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1.
Søndergaard H Frederiksen KS Thygesen P Galsgaard ED Skak K Kristjansen PE Odum N Kragh M 《Cancer immunology, immunotherapy : CII》2007,56(9):1417-1428
Interleukin (IL)-21 is a recently discovered cytokine in early clinical development, which has shown anti-tumor activity in
various animal models. In the present study, we examine the anti-tumor activity of IL-21 protein therapy in two syngeneic
tumor models and its effect on the density of tumor infiltrating T cells. We treated mice bearing established subcutaneous
B16 melanomas or RenCa renal cell carcinomas with intraperitoneal (i.p.) or subcutaneous (s.c.) IL-21 protein therapy and
subsequently scored the densities of tumor infiltrating CD4+ and CD8+ T cells by immunohistochemistry. Whereas both routes of IL-21 administration significantly inhibited growth of small, established
RenCa and B16 tumors, only s.c. therapy significantly inhibited the growth of large, established tumors. We found a greater
bioavailability and significant drainage of IL-21 to regional lymph nodes following s.c. administration, which could account
for the apparent increase in anti-tumor activity. Specific depletion of CD8+ T cells with monoclonal antibodies completely abrogated the anti-tumor activity, whereas NK1.1+ cell depletion did not affect tumor growth. In accordance, both routes of IL-21 administration significantly increased the
density of tumor infiltrating CD8+ T cells in both B16 and RenCa tumors; and in the RenCa model s.c. administration of IL-21 led to a significantly higher density
of tumor infiltrating CD8+ T cells compared to i.p. administration. The densities of CD4+ T cells were unchanged following IL-21 treatments. Taken together, these data demonstrate that IL-21 protein has anti-tumor
activity in established syngeneic tumors, and we show that IL-21 therapy markedly increases the density of tumor infiltrating
CD8+ T cells. 相似文献
2.
Cristina Maccalli Samantha Scaramuzza Giorgio Parmiani 《Cancer immunology, immunotherapy : CII》2009,58(5):801-808
Innate and adaptive immune responses have many interactions that are regulated by the balance of signals initiated by a variety
of activatory and inhibitory receptors. Among these, the NKG2D molecule was identified as expressed by T lymphocytes, including
most CD8+ cells and a minority of CD4+ cells, designated TNK cells in this paper. Tumor cells may overexpress the stress-inducible NKG2D ligands (NKG2DLs: MICA/B,
ULBPs) and the NKG2D signaling has been shown to be involved in lymphocyte-mediated anti-tumor activity. Aberrant expression
of NKG2DLs by cancer cells, such as the release of soluble form of NKG2DLs, can lead to the impairment of these immune responses.
Here, we discuss the significance of NKG2D in TNK-mediated anti-tumor activity. Our studies demonstrate that NKG2D+ T cells (TNK) are commonly recruited at the tumor site in melanoma patients where they may exert anti-tumor activity by engaging
both TCR and NKG2D. Moreover, NKG2D and TCR triggering was also observed by peripheral blood derived T lymphocyte- or T cell
clone-mediated tumor recognition, both in melanoma and colorectal cancer (CRC) patients. Notably, heterogeneous expression
of NKG2DLs was found in melanoma and CRC cells, with a decrease of these molecules along with tumor progression. Therefore,
through the mechanisms that govern NKG2D engagement in anti-tumor activity and the expression of NKG2DLs by tumor cells that
still need to be dissected, we showed that NKG2D expressing TNK cells are a relevant T cell subtype for immunosurveillance
of tumors and we propose that new immunotherapeutic interventions for cancer patients should be aimed also at enhancing NKG2DLs
expression by tumor cells.
This paper is a focused research review based on a presentation given at the sixth annual meeting of the Association for Immunotherapy
of Cancer (CIMT), held in Mainz, Germany, 15–16 May 2008. 相似文献
3.
