scholarly journals Distinct tumour antigen-specific T-cell immune response profiles at different hepatocellular carcinoma stages

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chaoran Zang ◽  
Yan Zhao ◽  
Ling Qin ◽  
Guihai Liu ◽  
Jianping Sun ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Response ◽  
T Cell ◽  
Early Stage ◽  
T Cell Responses ◽  
Tumour Antigen ◽  
Cell Immune Response ◽  
Cell Responses ◽  
Ifn Γ

Abstract Background Cancer-testis antigens (CTAs) and tumour-associated antigens (TAAs) are frequently expressed in hepatocellular carcinoma (HCC); however, the role of tumour-antigen-specific T cell immunity in HCC progression is poorly defined. We characterized CTA- and TAA-specific T cell responses in different HCC stages and investigated their alterations during HCC progression. Methods Fifty-eight HCC patients, 15 liver cirrhosis patients, 15 chronic hepatitis B patients and 10 heathy controls were enrolled in total. IFN-γ ELSPOT using CTAs, including MAGE-A1, MAGE-A3, NY-ESO-1, and SSX2, and two TAAs, SALL4 and AFP, was performed to characterize the T-cell immune response in the enrolled individuals. The functional phenotype of T cells and the responsive T cell populations were analyzed using short-term T-cell culture. Results T cell responses against CTAs and TAAs were specific to HCC. In early-stage HCC patients, the SALL4-specific response was the strongest, followed by MAGE-A3, NY-ESO-1, MAGE-A1 and SSX2. One-year recurrence-free survival after transcatheter arterial chemoembolization plus radiofrequency ablation treatment suggested the protective role of CTA-specific responses. The four CTA- and SALL4-specific T cell responses decreased with the progression of HCC, while the AFP-specific T cell response increased. A higher proportion of CD4+ T cells specific to CTA/SALL4 was observed than AFP-specific T cell responses. Conclusions The IFN-γ ELISPOT assay characterized distinct profiles of tumour-antigen-specific T cell responses in HCC patients. CTA- and SALL4-specific T cell responses may be important for controlling HCC in the early stage, whereas AFP-specific T cell responses might be a signature of malignant tumour status in the advanced stage. The application of immunotherapy at an early stage of HCC development should be considered.

Characterization of the Immune Response to Canine Factor IX Following AAV-Mediated Intravascular Gene Delivery to Skeletal Muscle in Hemophilia B Dogs.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1297-1297
Author(s):  
Daniel J. Hui ◽  
Federico Mingozzi ◽  
Denise E. Sabatino ◽  
Stephanie McCorquodale ◽  
Aaron Dillow ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Immune Response ◽  
T Cell ◽  
T Cell Responses ◽  
Route Of Administration ◽  
Factor Ix ◽  
Hemophilia B ◽  
Cell Responses ◽  
Chapel Hill ◽  
Ifn Γ

