip.

Mijloacele de imunomodulare fortuita (specifice si nespecifice) vizeaza
stimularea unui raspuns imun deficitar sau supresia/reprimarea raspunsului imun exagerat.

Imunomodulatoarele sau agentii care modifica raspunsul imun biologic utilizati in tratamentul bolilor autoimune asociate cu secretia de anticorpi antistructuri proprii alterate, denaturate si nerecunoscute ca structuri self, includ o gama largita de agenti reprezentati de: amplificatori ai
raspunsului imun deprimat (cunoscuti si ca imunostimulatori), supresori (cunoscuti ca agenti imunosupresivi), interferoni si inductorii lor, produsi de secretie celulara (limfokine, monokine) si antagonistii acestora, factori de crestere celulara, factori de maturare, derivate din organele limfoide centrale sau substitute ale acestora (factori timici, grefe de timus si medulare), inlocuitori de celule stem, antigene, anticorpi, celule efectoare si chiar gene modificate prin inginerie genetica.

Desi sunt inalt eficiente, majoritatea mijloacelor de interventie imunomodulatoare folosite in bolile cu componenta autoimuna ca si in alte imunopatii sunt marcate de lipsa de specificitate de raspuns, prezentand inabilitatea de disjunctie intre raspunsul imun normal/fiziologic si
raspunsurile imune patologice coexistente si, ca urmare, induc reducerea raspunsului imun normal sau agravarea fenomenelor imunodepresive coexistente.

Consecinta a acestei neselectivitati, alegerea momentului, dozelor si regimurilor terapeutice ce folosesc imunomodulatoare din clasele amintite se stabilesc dupa o evaluare imunologica celulara si umorala complexa si dinamica si se utilizeaza numai in forme severe de boala autoimuna.

Spre deosebire de bolile autoimune, in malignitati si in alte morbiditati asociate cu imunodeficiente secundare, ca si in imunodeficientele primare, interventia imuno-modulatoare se face activ (indepartarea tumorii, stimulare bacteriana, cu celule sau antigene specifice tumorale si antigene asociate cu tumorile), pasiv (transfer de anticorpi/imunoconjugate, imunotoxine,
anticorpi anti-idiotip, heteroconjugate/anticorpi bispecifici), adoptiv (transfer de celule imunocompetente plus sau minus citokine, plus sau minus antireceptori, costimulatori etc.), restaurativ (normalizarea populatiilor/subpopulatiilor deficitare - prin factori timici si agenti
farmacoterapeutici timomimetici), blocante ale factorilor sau numai ale receptorilor celulelor supresoare.

Dozele, ritmul de administrare, durata si complexitatea regimurilor imunomodulatorii reprezinta decizii cu multiple implicatii care se iau cu responsabilitate numai dupa o investigare complexa si dinamica a statusului imun.

B. Imunomodularea in bolile alergice IgE mediate

Bolile alergice IgE mediate reprezinta in practica medicala cea mai raspandita paleta a bolilor datorate hipersensibilizarii, ca raspuns imun exagerat fata de structuri non-self.

Corelate cu atopia si avand deci un important determinism poligenic, bolile alergice IgE mediate incep precoce in copilarie, exprimandu-se pe durata intregii vieti.

Deja amintita, principala lor caracteristica este data de aptitudinea individuala de raspuns particular si exagerat in anticorpi din clasa imunoglobulinelor E (IgB), anticorpi rar intalniti sau prezenti in concentratii nesemnificative la indivizii normali sau non-atopici.

Imunoglobuinele E totale, reprezentate de suma imunoglobulinelor E specifice, sunt induse de expunerea la o imensitate de alergene neagresive pentru non-atopici (al caror raspuns in anticorpi se face prin anticorpi naturali din clasa IgM, IgG, IgA, raspuns corelat cu expunerea la antigene virale, microbiene, parazitare, potential agresive pentru orice individ non-atopic sau atopic).

Expunerea la alergene asociate cu atopia genereaza la un prim contact al individului predispus genetic ”starea de sensibilizare”, asociata cu secretia imunoglobulinelor E, precum si cu pastrarea in memoria imunologica a limfocitelor T specializate a specificitatii ei. Repetarea expunerii la
acelasi alergen sau la alergene cu epitopi asemanatori/identici pot declansa ”cascada” raspunsului alergic precoce si tardiv si a inflamatiei alergice secundare, ce evolueaza de la inflamatie acuta catre cronicitate si remodelare.

