Toll-like receptor (TLR) stimulation plays a crucial role in the homeostasis of human B cells. We investigated the expression of TLRs 1-9 on the cells of B-cell chronic lymphocytic leukemia (B-CLL) and analyzed the functional consequences of TLR stimulation on leukemic cells. We showed that B-CLL cells express similar set of TLRs as memory B cells of healthy donors, i.e. TLR-1, TLR-2, TLR-6, TLR-7 and TLR-9. However, in contrast to memory B cells, B-CLL cells lack TLR-4 expression. Expression of TLRs correlates with their capacity to respond to specific TLR agonists. At the level of phenotype, ODN2006 (TLR-9 agonist) is the most potent stimulus. B-CLL cells also respond to the stimulation with loxoribine, Pam3CSK4 and MALP-2 (TLR-7, TLR1/TLR2 and TLR2/TLR6 agonists, respectively). TLR-7 and TLR-9 stimulation induces production of IL-6 and TNFalpha. In 47% of tested patients, treatment with ODN2006, MALP-2 and Pam3CSK4 reduced leukemic cells survival. Stimulation of B-CLL cells with TLR-9 agonists, loxoribine, MALP-2 and Pam3CSK4 induces significant proliferation. We report that TLR stimulation induces expression of CD38, a negative prognostic marker, on B-CLL cells. Expression of CD38 is induced by direct stimulation of B-CLL cells through TLR-7 and TLR-9 or CD38 can be induced on B-CLL cells indirectly by a soluble factor induced in non-B-CLL cells after stimulation with TLR-2, TLR-3 or TLR-5 agonists; the nature of this factor remains unknown. Our results argue for cautious evaluation of immunointervention strategies based on the administration of TLR agonists in the treatment of B-CLL as their effects on B-CLL cells may be tumor promoting as well as tumor suppressing.
- MeSH
- aktivace lymfocytů imunologie MeSH
- antigeny CD38 biosyntéza MeSH
- chronická lymfatická leukemie imunologie metabolismus patologie MeSH
- fenotyp MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proliferace buněk MeSH
- průtoková cytometrie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- toll-like receptory agonisté imunologie metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Immunotherapy has emerged as another treatment modality in cancer. The goal of immunotherapy in advanced cancer patients does not have to be the complete eradication of tumor cells but rather the restoration of a dynamic balance between tumor cells and the immune response. Appropriate combination of tumor mass reduction (by surgery and/or chemotherapy) and neutralization of tumor-induced immunosuppression might set the right conditions for the induction of anti-tumor immune response by active immunotherapy. We review experimental basis and key concepts of combined chemo-immunotherapy and document its principles in the case report of patient with hormone refractory metastatic prostate cancer with sinister prognosis. More than four hundred prostate cancer patients have been treated with DC-based immunotherapy and tumor-specific immune responses have been reported in two-thirds of them. In half of these patients, DC immunotherapy resulted in transient clinical responses. Tregs, among other factors, potently inhibit tumor-specific T cells. Prostate cancer patients have elevated numbers of circulating and tumor infiltrating Tregs and there is evidence that Tregs increase tumor growth in vivo. Because of the high frequency of circulating Tregs in our patients, we first administered metronomic cyclophosphamide. After obtaining IRB approval, we started regular vaccinations with dendritic cells (DCs) loaded with killed prostate cancer cells. In accordance with the principles of combined immunotherapy, we continued palliative chemotherapy with docetaxel to reduce the tumor cell burden. DC-based vaccination induced prostate cancer cell-specific immune response. Combined chemo-immunotherapy consisting of alternate courses of chemotherapy and vaccination with mature DCs pulsed with LNCap prostate cancer cell line led to the marked improvement in the clinical and laboratory presentation and to the decrease of PSA levels by more than 90%.
- MeSH
- adenokarcinom sekundární terapie MeSH
- financování organizované MeSH
- imunoterapie metody MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- nádory kostí sekundární terapie MeSH
- nádory prostaty patologie terapie MeSH
- nádory závislé na hormonech sekundární terapie MeSH
- protinádorové látky terapeutické užití MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive agents. Effects of GC have mainly been attributed to the suppression of T cells. Recently, several studies have indicated the role of dendritic cells (DC) in GC-mediated immunosuppression. We investigated the effect of GC on characteristics of DC. Given the crucial role of Toll-like receptor (TLR) triggering for the initiation of DC maturation program, we analyzed the expression of TLR2, 3, 4 by GC-treated DC. To extend our in vitro findings, we analyzed the distribution of DC subsets in the blood of patients treated with high-dose corticosteroids. DC differentiation in presence of GC was skewed to a qualitatively distinct population incapable of inducing an efficient immune response, whereas GC presence during the process of maturation significantly reduced DC IL-12 p70 and TNF production and T cell stimulatory function. Despite the fact that GC increased expression of TLR2, 3 and 4 on DC, their stimulation with TLR-derived signals did not induce maturation. Administration of high-dose GC to the patients with systemic autoimmunity induced a decrease of circulating myeloid DC and abrogated plasmacytoid DC. These findings provide further insights into the mechanisms of GC immunosuppressive functions and reveal additional mechanisms of their therapeutic efficiency.
