Иммунотропная терапия: блокада CTLA-4 / B7 и PD-1 / PD-L1 путей в терапии злокачественных новообразований. Часть 1. Иммунологические аспекты.



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Сигнальные пути CTLA-4/B7 и PD-1/PD-L1 являются ключевыми при формировании и поддержании периферической иммунологической толерантности. Взаимодействие рецепторов PD-1 и CTLA-4 со своими лигандами запускает каскад реакций, способствующий подавлению активности эффекторных CD4+ и CD8+ Т-лимфоцитов. Однако роль этих сигнальных каскадов в иммунных реакциях достаточно многогранна. Так, на поверхности Т-клеток CTLA-4 конкурирует с CD28 за лиганды и, при взаимодействии с молекулами семейства В7, ингибирует передачу сигнала с Т-клеточного рецептора (TCR). В то же время, данное взаимодействие способствует выработке противовоспалительных цитокинов IL-10 и TGF-β регуляторными Т-лимфоцитами (Трег). На Трег CTLA-4 после связывания с молекулами семейства В7 (CD80 и CD86) на поверхности антигенпрезентирующей клетки (АПК) опосредует CTLA-4-зависимый трогоцитоз, следствием которого является снижение экспрессии молекул семейства B7 на АПК. Это снижает эффективность АПК в стимуляции клональной экспансии и выживания активированных Т-клеток в лимфоидной ткани. Молекула PD-1, в свою очередь, экспрессируется на широком спектре клеток, включая эффекторные CD4+ и CD8+ Т-лимфоциты. Данная молекула крайне важна для выживания и проявления эффекторных свойств активированных антиген-специфических Т-лимфоцитов в воспаленных периферических тканях. Кроме того, взаимодействие PD-1 с PD-L1 может стимулировать выработку противовоспалительных цитокинов Трег. При онкологических заболеваниях опухолевые клетки могут использовать преимущества периферической толерантности, реализуемой как молекулой CTLA-4, так и молекулой PD-1. Следовательно, блокада этих рецепторов может выступать эффективным терапевтическим подходом в клинической практике при лечении злокачественных новообразований.

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