scholarly journals Immunogenicity of Eight Dormancy Regulon-Encoded Proteins of Mycobacterium tuberculosis in DNA-Vaccinated and Tuberculosis-Infected Mice

2006 ◽  
Vol 75 (2) ◽  
pp. 941-949 ◽  
Author(s):  
Virginie Roupie ◽  
Marta Romano ◽  
Lei Zhang ◽  
Hannelie Korf ◽  
May Young Lin ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Interleukin 2 ◽  
Cell Epitope ◽  
Dna Encoding ◽  
Histocompatibility Complex ◽  
Low Concentrations ◽  
Dosr Regulon

ABSTRACT Hypoxia and low concentrations of nitric oxide have been reported to upregulate in vitro gene expression of 48 proteins of the dormancy (DosR) regulon of Mycobacterium tuberculosis. These proteins are thought to be essential for the survival of bacteria during persistence in vivo and are targeted by the immune system during latent infection in humans. Here we have analyzed the immunogenicity of eight DosR regulon-encoded antigens by plasmid DNA vaccination of BALB/c and C57BL/6 mice, i.e., Rv1733c, Rv1738, Rv2029c (pfkB), Rv2031c/hspX (acr), Rv2032 (acg), Rv2626c, Rv2627c, and Rv2628. Strong humoral and/or cellular Th1-type (interleukin-2 and gamma interferon) immune responses could be induced against all but one (Rv1738) of these antigens. The strongest Th1 responses were measured following vaccination with DNA encoding Rv2031c and Rv2626c. Using synthetic 20-mer overlapping peptides, 11 immunodominant, predicted major histocompatibility complex class II-restricted epitopes and one Kd-restricted T-cell epitope could be identified. BALB/c and (B6D2)F1 mice persistently infected with M. tuberculosis developed immune responses against Rv1733c, Rv2031c, and Rv2626c. These findings have implications for proof-of-concept studies in mice mimicking tuberculosis (TB) latency models and their extrapolation to humans for potential new vaccination strategies against TB.

scholarly journals Lack of Immune Responses to Mycobacterium tuberculosis DosR Regulon Proteins following Mycobacterium bovis BCG Vaccination

2007 ◽  
Vol 75 (7) ◽  
pp. 3523-3530 ◽  
Author(s):  
May Young Lin ◽  
Annemieke Geluk ◽  
Steven G. Smith ◽  
Amanda L. Stewart ◽  
Annemieke H. Friggen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Mycobacterium Bovis ◽  
Protective Efficacy ◽  
Transcriptional Profiling ◽  
In Silico Analysis ◽  
Dna Encoding ◽  
Bcg Vaccination ◽  
Dosr Regulon

ABSTRACT Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis (TB), despite its variable protective efficacy. Relatively little is known about the immune response profiles following BCG vaccination in relation to protection against TB. Here we tested whether BCG vaccination results in immune responses to DosR (Rv3133c) regulon-encoded proteins. These so-called TB latency antigens are targeted by the immune system during persistent Mycobacterium tuberculosis infection and have been associated with immunity against latent M. tuberculosis infection. In silico analysis of the DosR regulon in BCG and M. tuberculosis showed at least 97% amino acid sequence homology, with 41 out of 48 genes being identical. Transcriptional profiling of 14 different BCG strains, under hypoxia and nitric oxide exposure in vitro, revealed a functional DosR regulon similar to that observed in M. tuberculosis. Next, we assessed human immune responses to a series of immunodominant TB latency antigens and found that BCG vaccination fails to induce significant responses to latency antigens. Similar results were obtained with BCG-vaccinated BALB/c mice. In contrast, responses to latency antigens were observed in individuals with suspected exposure to TB (as indicated by positive gamma interferon responses to TB-specific antigens ESAT-6 and CFP-10) and in mice vaccinated with plasmid DNA encoding selected latency antigens. Since immune responses to TB latency antigens have been associated with control of latent M. tuberculosis infection, our findings support the development of vaccination strategies incorporating DosR regulon antigens to complement and improve the current BCG vaccine.

scholarly journals Mitogenicity of the Recombinant Mycobacterial 27-Kilodalton Lipoprotein Is Not Connected to Its Antiprotective Effect

2004 ◽  
Vol 72 (6) ◽  
pp. 3383-3390 ◽  
Author(s):  
Avi-Hai Hovav ◽  
Liuba Davidovitch ◽  
Gabriel Nussbaum ◽  
Jacob Mullerad ◽  
Yolanta Fishman ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
B Cell ◽  
Interleukin 2 ◽  
Independent Manner ◽  
Lipid Moiety ◽  
High Gamma ◽  
Type Response

