Avaliação fenotípica e funcional dos linfócitos T citotóxicos de indivíduos infectados pelo HTLV-1 com diagnóstico de HAM/TSP / Phenotypic and functional assessment of cytotoxic T lymphocytes from individuals infected with HTLV-1 diagnosed with HAM / TSP

O Brasil representa uma das áreas endêmicas para o vírus linfotrópico de células T humanas do tipo 1 (HTLV-1) e a cidade de Salvador, Bahia, possui a maior prevalência nacional da infecção por este retrovírus (1,8%), com cerca de 50.000 pessoas infectadas. O HTLV-1 foi o primeiro retrovírus humano descrito e está classicamente associado à leucemia/linfoma de células T do adulto (ATLL) e à mielopatia associada ao HTLV-1/paraparesia espástica tropical (HAM/TSP). A HAM/TSP é uma doença inflamatória do sistema nervoso central, cujos mecanismos imunopatogênicos não estão completamente elucidados. O papel dos linfócitos T citotóxicos na patogênese desta doença ainda não está bem definido. Neste estudo, foram avaliados o fenótipo e a função de linfócitos T citotóxicos de pacientes infectados pelo HTLV-1 com HAM/TSP...

Brazil represents one of the largest endemic areas for human T-lymphotropic virus cells type 1 (HTLV-1) infection and associated diseases. Salvador, Bahia, is considered as the Brazilian city with the highest national HTLV-1prevalence (around 1.8% in the general population). HTLV -1 was the first human retrovirus described and is classically associated with adult Tcell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic and progressive inflammatory disease of the central nervous system and your immunopathogenic mechanisms are not completely understood. The role of cytotoxic T-lymphocytes (CTLs) in the pathogenesis of this disease is still undefined. In this study we evaluated the phenotype and function of cytotoxic Tlymphocytes from HTLV-1-infected patients with HAM/TSP...

Rhamnogalacturonan II is a Toll-like receptor 4 agonist that inhibits tumor growth by activating dendritic cell-mediated CD8+ T cells

We evaluated the effectiveness of rhamnogalacturonan II (RG-II)-stimulated bone marrow-derived dendritic cells (BMDCs) vaccination on the induction of antitumor immunity in a mouse lymphoma model using EG7-lymphoma cells expressing ovalbumin (OVA). BMDCs treated with RG-II had an activated phenotype. RG-II induced interleukin (IL)-12, IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) production during dendritic cell (DC) maturation. BMDCs stimulated with RG-II facilitate the proliferation of CD8+ T cells. Using BMDCs from the mice deficient in Toll-like receptors (TLRs), we revealed that RG-II activity is dependent on TLR4. RG-II showed a preventive effect of immunization with OVA-pulsed BMDCs against EG7 lymphoma. These results suggested that RG-II expedites the DC-based immune response through the TLR4 signaling pathway.

Selective addition of CXCR3+CCR4-CD4+ Th1 cells enhances generation of cytotoxic T cells by dendritic cells in vitro

Increasing importance is being given to the stimulation of Th1 response in cancer immunotherapy because its presence can shift the direction of adaptive immune responses toward protective immunity. Based on chemokine receptor expression, CXCR3+CCR4-CD4+ T cells as Th1-type cells were investigated its capacity in monocyte-derived dendritic cell (DC) maturation and polarization, and induction of antigen specific cytotoxic T lymphocytes (CTL) in vitro. The levels of IL-4, IL-5 and IL-10 were decreased to the basal level compared with high production of IFN-gamma, TNF-alpha, and IL-2 in CXCR3+CCR4-CD4+ T cells stimulated with anti-CD3 and anti-CD28 antibodies. Co-incubation of activated CD4+ or CXCR3+CCR4-CD4+ T cells with DC (CD4+/DC or CXCR3+CD4+/DC, respectively) particularly up-regulated IL-12 and CD80 expression compared with DC matured with TNF-alpha and LPS (mDC). Although there was no significant difference between the effects of the CXCR3+CCR4-CD4+ and CD4+ T cells on DC phenotype expression, CXCR3+CD4+/DC in CTL culture were able to expand number of CD8+ T cells and increased frequencies of IFN-gamma secreting cells and overall cytolytic activity against tumor antigen WT-1. These results demonstrated that the selective addition of CXCR3+CCR4-CD4+ T cells to CTL cultures could enhance the induction of CTLs by DC in vitro, and implicated on a novel strategy for adoptive T cell therapy.

Frequencies of cytotoxic T lymphocyte precursor estimate in three different populations.

There is speculation that high cytotoxic T lymphocyte precursor frequencies (CTLpf) correlate with poor clinical outcome of bone marrow/organ transplantation. It is also believed that human umbilical cord blood is immunologically naive, and, therefore cord blood T cells may be less able to mediate graft versus host disease than marrow-derived T cells. CTLpf were determined in peripheral blood mononuclear cells collected from healthy adults, human umbilical cord blood and renal dialysis patients who were randomly selected and entered into this study. A highly sensitive non-radioactive Europium release cytotoxicity assay was optimized and modified to carry out the CTLpf estimation by using the principle of limiting dilution analysis. The results of CTLpf in healthy adults ranged from 1/694 to 1/66,666, median 1/7,339 (n=10); cord blood ranged from 1/1,562 to 1/35,714, median 1/10,162 (n=6) and dialysis patients ranged from 1/1,054 to 1/17,857 median 1/5,208 (n=9). The results demonstrated that there is little difference of CTLpf median values between the groups, but there is a wide variation of CTLpf between individuals within a population. It suggests that this variation should be taken into account when considering CTLpf assay as pre-transplantation cross-match procedure.