- MeSH
- aktivace lymfocytů účinky záření MeSH
- buněčná diferenciace imunologie účinky léků MeSH
- cytokiny imunologie MeSH
- dexamethason farmakologie terapeutické užití MeSH
- dítě MeSH
- financování organizované MeSH
- glukokortikoidy farmakologie MeSH
- imunofenotypizace MeSH
- juvenilní artritida farmakoterapie imunologie krev MeSH
- lidé MeSH
- methylprednisolon farmakologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- prednison farmakologie MeSH
- prezentace antigenu imunologie účinky léků MeSH
- průtoková cytometrie MeSH
- toll-like receptory biosyntéza genetika imunologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
Východisko. Dendritické buňky přestavují hlavní buňky, které zahajují imunitní reakci. Podílejí se na rozlišování cizího a vlastního a signálů nebezpečí, které pro organizmus představují škodliviny vnější, ale i vnitřní. Dendritické buňky také přispívají k udržování tolerance vůči vlastním tkáním. Glukokortikoidy jsou používány jako imunosupresiva a protizánětlivé léky a v transplantační medicíně k potlačení rejekce. Působení glukokortikoidů bylo zkoumáno zejména u monocytů a lymfocytů, ale jen ojedinělé studie byly zaměřeny na ovlivnění dendritických buněk glukokortikoidy. V naší studii jsme zkoumali vliv glukokortikoidů na diferenciaci a maturaci dendritických buněk in vitro a na ovlivnění subpopulací dendritických buněk in vivo po vysokodávkované kortikoterapii. Metody a výsledky. Na in vitro modelu (dendritické buňky vypěstované z periferních monocytů) jsme zjistili, že glukokortikoidy v koncentraci vyšší než 10-6Mindukují apoptózu dendritických buněk. V koncentracích nižších pak glukokortikoidy ovlivňují jak proces diferenciace, tak maturace dendritických buněk. Po podání Solumedrolu v bolusové dávce 1000 mg dochází in vivo během jednoho dne k praktickému vymizení plazmacytoidních dendritických buněk a výraznému snížení myeloidních dendritických buněk. Závěry. Tato studie prokazuje hluboký vliv kortikoidů na zahájení imunitní reakce, na funkci dendritických buněk. Dysfunkce dendritických buněk pod vlivem kortikoidů může být žádoucí ve smyslu potlačení patologické imunitní reakce, pro niž jsou kortikoidy indikovány, ale zároveň vysvětluje sklon ke zvýšené náchylnosti k infekcím u pacientů léčených kortikoidy.
Background. Dendritic cells represent the most effective antigen presenting cells and they are the only cell type capable of initiating the primary immune response. They use several sets of germ-line encoded receptors to differentiate between self and non-self and to detect the presence of danger signals. Danger signals are mainly represented by microbial pathogens but it can be also a necrotic or malignant cell. At various stages of their lifecycle dendritic cells play a key role in maintaining the peripheral tolerance towards self-antigens and in the initiation of an effective immune response. Glucocorticoids have been widely used in the treatment of autoimmune or inflammatory disorders and their immunosuppressive effect has been mainly attributed to the inhibition of lymphocytes functions. Methods and Results. In this study, we discuss the effects of glucocorticoids on in vitro generated myeloid dendritic cells and on peripheral blood myeloid and plasmacytoid dendritic cells subsets. Conclusions. Experimental results point to the profound suppressive effect of glucocorticoids on the antigen presenting functions of dendritic cells and to contribute to better understanding of glucocorticoids -mediated immunosuppressive effect.
- MeSH
- apoptóza MeSH
- buněčná diferenciace MeSH
- buněčná imunita účinky záření MeSH
- dendritické buňky imunologie účinky léků MeSH
- finanční podpora výzkumu jako téma MeSH
- glukokortikoidy farmakologie škodlivé účinky terapeutické užití MeSH
- imunosupresivní léčba MeSH
- kultivační média MeSH
- průtoková cytometrie MeSH
- techniky in vitro MeSH