ABSTRACT We reported previously that even though immunization with the recombinant mycobacterial 27-kDa lipoprotein (r27) induced a Th1-type response in mice, the vaccinated mice became more susceptible to challenge with Mycobacterium tuberculosis. In this study we show that r27 stimulates naive splenocytes to proliferate. Acylation of r27 was crucial for this effect, since a nonacylated mutant of r27, termed r27ΔSP, failed to stimulate splenocytes either in vitro or in vivo. Depletion experiments indicated that only B cells were proliferating in a T-cell-independent manner. We also found that r27 is recognized by TLR2, which is involved in mitogenic stimulation. Interestingly, r27 but not r27ΔSP induced high gamma interferon levels in splenocyte supernatants, whereas no significant interleukin-2 levels were detected. Since B-cell polyclonal activation might aggravate pathogen infection, we asked whether the antiprotective effect of the r27 lipoprotein is associated with its mitogenicity. We showed that, as in the case of r27, immunization of mice with the nonmitogenic r27ΔSP lipoprotein resulted in increased M. tuberculosis multiplication. We conclude that the antiprotective effect of the r27 lipoprotein must be linked to properties of the polypeptide portion of the lipoprotein rather than to its lipid moiety and its mitogenicity.

Suppression of immune responses to acetylcholine receptor by interleukin 2-fusion toxin: in vivo and in vitro studies

1991 ◽  
Vol 31 (2) ◽  
pp. 115-122 ◽  
Author(s):  
Laura J. Balcer ◽  
Kevin R. McIntosh ◽  
Jean C. Nichols ◽  
Daniel B. Drachman
Keyword(s):  
Immune Responses ◽  
Acetylcholine Receptor ◽  
Interleukin 2 ◽  
In Vitro Studies ◽  
Fusion Toxin

scholarly journals Deglycosylation of the 45/47-Kilodalton Antigen Complex of Mycobacterium tuberculosis Decreases Its Capacity To Elicit In Vivo or In Vitro Cellular Immune Responses

1999 ◽  
Vol 67 (11) ◽  
pp. 5567-5572 ◽  
Author(s):  
Félix Romain ◽  
Cynthia Horn ◽  
Pascale Pescher ◽  
Abdelkader Namane ◽  
Michel Riviere ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Lymphocytes ◽  
Immune Responses ◽  
Delayed Type Hypersensitivity ◽  
Cellular Immune Responses ◽  
Antigen Complex ◽  
Cellular Immune ◽  
Living Bacteria

ABSTRACT A protection against a challenge with Mycobacterium tuberculosis is induced by previous immunization with living attenuated mycobacteria, usually bacillus Calmette-Guérin (BCG). The 45/47-kDa antigen complex (Apa) present in culture filtrates of BCG of M. tuberculosis has been identified and isolated based on its ability to interact mainly with T lymphocytes and/or antibodies induced by immunization with living bacteria. The protein is glycosylated. A large batch of Apa was purified from M. tuberculosis culture filtrate to determine the extent of glycosylation and its role on the expression of the immune responses. Mass spectrometry revealed a spectrum of glycosylated molecules, with the majority of species bearing six, seven, or eight mannose residues (22, 24, and 17%, respectively), while others three, four, or five mannoses (5, 9, and 14%, respectively). Molecules with one, two, or nine mannoses were rare (1.5, 3, and 3%, respectively), as were unglycosylated species (in the range of 1%). To eliminate the mannose residues linked to the protein, the glycosylated Apa molecules were chemically or enzymatically treated. The deglycosylated antigen was 10-fold less active than native molecules in eliciting delayed-type hypersensitivity reactions in guinea pigs immunized with BCG. It was 30-fold less active than native molecules when assayed in vitro for its capacity to stimulate T lymphocytes primed in vivo. The presence of the mannose residues on the Apa protein was essential for the antigenicity of the molecules in T-cell-dependent immune responses in vitro and in vivo.