Abstract Progress towards an effective gene therapy for hemophilia B (HB) has been facilitated by large animal studies. Previous work has shown intravascular delivery of an adeno-associated viral (AAV) serotype 2 vector expressing canine factor IX (cF.IX) to skeletal muscle in HB dogs resulted in long-term expression of cF.IX at levels of 4–20% of normal, which nearly corrected the disease phenotype. However, occurrence of inhibitors to F.IX in some animals raises concerns of a potential immune response to the transgene product, prompting a more thorough examination of T cell responses in this setting. Early work revealed that transient immunosuppression (IS) with cyclophosphamide was required to avoid inadvertent antibody formation to F.IX. Here we report in detail the nature and the duration of T cell responses against the transgene product. Six HB dogs from the Chapel Hill colony received AAV2 vector at three different doses (1x1012 vg/kg, n=3; 3 x 1012 vg/kg, n=2; 8 x 1012 vg/kg, n=1) in addition to weekly infusion with cyclophosphamide (6 doses total). PBMCs were isolated from whole blood prior to vector infusion, during IS and after removal from IS, and used to measure the T cell response to F.IX by ELISpot assay for IL-10 and IFN-γ secretion using a cF.IX peptide library composed of 15-mers overlapping by 10 amino acids, spanning the entire protein sequence. Peptides were arranged into a matrix of pools, such that each peptide was contained in two orthogonal pools. Interestingly, in the IL-10 assay, one common T cell epitope corresponding to peptide 68 in the cF.IX library was found in all intravascularly-administered dogs from each of the three dose groups. The same epitope was also detectable in naïve HB dogs. Another epitope, corresponding to peptide 84, was found in a dog injected with the highest dose of vector after it developed a non-neutralizing antibody response against the cF.IX transgene product. Peptide 84 spans the region of the protein that contains the missense mutation responsible for HB (Chapel Hill mutation, Glu379 → Gly), which is a key difference in the newly introduced transgene product. Furthermore, the lack of any IFN-γ secretion coupled with the marked IL-10 response gives a cytokine profile that is characteristic of a Th2 response. This is in contrast with the Th1 response seen in previous studies with direct intramuscular injection of an AAV serotype 1 expressing cF.IX in dogs from the same colony. IS successfully reduced T cell responses to undetectable levels, while IL-10 secretion was detectable in PBMCs before vector delivery and one month after IS was discontinued. Overall circulating cF.IX levels did not seem to be affected by late restoration of T cells responses. No T cell responses against AAV capsid were detectable by ELISpot on PBMCs in any of the dogs studied. Interestingly, the relatively mild IS regimen also appeared to reduce the formation of neutralizing antibodies against AAV capsid, regardless of the route of administration. In summary, the nature of T cell responses (Th2 vs. Th1) suggests that route of administration, and/or AAV serotype, may play a role in the determination of the immune response elicited. We conclude that IS may provide a means to decrease T cell responses to the transgene following intravascular delivery of AAV-F.IX to skeletal muscle.

scholarly journals T-Cell Immune Response Assessment as a Complement to Serology and Intranasal Protection Assays in Determining the Protective Immunity Induced by Acellular Pertussis Vaccines in Mice

2003 ◽  
Vol 10 (4) ◽  
pp. 637-642 ◽  
Author(s):  
C. M. Ausiello ◽  
R. Lande ◽  
P. Stefanelli ◽  
C. Fazio ◽  
G. Fedele ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Pertussis Toxin ◽  
Protective Immunity ◽  
T Cell Responses ◽  
Additional Tool ◽  
Cell Responses ◽  
T Cell Immune Responses ◽  
Ifn Γ

ABSTRACT The relative value of antibodies and/or T-cell immune responses to Bordetella pertussis antigens in the immunity induced by acellular pertussis (aP) vaccines is still an open issue, probably due to the incomplete knowledge on the mechanisms of protective immunity to pertussis. The relevance of T-cell immune responses in protection from pertussis has been demonstrated in murine and human models of infection; thus, in this study, the ability of different vaccine preparations of three component (pertussis toxin, filamentous hemagglutinin, and pertactin) aP vaccines to induce T-cell responses was investigated in mice. All vaccine preparations examined passed the immunogenicity control test, based on antibody titer assessment, according to European Pharmacopoeia standards, and protected mice from B. pertussis intranasal challenge, but not all preparations were able to prime T cells to pertussis toxin, the specific B. pertussis antigen. In particular, one vaccine preparation was unable to induce proliferation and gamma interferon (IFN-γ) production while the other two gave borderline results. The evaluation of T-cell responses to pertussis toxin antigen may provide information on the protective immunity induced by aP vaccines in animal models. Considering the critical role of the axis interleukin-12-IFN-γ for protection from pertussis, our results suggest that testing the induction of a key protective cytokine such as IFN-γ could be an additional tool for the evaluation of the immune response induced by aP vaccines.

scholarly journals Role of IL-12-Independent and IL-12-Dependent Pathways in Regulating Generation of the IFN-γ Component of T Cell Responses toSalmonella typhimurium