Hiperreactivitatea IgE mediata este orchestrata de prevalenta profilului citokinelor TH2 dependente (IL4, IL13) fiind nu numai un marker de predispozitie genetica, ci si rezultanta impactului intre aceasta constitutie particulara si polivalenta factorilor ambientali, intre care
alergenele nu joaca decat un rol ce este modulat si de interrelatia cu numerosi alti agenti: poluanti, infectiosi (virusali, microbieni si parazitari), ei insisi adevarati modificatori ai raspunsului imun nespecific si specific.

In acest context, imunomodularea in general, si imunomodularea la atopici si in bolile alergice IgE mediate este o adevarata provocare a carei complexitate pe departe este inca neinteleasa si nestapanita in ciuda progreselor evidente.

Principalele caracteristici imunologice ale atopiei si bolilor alergice IgE mediate sunt: hipersecretia de IgE si imbalanta celularitatii functionale TH1/TH2 in favoarea TH2 si citokinelor dependente (IL4, IL13). Multiple studii recente documentate au crescut premizele corectarii acestor caracteristici si sustinerii efectelor imunomodulare alergen-specifice prin
tehnica imunoterapiei cu alergen, cunoscuta in prezent sub denumirea vaccinarea alergen specifica (V.A.S.).

Practicata clasic sau prin metode neconventionale standardizate si ameliorate in timp, imunomodularea cu vaccinuri alergen specifice s-a dovedit ca singura metoda asociata cu schimbarea cursului natural al bolilor alergice IgE mediate.

Din punct de vedere imunologic prin V.A.S se remarca urmatoarele beneficii: schimbari in raportul TH1 /TH2 in favoarea TH1 si a citokinelor dependente (INFg, IL10), alterarea productiei de anticorpi (scaderea IgE totale si specifice de alergen, cresterea IgG4 si a raportului IgG4/IgE, reducerea eosinofiliei tisulare (un alt marker al atopiei) si inhibarea activarii IgE
dependente a celulelor efectorii mai ales a mastocitelor si bazofilelor, ele insele inhibitorii ale rolului IgE in facilitarea prezentarii precum si inhibarea raspunsului alergic precoce si tardiv.

Limitata ca indicatii la anumite fenotipuri clinice de boala atopica si in anumite stadii evolutive, ca si la anumiti alergeni (veninuri de insecte, polenuri, alergeni proveniti de la pisica, dermatophagoides pteronissinus etc.), V.A.S este asociata cu riscul anafilaxiei si altor reactii
adverse severe (ca reactia de organ).

Aceste neajunsuri par a fi corectate prin utilizarea altor mijloace terapeutice imunomodulatoare mai apropiate bolilor prin hipersensibilizare IgE mediate si reprezentate de:
- terapia cu citokine antiinflamatoare (IL10, INFg, IL12);
- terapia cu inhibitori de citokine (anti IL5, anti IL4, anti IL13);
- tratament cu inhibitori de chemokine (anti CCR3);
- inhibitori ai factorilor de transcriptie (anti IkB);
- imunosupresive;
- blocanti ai moleculelor de adeziune celulara (anticorpi monoclonali pentru ICAM1,VLA4); inhibitori de celule T;
- anti IgE;
- vaccinarea cu peptide;
- terapie genica;
- terapia imunomodulatoare cu lizate microbiene si extracte microbiene si virale atenuate/inactivate aplicate ca inductori ai citokinelor de profil TH1 deficitare in bolile alergice IgE mediate.

Revenind la imunoterapie, aceasta este regandita si practicata in scheme terapeutice si - mai ales - in conditii deosebite, utilizand alergene recombinante, variante alergenice care nu leaga IgE, deci nu induc anafilaxia, peptide alergenice, alergeni legati de adjuvanti, vaccinuri cu plasmide DNA, anticorpi monoclonali, anti IgE (omalizumab etc.).

Dintre toate aceste intentii de imunomodulare, studiile recente experimentale si clinice pozitioneaza avantajos, in mod particular: terapia cu alergene recombinante, terapia cu peptide ce induc anergia celulelor T si terapia cu anticorpi monoclonali anti IgE ce intervine IgE nespecific de alergen si este neanafilactogena.

(Jeana-Rodica Radu, Profesor universitar - UMF "Carol Davila"- Catedra Alergologie, Spital Clinic ”N. Malaxa”)

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