{"id":141,"date":"2021-08-03T21:41:47","date_gmt":"2021-08-03T19:41:47","guid":{"rendered":"https:\/\/www.imunomed.ro\/?p=141"},"modified":"2021-08-03T21:59:51","modified_gmt":"2021-08-03T19:59:51","slug":"afectarea-sistemului-imunitar-posibila-din-punct-de-vedere-al-tolerantei-imune-indusa-de-prima-celula-neoplazica-similara-cu-toleranta-indusa-de-celula-ovul-in-timpul-sarcinii","status":"publish","type":"post","link":"https:\/\/www.imunomed.ro\/?p=141&lang=ro","title":{"rendered":"afectarea sistemului imunitar – posibil\u0103 din punct de vedere al toleran\u021bei imune indus\u0103 de prima celul\u0103 neoplazic\u0103 similar\u0103 cu toleran\u021ba indus\u0103 de celula ovul \u00een timpul sarcinii"},"content":{"rendered":"

\u00cen oncologie nu se \u0219tie cum s\u0103 capteze \u0219i s\u0103 proceseze antigene neoplazice la nivelul APC (celule care prezint\u0103 antigen), dar celulele neoplazice \u0219i antigenele neoplazice pot s\u0103 nu fie preluate de APC \u0219i s-ar putea s\u0103 nu fie prezente \u00een limfocitele Th, deoarece acest lucru ar declan\u0219a o puternic\u0103 r\u0103spuns de respingere a celulelor tumorale de la debutul neoplaziei. Deci, probabil, defectul imunitar \u00een neoplasme este major, este prezent de la \u00eenceput \u0219i este mai mult legat de sistemul imunitar specific, de cooperarea limfocitului APC \/ Th. Se pare c\u0103 defectul este mai mult la nivelul limfocitelor Th, Ts, T \u0219i al APC \u0219i mai pu\u021bin la Tc, cu blocaj la nivelul imunit\u0103\u021bii specifice, \u00een timp ce imunitatea nespecific\u0103 func\u021bioneaz\u0103 mai normal: celulele NK joac\u0103 rolul principal \u0219i, prin urmare, pot s\u0103 fie considera\u021bi c\u0103 fac parte din imunitatea specific\u0103; par s\u0103 preia conducerea \u00een oncologie, dep\u0103\u0219ind Th \u0219i Tc. Macrofagele au func\u021bii fagocitare \u0219i secretoare \u0219i s-ar p\u0103rea c\u0103 nu pot func\u021biona ca APC, deoarece nu este descris \u00een literatur\u0103 preluarea \u0219i prelucrarea celulelor neoplazice, ci doar celulele somatice modificate, care au devenit antigenice. De asemenea, nu sunt descri\u0219i receptorii pentru antigenele neoplazice, ci doar receptorii pentru antigenele din celulele somatice modificate (receptori de captare, superfamilie de clasa A, implica\u021bi \u00een apoptoz\u0103, homeostazie, clearance). \u00cen caz contrar, sistemul imunitar nespecific particip\u0103 cu toate elementele variabile \u00een ap\u0103rarea antineoplazic\u0103.
\nDeterminarea genetic\u0103 a limfocitelor NK este de asemenea important\u0103; pe m\u0103sur\u0103 ce boala progreseaz\u0103, num\u0103rul acestora scade \u00een etapele finale. Una dintre explica\u021bii ar fi c\u0103 Th \u0219i Ts iau m\u0103suri pentru a suprima sistemul imunitar nespecific tocmai pentru c\u0103 Th, fiind defect, nu consider\u0103 oportun\u0103 interven\u021bia sistemului imunitar nespecific \u0219i d\u0103 comenzi lui Ts pentru a-l suprima. Aceasta ar fi o dovad\u0103 c\u0103 Th, Ts \u0219i Tcontrasupressor nu v\u0103d celulele neoplazice, deci au un defect major sau au stabilit de la \u00eenceput o toleran\u021b\u0103 total\u0103 la aceste celule, care seam\u0103n\u0103 cu cea a sarcinii; numai celelalte celule reac\u021bioneaz\u0103, deci nu au stabilit toleran\u021b\u0103: limfocite NK, limfocite B probabil mai independente de T (secre\u021bia de anticorpi este ineficient\u0103), complement, macrofage, celule polimorfonucleare. Unii exper\u021bi au avansat ideea c\u0103 celulele neoplazice sunt acoperite de anticorpi, cu toate acestea pare mai degrab\u0103 o sarcin\u0103 asupra lor care este din stadiul in situ, din prima celul\u0103 ap\u0103rut\u0103. Dac\u0103 