Functional CD8<Superscript>+</Superscript> T cells infiltrate into nonsmall cell lung carcinoma 总被引:1,自引:0,他引:1
Verdegaal EM Hoogstraten C Sandel MH Kuppen PJ Brink AA Claas FH Gorsira MC Graadt van Roggen JF Osanto S 《Cancer immunology, immunotherapy : CII》2007,56(5):587-600
Infiltration of CD3(+)CD8(+) cytotoxic T cells was analyzed by multiparameter confocal laser microscopy in a panel of 16 randomly selected stage I nonsmall cell lung carcinomas. T-cell infiltration was observed in the stroma (range 57-2,093 T cells/mm(2)) but also in the tumor epithelium (range 21-892 T cells/mm(2)) and showed wide variation between individual tumors. Interestingly, a significantly higher percentage of CD3(+)CD8(+) T cells was detected in the tumor epithelium compared to the stroma illustrating that cytotoxic T cells may preferentially migrate into tumor epithelium. Aberrant HLA class I antigen expression was observed in 69% of the nonsmall-cell lung carcinoma (NSCLC) tumors. One tumor of a squamous cell lung carcinoma patient with the highest number of tumor infiltrating CD3(+) and CD3(+)CD8(+) cells was studied in detail and the majority (90%) of these cells were shown to be functionally activated granzyme B-positive cytotoxic T cells. DNA oligotyping of a lung carcinoma cell line established from this tumor revealed loss of one HLA haplotype corresponding with a translocation involving chromosome 6, as observed by COBRA-FISH. HLA class I-restricted tumor specific T cells could be isolated from PBMC. One further characterized cytotoxic CD8(+) T cell clone, that released TNF-alpha, IFN-gamma, and granzyme B upon co-incubation with the autologous tumor cells, was shown to be restricted by the remaining HLA-A11 allele, which was also shown to be expressed in the tumor tissue. Our data indicate that, despite HLA-haplotype loss a vigorous antitumor immune response mediated by CD8(+ )T-cells can be present in NSCLC offering possibilities for specific immunotherapy. 相似文献
4.
Wölfl M Merker K Morbach H Van Gool SW Eyrich M Greenberg PD Schlegel PG 《Cancer immunology, immunotherapy : CII》2011,60(2):173-186
T cell-mediated immunotherapy against malignancies has been shown to be effective for certain types of cancer. However, ex vivo expansion of tumor-reactive T cells has been hindered by the low precursor frequency of such cells, often requiring multiple rounds of stimulation, resulting in full differentiation, loss of homing receptors and potential exhaustion of the expanded T cells. Here, we show that when using highly purified naïve CD8+ T cells, a single stimulation with peptide-pulsed, IFNγ/LPS-matured dendritic cells in combination with the sequential use of IL-21, IL-7 and IL-15 is sufficient for extensive expansion of antigen-specific T cells. Short-term expanded T cells were tumor-reactive, multifunctional and retained a central-memory-like phenotype (CD62L+, CCR7+, CD28+). The procedure is highly reproducible and robust as demonstrated for different healthy donors and for cancer patients. Such short-term tumor-antigen-primed, multifunctional T cells may therefore serve as a platform to target different malignancies accessible to immunotherapy. 相似文献
5.
Diederichsen AC Hjelmborg Jv Christensen PB Zeuthen J Fenger C 《Cancer immunology, immunotherapy : CII》2003,52(7):423-428
The purpose of this study was to clarify whether HLA-DR expression of colorectal tumour cells or the CD4+/CD8+ ratio of the tumour infiltrating lymphocytes is significantly associated with the prognosis of colorectal cancer. Using flow cytometry, we studied the tumour cell expression of the HLA class II in 70 enzymatically dissociated colorectal cancers and the phenotype of tumour infiltrating lymphocytes (TILs) in 41 cases. There was no trend in 5-year survival between three levels (low, medium, high) of HLA-DR expression on the tumour cells. Patients with low CD4+/CD8+ ratios had a better clinical course, with significantly higher 5-year survival, p=0.046, independent of the Dukes stage and age. Our results have implications for tumour immunology; colorectal cancer cells might be a target for cytotoxic T-lymphocytes, however the tumour cells are not able to initiate an immune response. Stimulation of the immune system could possible be obtained using dendritic cells cultured in vitro and loaded with tumour antigens. 相似文献
6.