Immunological and pathological responses in BALB/c mice induced by genetic administration ofTc13 Tul antigen ofTrypanosoma cruzi

Parasitology ◽  
2006 ◽  
Vol 132 (6) ◽  
pp. 855-866 ◽  
Author(s):  
G. A. GARCÍA ◽  
M. R. ARNAIZ ◽  
S. A. LAUCELLA ◽  
M. I. ESTEVA ◽  
N. AINCIART ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dna Encoding ◽  
Genetic Immunization ◽  
Humoral Immune ◽  
Specific Memory ◽  
Family Protein ◽  
Ifn Γ

Tc13 is atrans-sialidase family protein ofTrypanosoma cruzi, the aetiological agent of Chagas' disease. Recently,in vitrostudies had suggested thatTc13 might participate in the pathogenesis of the disease. In order to study the role ofTc13 antigens in anin vivomodel, we administered plasmid DNA encoding aTc13 antigen from the Tulahuén strain (Tc13 Tul) to BALB/c mice and evaluated the immunological and pathological manifestations as well as the capacity of this antigen to confer protection againstT. cruziinfection.Tc13 Tul immunization did not elicit a detectable humoral immune response but induced specific memory T-cells with no capacity to produce IFN-γ. Five months after DNA-immunization withTc13 Tul, signs of hepatotoxicity and reactive changes in the heart, liver and spleen were observed in 40–80% of mice. WhenTc13 Tul DNA-immunized animals were challenged with trypomastigotes, a significant decrease in parasitaemia in early and late acute phase was observed without modification in the survival rate. Surprisingly,Tc13 Tul-immunized mice chronically infected withT. cruzishowed a decrease in the severity of heart damage. We conclude that, in BALB/c mice, genetic immunization withTc13 Tul mainly induces immune responses associated with pathology.

Serum levels of interleukin-2 in cancer patients: Preliminary considerations

1989 ◽  
Vol 4 (4) ◽  
pp. 203-206 ◽  
Author(s):  
P. Lissoni ◽  
S. Viviani ◽  
A. Santoro ◽  
S. Barni ◽  
G. Tancini
Keyword(s):  
Cancer Patients ◽  
Solid Tumors ◽  
Healthy Subjects ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Low Concentrations ◽  
Preliminary Study ◽  
Low Levels

In order to investigate the production of interleukin-2 (IL-2) in human neoplasms, we determined IL-2 and soluble IL-2 receptors (sIL-2R) in serum from 18 patients with lymphoma and 28 patients with solid tumors, with (15 cases) or without (13 cases) metastases. As controls, 58 healthy subjects were evaluated. Low levels of IL-2 were not observed in patients with lymphoma or limited solid tumor but abnormally low concentrations of IL-2 were seen in 4/15 metastatic solid tumors, associated with abnormally high values of sIL-2R. This preliminary study confirms in vivo the reduced IL-2 production in metastatic solid neoplasms, previously documented in vitro

scholarly journals Identification of an HLA-A*0201–restricted CD8+ T-cell epitope SSp-1 of SARS-CoV spike protein

Blood ◽  
2004 ◽  
Vol 104 (1) ◽  
pp. 200-206 ◽  
Author(s):  
Baomei Wang ◽  
Huabiao Chen ◽  
Xiaodong Jiang ◽  
Minghui Zhang ◽  
Tao Wan ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Immune Responses ◽  
Cell Epitope ◽  
Specific Cell ◽  
Control Mechanisms ◽  
S Protein ◽  
Specific Ctls ◽  
Hla A2.1

Abstract A novel coronavirus, severe acute respiratory syndrome (SARS)–associated coronavirus (SARS-CoV), has been identified as the causal agent of SARS. Spike (S) protein is a major structural glycoprotein of the SARS virus and a potential target for SARS-specific cell-mediated immune responses. A panel of S protein–derived peptides was tested for their binding affinity to HLA-A*0201 molecules. Peptides with high affinity for HLA-A*0201 were then assessed for their capacity to elicit specific immune responses mediated by cytotoxic T lymphocytes (CTLs) both in vivo, in HLA-A2.1/Kb transgenic mice, and in vitro, from peripheral blood lymphocytes (PBLs) sourced from healthy HLA-A2.1+ donors. SARS-CoV protein-derived peptide-1 (SSp-1 RLNEVAKNL), induced peptide-specific CTLs both in vivo (transgenic mice) and in vitro (human PBLs), which specifically released interferon-γ (IFN-γ) upon stimulation with SSp-1–pulsed autologous dendritic cells (DCs) or T2 cells. SSp-1–specific CTLs also lysed major histocompatibility complex (MHC)–matched tumor cell lines engineered to express S proteins. HLA-A*0201–SSp-1 tetramer staining revealed the presence of significant populations of SSp-1–specific CTLs in SSp-1–induced CD8+ T cells. We propose that the newly identified epitope SSp-1 will help in the characterization of virus control mechanisms and immunopathology in SARS-CoV infection, and may be relevant to the development of immunotherapeutic approaches for SARS.

scholarly journals Regulatory mechanisms in cell-mediated immune responses. V. H-2 homology requirements for the production of a minor locus-induced suppressor factor.