este o sarcin\u0103 electromagnetic\u0103 care seam\u0103n\u0103 cu celula de ou, ar putea declan\u0219a un semnal de inducere a toleran\u021bei ca \u0219i \u00een timpul sarcinii, printr-un mecanism necunoscut, acela de a induce toleran\u021ba la sarcin\u0103, care, desigur, este declan\u0219at\u0103 din celula de ou. Dac\u0103 prima celul\u0103 neoplazic\u0103 poart\u0103 \u00een mod accidental acela\u0219i semnal (poten\u021bial de membran\u0103 electromagnetic\u0103?) Ca celula de ou \u0219i celulele embrionare, acest lucru ar putea explica lipsa respingerii tumorii.<\/strong>
\nCelulele NK joac\u0103, de asemenea, un rol central \u00een patologia respingerii sarcinii, \u00een special la nivel placentar.<\/strong>
\nO alt\u0103 dovad\u0103 c\u0103 limfocitul Th a stabilit toleran\u021ba la celulele neoplazice este ineficien\u021ba vaccinurilor care utilizeaz\u0103 celule tumorale \u0219i care nu stimuleaz\u0103 Th, deoarece vaccinurile microbiene \u00eel stimuleaz\u0103.<\/strong><\/p>\n

Possibilities of using Cyclophosphamide in oncology at low doses as an immunostimulator by inhibiting the regulatory T lymphocyte ( Treg )<\/p>\n

\u00a0Cyclophosphamide<\/strong> (Cy), este un agent alchilant care reac\u021bioneaz\u0103 chimic cu centrele nucleofile ale ADN, ARN sau molecule de proteine \u200b\u200blimfocitare, provoc\u00e2nd astfel sc\u0103derea sau inactivarea func\u021biilor imune. \u00cen func\u021bie de doz\u0103, poate fi imunosupresor, teoretic poate fi antiinflamator sau poate suprima complet r\u0103spunsul imun, fiind de preferin\u021b\u0103 \u00een transplantul de celule STEM alogene \u0219i alte tipuri de transplant.
\nLa doze mici, ciclofosfamida poate fi imunostimulatoare prin inhibarea regulatorului T (Treg: CD4 + CD25 + Foxp3) \u0219i a unor linii Ts (care ac\u021bioneaz\u0103 \u00een stadiile incipiente ale r\u0103spunsului imun). Efectul a fost demonstrat \u00een unele studii efectuate pe animale \u0219i oameni cu neoplasme (exemplu: cancer colorectal metastatic). Aceast\u0103 proprietate seam\u0103n\u0103 cu una dintre ac\u021biunile exercitate de vaccinarea BCG (vaccinul Mycobacterium tuberculosis) asupra limfocitului Ts (stimularea prin inhibarea limfocitelor).
\n\u00cen tumori, sunt eviden\u021biate subseturi de reglare T puternic activate (celule Treg foarte supresive), care exprim\u0103 o multitudine de receptori \u0219i au o secre\u021bie maxim\u0103 de citokine (\u00een special IL 10), care trebuie reprimat\u0103; \u00een schimb, alte subseturi de T reg sunt exprimate \u00een bolile autoimune, cu un num\u0103r \u00een general sc\u0103zut \u0219i densitate sc\u0103zut\u0103 a receptorilor \u0219i alte limit\u0103ri de absorb\u021bie imunomodulatoare care ar trebui activate. Acestea ar putea fi implicate \u00een rezisten\u021ba la tratament.
\n\u00cen concluzie, dac\u0103 imunomodularea la nivelul Th este mai dificil de realizat datorit\u0103 rezisten\u021bei sale, imunomodularea la nivelul Treg sau Ts poate fi \u00eencercat\u0103 at\u00e2t \u00een \u200b\u200bceea ce prive\u0219te stimularea (Levamisol), c\u00e2t \u0219i inhibarea prin diferite doze imunomodulatoare (Ciclofosfamid\u0103, vaccin BCG). Studiile ar putea fi extinse \u0219i la domeniul imunostimulan\u021bilor antiinfec\u021bio\u0219i sau anti-neoplazici.
\nEfectele ciclofosfamidei difer\u0103 \u00een primul r\u00e2nd \u00een ceea ce prive\u0219te sincronizarea dozei. \u00cen plus, calendarul este important, precum \u0219i caden\u021ba administra\u021biilor.
\nLa doze mici: 50 mg \/ zi (sau 50 de dou\u0103 ori pe zi), cercet\u0103torii \u00een oncologie au ob\u021binut efectul amplific\u0103rii r\u0103spunsului antitumoral \u00een principal prin inhibarea Treg.