Cytotoxic T lymphocytes (CTL) are essential effectors of the cell-mediated immune response. The ability of CTL to specifically recognise and lyse malignant cells expressing the relevant surface antigens under optimal in vitro conditions justifies attempts to boost their number and activity through various forms of immunotherapy. Considering the high prevalence of colorectal cancer and poor survival rates for patients with advanced-stage disease, the development of new protocols based on CTL stimulation represents a genuine and promising treatment option. Significant advances in recombinant DNA technology and molecular biology have led to the identification of a number of tumour-associated antigens (TAA). These have served as vaccine constituents and/or stimuli for obtaining CTL used for adoptive immunotherapy after in vitro stimulation and expansion. The present review describes the properties and functions of CTL as effectors of the immune response against tumours, and summarises the known TAA recognised by CTL and the current status of CTL-related immunotherapeutic interventions in colorectal cancer patients. 相似文献
7.
Lionello I Mangia P Gattinoni L Pende D Cippone A Sensi M Rigatti P Traversari C 《Cancer immunology, immunotherapy : CII》2007,56(7):1065-1076
PURPOSE: The aim of this study was to characterize the immune response of patients affected by renal cell carcinoma (RCC). METHODS: Long-term RCC lines were established by retroviral-mediated transfer of the large T-antigen of SV40 into fresh carcinoma cells. Reactive T cell effectors were generated by iterative stimulations of patients' PBMC with autologous tumour cells. RESULTS: This protocol led to the induction of CD8(+) T cell clones reactive against the autologous tumour, but not against NK-sensitive cell lines. However, some of these effectors recognize normal renal cells, allogeneic renal carcinoma cell lines and colon and non-small cell lung carcinomas but not melanomas and lymphoblastoid lines, without evidence of shared classical HLA class I (HLA-I) molecules. Further characterization performed on the CD8(+) TCR alpha/beta(+) clone, CTL30, demonstrated that neither expression of CD1, HLA-Ia nor HLA-Ib, correlated with the T cells' recognition. Moreover, beta2m expression by target cells was not required to achieve interaction of tumour-effector cells. In agreement with this observation, the lytic activity of CTL30 was not inhibited by anti-HLA-I Ab, and antigen expression was not affected by inhibitors of antigen processing. Lytic activity of CTL30, while partially inhibited by anti-NKG2D, could not be abolished by anti-CD3 Abs. Moreover, growth and expansion of CTL30 was sustained only by T cell interaction with antigen-expressing tumour cells; unspecific mitogenic stimuli, such as anti-CD3 and PHA, did not allow T cell expansion. These results demonstrated the existence of an alpha/beta T cell population, recognizing epithelial tumour cells through an HLA-unrestricted, CD3-independent mechanism. 相似文献
8.
9.
Guenterberg KD Lesinski GB Mundy-Bosse BL Karpa VI Jaime-Ramirez AC Wei L Carson WE 《Cancer immunology, immunotherapy : CII》2011,60(9):1281-1288
Interferon-alpha (IFN-α) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant
setting. The cellular actions of IFN-α are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We
hypothesized that the anti-tumor activity of exogenous IFN-α would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1−/−) or control (SOCS1+/+) mice on an IFN-γ−/− C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections
of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1+/+ mice receiving IFN-A/D had significantly enhanced survival versus PBS–treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1−/− mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1−/− mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8+ T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1−/− mice as compared with mice receiving a control antibody (P = 0.0021). CD4+ T-cell depletion from SOCS1−/− mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1+/+ or SOCS1−/− mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1+/+ or SOCS1−/− mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in
response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor
effects of IFN-α in the setting of melanoma. 相似文献
10.