2002 ◽  
Vol 169 (5) ◽  
pp. 2545-2552 ◽  
Author(s):  
Beena John ◽  
Deepa Rajagopal ◽  
Achal Pashine ◽  
Satyajit Rath ◽  
Anna George ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Cell Responses ◽  
Ifn Γ

scholarly journals Kinetics of CD4+ and CD8+ Memory T-Cell Responses during Hepatitis C Virus Rechallenge of Previously Recovered Chimpanzees

2003 ◽  
Vol 77 (8) ◽  
pp. 4781-4793 ◽  
Author(s):  
Michelina Nascimbeni ◽  
Eishiro Mizukoshi ◽  
Markus Bosmann ◽  
Marian E. Major ◽  
Kathleen Mihalik ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hepatitis C ◽  
T Cell ◽  
T Cell Responses ◽  
Rt Pcr ◽  
Cell Responses ◽  
Ifn Γ ◽  
Cellular Immune ◽  
Kinetics Of

ABSTRACT The immunological correlates of hepatitis C virus (HCV)-specific immunity are not well understood. Antibodies to HCV structural proteins do not appear to play a key role in clearance of the virus and do not persist after recovery. Here, we studied the kinetics of the cellular immune responses of three HCV-recovered chimpanzees during rechallenge with increasing doses of homologous HCV. Although HCV envelope antibodies remained undetectable throughout the rechallenge, all animals mounted rapid HCV-specific T-cell responses. The pattern of the cellular immune response in blood and liver correlated with the virological outcome. The animal that most rapidly cleared circulating HCV as determined by nested reverse transcription-PCR (RT-PCR) displayed the most vigorous and sustained response of gamma interferon (IFN-γ)-producing and proliferating CD4+ T cells in the blood. Vigorous CD4+ T-cell proliferation during viremia was followed by an increased frequency and a phenotypic and functional change of the tetramer+ CD8+ T-cell population. The second animal cleared HCV initially with strong peripheral and intrahepatic CD4+ T-cell responses but experienced low-level HCV recrudescence 12 weeks later, when HCV-specific T cells became undetectable. The third animal maintained minute amounts of circulating HCV, detectable only by nested RT-PCR, in the face of a weak IFN-γ+ T-cell response. Collectively, the results suggest protective rather than sterilizing immunity after recovery from hepatitis C. The rate of HCV clearance following reexposure depends on the cellular immune response, the quality and quantity of which may vary among chimpanzees that recovered from HCV infection.

scholarly journals The Th1 Immune Response to Plasmodium falciparum Circumsporozoite Protein Is Boosted by Adenovirus Vectors 35 and 26 with a Homologous Insert

2010 ◽  
Vol 17 (11) ◽  
pp. 1687-1694 ◽  
Author(s):  
Katarina Radošević ◽  
Ariane Rodriguez ◽  
Angelique A. C. Lemckert ◽  
Marjolein van der Meer ◽  
Gert Gillissen ◽  
...  
Keyword(s):  
Immune Response ◽  
Plasmodium Falciparum ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Virus Surface ◽  
Cell Responses ◽  
Ifn Γ ◽  
Th1 Immune Response