\nEfectul asupra Treg este tranzitoriu (se regenereaz\u0103 \u00een aproximativ 10 zile).
\nCele mai sensibile la ciclofosfamid\u0103 sunt celulele Treg \u0219i unele linii Ts (care intr\u0103 \u00een stadiile incipiente ale r\u0103spunsului imun), celulele NK, liniile B \u0219i liniile CD8 sunt deprimate de la 200 mg \/ m ^ 2. Cele mai rezistente sunt liniile CD4 (rezist\u0103 p\u00e2n\u0103 la 600mg \/ m ^ 2) \u0219i unele linii Ts.
\nProfilul imunologic indus de doze mici de ciclofosfamid\u0103 este de obicei:
\n– Inhibarea Treg (\u0219i unele linii Ts) care rezult\u0103, conform unor autori, activarea macrofagelor simultan cu cre\u0219terea efectorilor CD8 +, produc\u021bia de IFN-.gamma \u0219i granzimele B;
\n– Dele\u021bii ale limfocitelor B, care nu ar afecta prea mult imunitatea.
\n– inhibi\u021bii NK – celul\u0103
\n– Tc: CD8 + rezist\u0103
\n– Th: rezisten\u021b\u0103 CD4 +; aceast\u0103 rezisten\u021b\u0103 cre\u0219te p\u00e2n\u0103 la 600 mg \/ m2<\/strong> from this dose, Th begins to be depressed (the dose has been determined by administering Cyclophosphamide from 50 to 700 mg\/m2, increasing every 3 weeks (Hengst, 1984). It also appears that CD4 cells recover faster than CD8.
\nAs an immunosuppressant, the effective doses also seem to be the lowest, 100mg\/day. It is interesting that at the beginning of immunosuppressive therapy the doses were even higher, between 50 and 150 mg\/day (1.5-3 mg\/kg\/day), some authors indicated in 1998 also average doses of 5 mg\/kg\/day up to high doses of 7 mg\/kg\/day 7-10 days up to a maximum of 3000 mg.
\nThe same 50 mg\/day doses that have been used in autoimmune diseases as immunosuppressants have recently been experienced as immunostimulants in colorectal cancer studies. At doses of 50 mg\/day administered experimentally in colorectal cancer, the researchers obtained an increase in the antitumor effect, probably mainly by inhibiting Treg. One explanation would be that in the two processes (autoimmune and tumour) the lines of the immune system are expressed differently:<\/em>
\n– in the case of autoimmune diseases, the most competent Th lymphocytes initiate commands to suppress the exaggerated immune response and slow it down. In these cases, the administration of immunosuppressants goes hand in hand with the higher commands of the immune system and the effect is maximum.<\/em>
\n– In the case of neoplasms, at least at the beginning the upper lines of the immune system, an antitumor stimulation is initiated and they can counteract the immunosuppressive effect of Cyclophosphamide, resisting up to high doses.<\/em>
\nEfectul asupra rezisten\u021bei Th CD4 +; aceast\u0103 rezisten\u021b\u0103 cre\u0219te p\u00e2n\u0103 la 600 mg \/ m2, conform studiilor Hengst din 1984, care au administrat doze \u00eentre 50 \u0219i 700 mg \/ m2 cu cre\u0219teri la 3 s\u0103pt\u0103m\u00e2ni; nu se \u0219tie exact pe ce loturi a fost efectuat experimentul, dar se pare c\u0103 acesta este pragul \u0219i acest lucru ar explica posibilitatea utiliz\u0103rii unor doze mari de acest tip \u00een oncologie: 400-1000 mg \/ m2. Pacien\u021bii tolereaz\u0103 aceste doze \u0219i, de obicei, nu recidiveaz\u0103 sau sufer\u0103 de o a doua neoplazie, deci rezist\u0103 unor linii Th care, coordon\u00e2ndu-se pe Tc, sus\u021bin imunitatea \u0219i supravie\u021buirea.<\/strong>
\nEfectul ciclofosfamidei pare s\u0103 difere at\u00e2t \u00een \u200b\u200bfunc\u021bie de doz\u0103, c\u00e2t \u0219i de starea \u00een care este utilizat\u0103:<\/strong>
\n– \u00een bolile autoimune, p\u00e2n\u0103 la doza prag, imunodepresia pare a fi mai indus\u0103 de afectarea liniilor imune inferioare \u0219i este mai eficient\u0103 la doze mai mici (50-150 mg \/ zi). C\u00e2nd se atinge nivelul de ac\u021biune asupra limfocitelor Th mai mari, terapia devine ineficient\u0103, deci este probabil s\u0103 nu se utilizeze doze mai mari dec\u00e2t imunosupresoarele (doze \u00een oncologie). Acela\u0219i lucru este valabil \u0219i pentru Ciclosporin\u0103 \u0219i Tacrolimus, doza nu trebuie testat\u0103 pentru a nu afecta prea mult Th pentru a optimiza efectul.<\/strong>