Albrecht J Frey M Teschner D Carbol A Theobald M Herr W Distler E 《Cancer immunology, immunotherapy : CII》2011,60(2):235-248
Clinical tumor remissions after adoptive T-cell therapy are frequently not durable due to limited survival and homing of transfused
tumor-reactive T cells, what can be mainly attributed to the long-term culture necessary for in vitro expansion. Here, we
introduce an approach allowing the reliable in vitro generation of leukemia-reactive cytotoxic T lymphocytes (CTLs) from naive
CD8+ T cells of healthy donors, leading to high cell numbers within a relatively short culture period. The protocol includes the
stimulation of purified CD45RA+ CD8+ T cells with primary acute myeloid leukemia blasts of patient origin in HLA-class I-matched allogeneic mixed lymphocyte-leukemia
cultures. The procedure allowed the isolation of a large diversity of HLA-A/-B/-C-restricted leukemia-reactive CTL clones
and oligoclonal lines. CTLs showed reactivity to either leukemia blasts exclusively, or to leukemia blasts as well as patient-derived
B lymphoblastoid-cell lines (LCLs). In contrast, LCLs of donor origin were not lysed. This reactivity pattern suggested that
CTLs recognized leukemia-associated antigens or hematopoietic minor histocompatibility antigens. Consistent with this hypothesis,
most CTLs did not react with patient-derived fibroblasts. The efficiency of the protocol could be further increased by addition
of interleukin-21 during primary in vitro stimulation. Most importantly, leukemia-reactive CTLs retained the expression of
early T-cell differentiation markers CD27, CD28, CD62L and CD127 for several weeks during culture. The effective in vitro
expansion of leukemia-reactive CD8+ CTLs from naive CD45RA+ precursors of healthy donors can accelerate the molecular definition of candidate leukemia antigens and might be of potential
use for the development of adoptive CTL therapy in leukemia. 相似文献
11.
John S. Cho Jeffrey V. Hsu Sherie L. Morrison 《Cancer immunology, immunotherapy : CII》2009,58(7):1057-1069
The systemic administration of an agonist antibody against glucocorticoid-induced tumor necrosis factor receptor related (GITR)
protein has been shown to be effective in overcoming immune tolerance and promoting tumor rejection in a variety of murine
tumor models. However, little is known regarding the functional consequence of ligation of GITR with its natural ligand (GITR-L)
in the context of regulatory T cell (Treg) suppression in vivo. To determine the mechanism of GITR-L action in vivo, we generated
a panel of tumor cell clones that express varying levels of GITR-L. The ectopic expression of GITR-L on the tumor cell surface
was sufficient to enhance anti-tumor immunity and delay tumor growth in syngeneic BALB/c mice. Within the range examined,
the extent of anti-tumor activity in vivo did not correlate with the level of GITR-L expression, as all clones tested exhibited
a similar delay in tumor growth. The localized expression of GITR-L on tumor cells led to a significant increase in CD8+ T cell infiltration compared to the levels seen in control tumors. The increased proportion of CD8+ T cells was only observed locally at the tumor site and was not seen in the tumor draining lymph node. Depletion studies
showed that CD8+ T cells, but not CD4+ T cells, were required for GITR-L mediated protection against tumor growth. These studies demonstrate that signaling between
GITR-L and GITR in the tumor microenvironment promotes the infiltration of CD8+ T cells, which are essential for controlling tumor growth.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
12.