ABSTRACT The most advanced malaria vaccine, RTS,S, is comprised of an adjuvant portion of the Plasmodium falciparum circumsporozoite (CS) protein fused to and admixed with the hepatitis B virus surface antigen. This vaccine confers short-term protection against malaria infection, with an efficacy of about 50%, and induces particularly B-cell and CD4+ T-cell responses. In the present study, we tested by the hypothesis that the Th1 immune response to CS protein, in particular the CD8+ T-cell response, which is needed for strong and lasting malaria immunity, is boosted to sustainable levels vectors adenovirus and 26 with an homologous insert 35 (Ad35.CS/Ad26.CS). In this study, we evaluated immune responses induced with vaccination regimens based on an adjuvant-containing, yeast-produced complete CS protein followed by two recombinant low-seroprevalence adenoviruses expressing P. falciparum CS antigen, Ad35.CS (subgroup B) and Ad26.CS (subgroup D). Our results show that (i) the yeast (Hansenula polymorpha)produced, adjuvanted full-length CS protein is highly potent in inducing high CS-specific humoral responses in mice but produces poor T-cell responses, (ii) the Ad35.CS vector boosts the gamma interferon-positive (IFN-γ+) CD8+ T-cell response induced by the CS protein immunization and shifts the immune response toward the Th1 type, and (iii) a three-component heterologous vaccination comprised of a CS protein prime followed by boosts with Ad35.CS and Ad26.CS elicits an even more robust and sustainable IFN-γ+ CD8+ T-cell response than one- or two-component regimens. The Ad35.CS/Ad26.CS combination boosted particularly the IFN-γ+ and tumor necrosis factor alpha-positive (TNF-α+) T cells, confirming the shift of the immune response from the Th2 type to the Th1 type. These results support the notion of first immunizations of infants with an adjuvanted CS protein vaccine, followed by a booster Ad35.CS/Ad26.CS vaccine at a later age, to induce lasting protection against malaria for which the Th1 response and immune memory is required.

scholarly journals Coinfection with Heligmosomoides polygyrus Fails To Establish CD8+ T-Cell Immunity against Toxoplasma gondii

2008 ◽  
Vol 76 (3) ◽  
pp. 1305-1313 ◽  
Author(s):  
Imtiaz A. Khan ◽  
Rubeena Hakak ◽  
Karen Eberle ◽  
Peter Sayles ◽  
Louis M. Weiss ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
T Cell Immunity ◽  
Cell Immune Response ◽  
Heligmosomoides Polygyrus ◽  
Cell Responses ◽  
Cell Immunity ◽  
Ifn Γ

ABSTRACT CD8+ T-cell immunity is important for long-term protection against Toxoplasma gondii infection. However, a Th1 cytokine environment, especially the presence of gamma interferon (IFN-γ), is essential for the development of primary CD8+ T-cell immunity against this obligate intracellular pathogen. Earlier studies from our laboratory have demonstrated that mice lacking optimal IFN-γ levels fail to develop robust CD8+ T-cell immunity against T. gondii. In the present study, induction of primary CD8+ T-cell immune response against T. gondii infection was evaluated in mice infected earlier with Heligmosomoides polygyrus, a gastrointestinal worm known to evoke a polarized Th2 response in the host. In the early stage of T. gondii infection, both CD4 and CD8+ T-cell responses against the parasite were suppressed in the dually infected mice. At the later stages, however, T. gondii-specific CD4+ T-cell immunity recovered, while CD8+ T-cell responses remained low. Unlike in mice infected with T. gondii alone, depletion of CD4+ T cells in the dually infected mice led to reactivation of chronic infection, leading to Toxoplasma-related encephalitis. Our observations strongly suggest that prior infection with a Th2 cytokine-polarizing pathogen can inhibit the development of CD8+ T-cell immune response against T. gondii, thus compromising long-term protection against a protozoan parasite. This is the first study to examine the generation of CD8+ T-cell immune response in a parasitic nematode and protozoan coinfection model that has important implications for infections where a CD8+ T-cell response is critical for host protection and reduced infection pathology.

scholarly journals Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma

2020 ◽  
Author(s):  
Katharina Leuchte ◽  
Elena Staib ◽  
Martin Thelen ◽  
Philipp Gödel ◽  
Axel Lechner ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Thermal Ablation ◽  
Microwave Ablation ◽  
T Cell Responses ◽  
Tumor Control ◽  
Free Survival ◽  
Cell Responses

Abstract Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (n = 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (> 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (n = 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease.

scholarly journals Impaired T cell functions along with elevated activated Tregs at the early stage of asymptomatic SARS-CoV-2 infection