\n– \u00een neoplasme, ciclofosfamida este probabil administrat\u0103 din acela\u0219i motiv doar \u00een doze mari, la care Th este foarte rezistent, av\u00e2nd \u00een vedere statutul imunitar particular al neoplazicului.<\/strong>
\n– la transplant, starea imunologic\u0103 a beneficiarului poate fi anterior normal\u0103 \u0219i rezisten\u021ba la Th este mare, deci este probabil ca pragul pentru inducerea imunosupresiei s\u0103 fie mai mare \u0219i diferit.<\/strong>
\nUpper Th lymphocytes appear to have a high resistance to external and internal influences by autonomy (autonomous secretion of \u3016IL\u3017_2 could be one of the mechanisms of self-protection, according to Engst); also, the Th lymphocyte never comes in contact with antigens, neither exogenous nor endogenous, only through APC, which seems an additional measure of conservation and self-protection of the leading Th lymphocyte.<\/em>
\nAceast\u0103 \u201eizolare\u201d imunologic\u0103 \u0219i rol de conducere ar fi una dintre explica\u021biile pentru rezisten\u021ba Th la medicamente at\u00e2t imunosupresoare, c\u00e2t \u0219i imunostimulatoare (majoritatea imunostimulatorilor pot influen\u021ba cu u\u0219urin\u021b\u0103 celulele imune nespecifice, celulele NK \u0219i limfocitele B, dar nu pot influen\u021ba Th in vivo. utilizate \u00een patologia neoplazic\u0103 \u0219i infec\u021bioas\u0103 au descris efectele cre\u0219terii activit\u0103\u021bii limfocitelor Th, dar aceasta este probabil doar in vitro. Ar fi de dorit s\u0103 se \u00eembun\u0103t\u0103\u021beasc\u0103 stimularea \u0219i coordonarea liniei Th \/ Tc, posibil prin g\u0103sirea de antigeni care s\u0103 stimuleze bine linia APC. , (deci dependent de T). Imunostimulatorii cu ac\u021biune mai slab\u0103 pot avea o stimulare T mai independent\u0103, pe linia limfocitelor B.
\nDe asemenea, rezisten\u021ba crescut\u0103 a limfocitului Th pare s\u0103 permit\u0103 utilizarea vaccinurilor \u00een infec\u021biile acute, inclusiv \u00eencerc\u0103ri de administrare a vaccinului \u00eempotriva hepatitei B \u00een hepatita cronic\u0103. Studii mai ample asupra limfocitelor Th ar putea extinde domeniul imunostimulatorilor.
\nVaccinurile puternice, cum ar fi preparatele de piocianin\u0103, sunt susceptibile de a avea stimulare Th prin procesare \u00een APC; cu toate acestea, dup\u0103 un timp majoritatea vaccinurilor \u00ee\u0219i scad eficien\u021ba, deoarece probabil c\u0103 r\u0103m\u00e2n doar cu o stimulare umoral\u0103 mai simpl\u0103 \u0219i un sistem imunitar nespecific, mai mult NK, macrofag – polimorfonuclear, complement. Este interesant\u0103 evolu\u021bia imunostimulatoarelor, cum ar fi extractele de ciuperci, folosite \u00een oncologie care au avut ini\u021bial o poten\u021b\u0103 ridicat\u0103 (probabil au avut aceea\u0219i stimulare a Th, care ulterior a sc\u0103zut, deoarece activarea celulelor dendritice este descris\u0103 \u00een imunitatea antimicrobian\u0103); calea de administrare oral\u0103 poate fi, de asemenea, important\u0103: MALT (\u021besutul limfatic asociat cu tractul digestiv) a prezentat ini\u021bial o bun\u0103 reactivitate, posibil prin r\u0103sp\u00e2ndirea sporilor \u00een popula\u021bia general\u0103, la pacien\u021bii mai noi cu MALT \u00eei distruge prea puternic.
\nToate aceste date demonstreaz\u0103 c\u0103 sistemul imunitar are capacitatea \u0219i inteligen\u021ba de a-\u0219i direc\u021biona propriile linii efectoare, precum \u0219i cele induse terapeutic \u00een func\u021bie de nevoi.<\/p>\n

Mihaela Ghimpu
\nMedic specialist imunologie clinic\u0103
\n\u0219i alergologie<\/p>\n

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