Background
Administration of recombinant G-CSF following cytoreductive therapy enhances the recovery of myeloid cells, minimizing the risk of opportunistic infection. Free G-CSF, however, is expensive, exhibits a short half-life, and has poor biological activity in vivo.Methods
We evaluated whether the biological activity of G-CSF could be improved by pre-association with anti-G-CSF mAb prior to injection into mice.Results
We find that the efficacy of G-CSF therapy can be enhanced more than 100-fold by pre-association of G-CSF with an anti-G-CSF monoclonal antibody (mAb). Compared with G-CSF alone, administration of G-CSF/anti-G-CSF mAb complexes induced the potent expansion of CD11b+Gr-1+ myeloid cells in mice with or without concomitant cytoreductive treatment including radiation or chemotherapy. Despite driving the dramatic expansion of myeloid cells, in vivo antigen-specific CD8+ T cell immune responses were not compromised. Furthermore, injection of G-CSF/anti-G-CSF mAb complexes heightened protective immunity to bacterial infection. As a measure of clinical value, we also found that antibody complexes improved G-CSF biological activity much more significantly than pegylation.Conclusions
Our findings provide the first evidence that antibody cytokine complexes can effectively expand myeloid cells, and furthermore, that G-CSF/anti-G-CSF mAb complexes may provide an improved method for the administration of recombinant G-CSF.13.
Bettahi I Dasgupta G Renaudet O Chentoufi AA Zhang X Carpenter D Yoon S Dumy P BenMohamed L 《Cancer immunology, immunotherapy : CII》2009,58(2):187-200
Molecularly defined synthetic vaccines capable of inducing both antibodies and cellular anti-tumor immune responses, in a
manner compatible with human delivery, are limited. Few molecules achieve this target without utilizing external immuno-adjuvants.
In this study, we explored a self-adjuvanting glyco-lipopeptide (GLP) as a platform for cancer vaccines using as a model MO5,
an OVA-expressing mouse B16 melanoma. A prototype B and T cell epitope-based GLP molecule was constructed by synthesizing
a chimeric peptide made of a CD8+ T cell epitope, from ovalbumin (OVA257–264) and an universal CD4+ T helper (Th) epitope (PADRE). The resulting CTL–Th peptide backbones was coupled to a carbohydrate B cell epitope based
on a regioselectively addressable functionalized templates (RAFT), made of four α-GalNAc molecules at C-terminal. The N terminus
of the resulting glycopeptides (GP) was then linked to a palmitic acid moiety (PAM), obviating the need for potentially toxic
external immuno-adjuvants. The final prototype OVA-GLP molecule, delivered in adjuvant-free PBS, in mice induced: (1) robust
RAFT-specific IgG/IgM that recognized tumor cell lines; (2) local and systemic OVA257–264-specific IFN-γ producing CD8+ T cells; (3) PADRE-specific CD4+ T cells; (4) OVA-GLP vaccination elicited a reduction of tumor size in mice inoculated with syngeneic murine MO5 carcinoma
cells and a protection from lethal carcinoma cell challenge; (5) finally, OVA-GLP immunization significantly inhibited the
growth of pre-established MO5 tumors. Our results suggest self-adjuvanting glyco-lipopeptide molecules as a platform for B
Cell, CD4+, and CD8+ T cell epitopes-based immunotherapeutic cancer vaccines.
Both I. Bettahi and G. Dasgupta have contributed equally to this work. 相似文献
14.
Kreiter S Konrad T Sester M Huber C Türeci O Sahin U 《Cancer immunology, immunotherapy : CII》2007,56(10):1577-1587
Assessment of antigen-specific T-cell responses has been greatly facilitated by development of ELISPOT and intracellular cytokine flow cytometry (CFC) assays. The use of autologous antigen presenting cells transfected with in vitro transcribed RNA as stimulators allows in principle quantification of antigen-specific T-cells independent of the knowledge of the epitopes. We describe here a cytokine secretion assay that enables simultaneous assessment of both antigen-specific CD4+ as well as CD8+ T-cells directly from clinical samples without the need for generation of dendritic cells. To this aim, bulk PBMCs were electroporated with RNA encoding the antigen fused to trafficking signal sequences derived from a MHC class I molecule and used as stimulators. With human cytomegalovirus (HCMV) phosphoprotein 65 (pp65) as antigen we show that for measuring ex vivo T-cell responses in ELISPOT and CFC such stimulators are superior or at least equivalent to a pool of overlapping peptides representing the entire pp65 sequence as well as to untagged pp65 encoding RNA. This approach avoids the time consuming generation of dendritic cells as immune stimulators and, in particular when used in the context of the CFC, is robust, broadly applicable and fast. 相似文献
15.