2020 ◽  
Author(s):  
Jingyi Yang ◽  
Ejuan Zhang ◽  
Maohua Zhong ◽  
Qingyu Yang ◽  
Ke Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Early Stage ◽  
Function Analysis ◽  
T Cell Responses ◽  
Cell Functions ◽  
Cell Responses ◽  
Ifn Γ

SummaryBackgroundLimited data are available on the T cell responses for the asymptomatic SARS-CoV-2 infection case.MethodsAn imported SARS-CoV-2 infection case in Wuhan was admitted in hospital for quarantine and observation. The T cell responses were followed up by flow cytometry analysis of the peripheral blood nonnuclear cells (PBMCs) at days 7, 13, 22, and 28 after admission.FindingsWe found the imported SARS-CoV-2 infection in Wuhan is an asymptomatic case. His T cell differentiation, proliferation and activation matched the classical kinetics of T cell responses induced by viral infection, but the activation maintained at a relatively low level. Function analysis indicated frequencies of IFN-γ producing CD4+ and CD8+ T cells were notably lower than that of the healthy controls (HC) at day 7, and then rebound gradually. But IFN-γ+CD8+ T cells were detained at a significant lower level even at day 28, when the SARS-CoV-2 virus had already become undetectable for 3 weeks. Moreover, percentage of IL-17 producing CD4+ T cells was also detained constantly at a much lower level compared to HC. At day 7, although percentage of Tregs was in normal range, the frequency of activated Treg (aTreg) was remarkably as high as 4·4-fold of that in HC.InterpretationThe T cell activation in the asymptomatic SARS-CoV-2 infection experienced a significant suppression and presented impairment of Th1/Th17 and CD8+ T cell functions. Early elevation of the aTregs might play role in the activation and function of T cells in the asymptomatic SARS-CoV-2 infection.

scholarly journals Batf3-Dependent Dendritic Cells Promote Optimal CD8 T Cell Responses against Respiratory Poxvirus Infection

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Pritesh Desai ◽  
Vikas Tahiliani ◽  
Georges Abboud ◽  
Jessica Stanfield ◽  
Shahram Salek-Ardakani
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Respiratory Infection ◽  
Host Resistance ◽  
T Cell Responses ◽  
Cell Responses ◽  
Ifn Γ ◽  
The Impact

ABSTRACTRespiratory infection with vaccinia virus (VacV) elicits robust CD8+T cell responses that play an important role in host resistance. In the lung, VacV encounters multiple tissue-resident antigen-presenting cell (APC) populations, but which cell plays a dominant role in priming of virus-specific CD8+effector T cell responses remains poorly defined. We used Batf3−/−mice to investigate the impact of CD103+and CD8α+dendritic cell (DC) deficiency on anti-VacV CD8+T cell responses. We found that Batf3−/−mice were more susceptible to VacV infection, exhibiting profound weight loss, which correlated with impaired accumulation of gamma interferon (IFN-γ)-producing CD8+T cells in the lungs. This was largely due to defective priming since early in the response, antigen-specific CD8+T cells in the draining lymph nodes of Batf3−/−mice expressed significantly reduced levels of Ki67, CD25, and T-bet. These results underscore a specific role for Batf3-dependent DCs in regulating priming and expansion of effector CD8+T cells necessary for host resistance against acute respiratory VacV infection.IMPORTANCEDuring respiratory infection with vaccinia virus (VacV), a member ofPoxviridaefamily, CD8+T cells play important role in resolving the primary infection. Effector CD8+T cells clear the virus by accumulating in the infected lungs in large numbers and secreting molecules such as IFN-γ that kill virally infected cells. However, precise cell types that regulate the generation of effector CD8+T cells in the lungs are not well defined. Dendritic cells (DCs) are a heterogeneous population of immune cells that are recognized as key initiators and regulators of T-cell-mediated immunity. In this study, we reveal that a specific subset of DCs that are dependent on the transcription factor Batf3 for their development regulate the magnitude of CD8+T cell effector responses in the lungs, thereby providing protection during pulmonary VacV infection.

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