1977 ◽  
Vol 146 (4) ◽  
pp. 1152-1157 ◽  
Author(s):  
D L Kastner ◽  
R R Rich ◽  
L Chu ◽  
S S Rich
Keyword(s):  
Major Histocompatibility Complex ◽  
Immune Responses ◽  
Regulatory Mechanisms ◽  
Mixed Leukocyte Reaction ◽  
Spleen Cells ◽  
Suppressor Factor ◽  
Histocompatibility Complex ◽  
A Minor

A mixed leukocyte reaction suppressor factor is produced by spleen cells sensitized in vivo and restimulated in vitro across non-H-2 antigenic barriers. Cells capable of producing this factor appear in the spleens of minor locus-immunized animals later than in animals sensitized to major histocompatibility complex-encoded antigens. However, both H-2 and non H-2-induced factors suppress proliferative responses to any alloantigen. Splenocytes from animals immunized with H-2-identical, minor locus-disparate cells produce suppressor factor in vitro only when restimulated with cells sharing both H-2 and non-H-2 antigens with the in vivo stimulators.

scholarly journals Experimental DNA-Launched Live-Attenuated Vaccines Against Yellow Fever

2019 ◽  
Vol 18 (1) ◽  
pp. 18-25 ◽  
Author(s):  
P. Pushko ◽  
А. А. Ishmukhametov ◽  
P. P. Bredenbeek ◽  
I. S. Lukashevich
Keyword(s):  
Immune Responses ◽  
Dna Vaccine ◽  
Yellow Fever ◽  
Vaccine Virus ◽  
Genomic Rna ◽  
Dna Encoding ◽  
Live Attenuated Vaccine ◽  
Pathogenic Virus

Background DNA-launched vaccine is “manufactured” in vaccinated individuals and does not require traditional vaccine manufacturing facility and technology. Goals. Using yellow fever 17D vaccine, we have provided proof-of-concept evidence that these vaccine can be launched from DNA and induce specific immune responses against pathogenic virus causing yellow fever. The infectious DNA vaccine technology is based on the transcription of the full-length genomic RNA of the live-attenuated virus from plasmid DNA in vitro and in vivo. A few ng of infectious DNA encoding the fulllength genomic RNA are required to initiate the replication of the vaccine virus in vitro. The in vivo-generated viral RNA initiates limited replication of the vaccine virus, which in turn leads to efficient immunization. Electroporation in vivo has induced specific immune responses against pathogenic virus and protected mice against fatal disease. Here we describe a novel infectious DNA vaccine technology which combines advantages of naked DNA vaccination and live-attenuated vaccine efficacy. Conclusions If successful in further testing, this technology can dramatically change the way we make vaccines as well as vaccination practice. 

scholarly journals Protective CD4+ and CD8+ T Cells against Influenza Virus Induced by Vaccination with Nucleoprotein DNA

1998 ◽  
Vol 72 (7) ◽  
pp. 5648-5653 ◽  
Author(s):  
Jeffrey B. Ulmer ◽  
Tong-Ming Fu ◽  
R. Randall Deck ◽  
Arthur Friedman ◽  
Liming Guan ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Effective Means ◽  
Interleukin 2 ◽  
T Cell Subsets ◽  
Dna Encoding ◽  
Virus Challenge

ABSTRACT DNA vaccination is an effective means of eliciting both humoral and cellular immunity, including cytotoxic T lymphocytes (CTL). Using an influenza virus model, we previously demonstrated that injection of DNA encoding influenza virus nucleoprotein (NP) induced major histocompatibility complex class I-restricted CTL and cross-strain protection from lethal virus challenge in mice (J. B. Ulmer et al., Science 259:1745–1749, 1993). In the present study, we have characterized in more detail the cellular immune responses induced by NP DNA, which included robust lymphoproliferation and Th1-type cytokine secretion (high levels of gamma interferon and interleukin-2 [IL-2], with little IL-4 or IL-10) in response to antigen-specific restimulation of splenocytes in vitro. These responses were mediated by CD4+ T cells, as shown by in vitro depletion of T-cell subsets. Taken together, these results indicate that immunization with NP DNA primes both cytolytic CD8+ T cells and cytokine-secreting CD4+ T cells. Further, we demonstrate by adoptive transfer and in vivo depletion of T-cell subsets that both of these types of T cells act as effectors in protective immunity against influenza virus challenge conferred by NP DNA.

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