Iero M Squarcina P Romero P Guillaume P Scarselli E Cerino R Carrabba M Toutirais O Parmiani G Rivoltini L 《Cancer immunology, immunotherapy : CII》2007,56(12):1979-1991
The use of “altered peptide ligands” (APL), epitopes designed for exerting increased immunogenicity as compared with native
determinants, represents nowadays one of the most utilized strategies for overcoming immune tolerance to self-antigens and
boosting anti-tumor T cell-mediated immune responses. However, the actual ability of APL-primed T cells to cross-recognize
natural epitopes expressed by tumor cells remains a crucial concern. In the present study, we show that CAP1-6D, a superagonist
analogue of a carcinoembriyonic antigen (CEA)-derived HLA-A*0201-restricted epitope widely used in clinical setting, reproducibly
promotes the generation of low-affinity CD8+ T cells lacking the ability to recognized CEA-expressing colorectal carcinoma (CRC) cells. Short-term T cell cultures, obtained
by priming peripheral blood mononuclear cells from HLA-A*0201+ healthy donors or CRC patients with CAP1-6D, were indeed found to heterogeneously cross-react with saturating concentrations
of the native peptide CAP1, but to fail constantly lysing or recognizing through IFN- γ release CEA+CRC cells. Characterization of anti-CAP1-6D T cell avidity, gained through peptide titration, CD8-dependency assay, and staining
with mutated tetramers (D227K/T228A), revealed that anti-CAP1-6D T cells exerted a differential interaction with the two CEA
epitopes, i.e., displaying high affinity/CD8-independency toward the APL and low affinity/CD8-dependency toward the native
CAP1 peptide. Our data demonstrate that the efficient detection of self-antigen expressed by tumors could be a feature of
high avidity CD8-independent T cells, and underline the need for extensive analysis of tumor cross-recognition prior to any
clinical usage of APL as anti-cancer vaccines. 相似文献
16.
The interest in naturally arising regulatory T (TR) cells as a paradigm for maintaining immunological self-tolerance has undergone an explosive re-emergence in recent years.
This renaissance was triggered by several key experimental observations and the identification of specific molecular markers
that have enabled the isolation and experimental manipulation of these cells. Although their existence was once controversial,
a large body of evidence now highlights the critical roles of TR cells in maintaining immunological self-tolerance. Furthermore, abnormality of natural TR cells can be a primary cause of autoimmune and other inflammatory diseases in humans. 相似文献
17.
Elkord E Burt DJ Drijfhout JW Hawkins RE Stern PL 《Cancer immunology, immunotherapy : CII》2008,57(6):833-847
Background The human 5T4 (h5T4) oncofoetal antigen is expressed by a wide variety of human carcinomas including colorectal, ovarian,
gastric and renal, but rarely on normal tissues. Its restricted expression on tumour tissues as well as its association with
tumour progression and bad prognosis has driven the development of a MVA-based vaccine (TroVax) which has been tested in several
early phase clinical trials and these studies have led to the start of a phase III trial in renal cell carcinoma patients.
We have recently shown that CD8+ T cells recognizing h5T4 can be generated in the absence of CD4+ T cells from peripheral blood lymphocytes of human healthy individuals.
