Transforming growth factor-beta-induced inhibition of T cell function. Susceptibility difference in T cells of various phenotypes and functions and its relevance to immunosuppression in the tumor-bearing state.

Abstract

The present study investigates the nature of humoral component(s) generated in tumor-bearing hosts to induce immune dysfunction of T cells. Cell-free ascitic fluid and culture supernatant (SN) were obtained from the ascites and cultures allowing MH134 hepatoma cells to grow. These ascites and SN samples were tested for their abilities to influence the generation of CTL responses to TNP and alloantigens. The generation of the anti-TNP CTL responses that require self H-2-restricted CD4+ Th cells was markedly suppressed by addition of the ascites or SN under conditions in which these samples did not inhibit anti-allo CTL responses capable of using alternate pathways of allo-restricted CD4+ and CD8+ Th. The activation of CD8+ CTL precursors and CTL activity were also resistant to the ascites or SN. The ascites- or SN-induced suppressive effect to which CD4+ Th were most susceptible was found to be mediated by transforming growth factor-beta (TGF-beta) activity, because: 1) the TGF-beta activity was detected in the MH134 ascites and culture SN; 2) the suppression of CD4+ Th function required for anti-TNP CTL responses was almost completely prevented by addition of anti-TGF-beta antibody to cultures and; 3) rTGF-beta also induced similar patterns of immunosuppression to those observed by ascites or SN. These results indicate that TGF-beta produced by tumor cells induces deleterious effects on T cell, especially on the CD4+ Th subset, and provide an explanation for the molecular mechanism underlying the previously observed CD4+ Th-selective suppression in the tumor-bearing state.

Characteristics of the Ehrlich ascites carcinoma model and prospects of its application in experimental pharmacology of veterinary drugs

“…Вырабатываемые клетками АКЭ растворимые протеины муцина-1 (MUC-1) препятствуют стимуляции Т-клеток благодаря активации системы комплимента к анти-MUC-1-антителам, связавшим антиген [24]. Экспрессия опухолевыми клетками во внеклеточное пространство трансформирующего фактора роста β (transforming growth factor beta, TGF-β) ингибирует пролиферацию NK-и Т-клеток через негативную регуляцию интерлейкином-2 (IL-2) пролиферативных сигналов [25,26], а также функции Th [27,28]. Обнаружено супрессивное действие опухолевых цитокинов на INF-γ-секретирующие клетки, в результате чего наблюдается торможение Т-хелперов типа 1 (Th1) клеточного действия, приводя к недостаточной активности опухолеспецифичных Т-лимфоцитов [29,30].…”

Atividade imunomoduladora da alga Chlorella vulgaris em camundongos portadores de tumos ascitico de Ehrlich

“…Isto se deve, em parte, a estimulação da citotoxicidade mediada por células NK. Neste ponto, é importante comentar a habilidade das células tumorais de inibir a resposta de células T mediadas por IFN-γ (Gosh et al 1995;Handel-Fernandez et al 1997;Huang et al 1995;Segura et al 1997;Elexpuru et al 1997;Stefanski et al 1996;Tada et al 1991). Células tumorais também têm a habilidade de suprimir a produção de TNFα.…”