Results We report the existence and expansion of human CD4+ T cells against h5T4 by stimulation with autologous monocyte-derived dendritic cells infected with a replication defective
adenovirus encoding the h5T4 cDNA (Ad-h5T4). The h5T4-specific T-cell responses in normal individuals are enhanced by initial
depletion of CD25+ cells (putative T regulatory cells) prior to the in vitro stimulation. We have identified a novel h5T4-derived 15-mer peptide
recognized by CD4+ T cells in HLA-DR4 positive healthy individuals. Interestingly, CD4+ T cells spontaneously recognizing a different 5T4 epitope restricted by HLA-DR were identified in tumour-infiltrating lymphocytes
isolated from a regressing renal cell carcinoma lung metastasis.
Conclusion Our data show that CD4+ T cells recognizing h5T4 can be expanded and detected in healthy individuals and a renal cell carcinoma patient. Such h5T4-specific
CD4+ T cells boosted or induced by vaccination could act to modulate both cell or antibody mediated anti-tumour responses.
This work was supported by Cancer Research UK. 相似文献
18.
Petrovas C Mueller YM Yang G Altork SR Jacobson JM Pitsakis PG Mounzer KC Altman JD Katsikis PD 《Apoptosis : an international journal on programmed cell death》2007,12(12):2175-2186
We have recently provided data suggesting a potential role for mitochondria and Bcl-2-family molecules in apoptosis sensitivity
of HIV-specific CD8+ T cells. Here, we report on the role of filamentous (F) actin in this process. Disruption of actin by cytochalasin D (cytD)
or lantrunculin A remarkably reduced CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells while their spontaneous apoptosis was unaffected. This inhibition cannot be attributed to changes of CD95/Fas distribution
or levels in these cells. Furthermore, cytD treatment reduced CD95/Fas-induced apoptosis of CD8+ T cells from HIV+ patients independently of their differentiation status. CD95/Fas-induced apoptosis of both CD38+ and CD38− HIV-specific CD8+ T cells was inhibited by cytD treatment indicating that actin mediates this apoptotic process independently of the activation
level of these cells. CytD was found to reduce the activation of caspase-8 induced by short treatment of purified CD8+ T cells from HIV+ patients with anti-CD95/Fas. Our data reveal actin as a critical mediator of HIV-specific CD8+ T cell apoptosis; further analysis of the molecular mechanisms governing this process may potentially contribute to design
new therapies targeting the enhancement of the immune system in HIV infection. 相似文献
19.
Background
Dendritic cells (DCs) are considered as key mediators of the early events in human immunodeficiency virus type 1 (HIV-1) infection at mucosal sites. Previous studies have shown that surface-bound virions and/or internalized viruses found in endocytic vacuoles of DCs are efficiently transferred to CD4+ T cells. Extracellular adenosine triphosphate (ATP) either secreted or released from necrotic cells induces a distorted maturation of DCs, transiently increases their endocytic capacity and affects their migratory capacity. Knowing that high extracellular ATP concentrations are present in situations of tissue injury and inflammation, we investigated the effect of ATP on HIV-1 transmission from DCs to CD4+ T lymphocytes.Results
In this study, we show that extracellular ATP reduces HIV-1 transfer from immature monocyte-derived DCs (iDCs) to autologous CD4+ T cells. This observed decrease in viral replication was related to a lower proportion of infected CD4+ T cells following transfer, and was seen with both X4- and R5-tropic isolates of HIV-1. Extracellular ATP had no effect on direct CD4+ T cell infection as well as on productive HIV-1 infection of iDCs. These observations indicate that extracellular ATP affects HIV-1 infection of CD4+ T cells in trans with no effect on de novo virus production by iDCs. Additional experiments suggest that extracellular ATP might modulate the trafficking pathway of internalized virions within iDCs leading to an increased lysosomal degradation, which could be partly responsible for the decreased HIV-1 transmission.Conclusion
These results suggest that extracellular ATP can act as a factor controlling HIV-1 propagation.20.
Ghiringhelli F Menard C Puig PE Ladoire S Roux S Martin F Solary E Le Cesne A Zitvogel L Chauffert B 《Cancer immunology, immunotherapy : CII》2007,56(5):641-648
CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy. 相似文献