scholarly journals LB19. Intramuscular therapeutic immunization targeting RelMtb/MIP-3 induces immune signatures associated with better TB control in vivo compared to

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S815-S815
Author(s):  
Styliani Karanika ◽  
James Gordy ◽  
Pranita Neupane ◽  
Richard Markham ◽  
Petros Karakousis
Keyword(s):  
T Cell ◽  
Dna Vaccine ◽  
Mononuclear Cells ◽  
Stringent Response ◽  
T Cell Responses ◽  
Eukaryotic Expression ◽  
Cell Responses ◽  
Immune Signatures ◽  
Mouse Tissues

Abstract Background Tuberculosis (TB) is one of the leading causes of death from a single infectious agent worldwide. The lengthy treatment regimen reflects the unique ability of a subpopulation of “persister” bacteria to remain in a nonreplicating state in the infected host through various adaptive strategies, including induction of the stringent response. The key stringent response enzyme, RelMtb, is essential for long-term Mycobacterium tuberculosis (Mtb) survival under physiologically relevant stresses in vitro and in animal lungs. Recently, our group has generated a therapeutic, parenteral, relMtb DNA vaccine, which induces RelMtb-specific cellular immunity and augments the activity of the first-line drug isoniazid against active TB in mice and guinea pigs. Our group also has applied a novel vaccination strategy involving the fusion of an antigen of interest with the immature dendritic cell (iDC)-targeting chemokine MIP-3α/CCL20, which significantly enhances antigen-specific T-cell responses. We sought to determine if this iDC-targeting strategy improves the immunogenicity of the therapeutic relMtb DNA vaccine. Methods We cloned the relMtb and chemokine MIP-3α genes into the eukaryotic expression plasmid pSectag2b. We conducted an immunogenicity study using C57BL/6J mice, comparing the T-cell responses between the relMtbvs. MIP-3α/relMtb DNA intramuscular vaccination groups. Results Intramuscular administration of the DNA vaccine expressing the MIP-3α/relMtb gene fusion induced increased production of various Mtb-protective cytokines (IL-17α, IL-2, TNF-α, IFN-γ) in various mouse tissues, including the spleen, draining lymph nodes and peripheral blood mononuclear cells, relative to the vaccine expressing relMtb alone. Conclusion Intramuscular immunization with a DNA vaccine expressing relMtb/MIP-3α induces robust in vivo Mtb-protective immune signatures, suggesting this may be a promising adjunctive approach in combination with standard anti-TB therapy. Disclosures All Authors: No reported disclosures

scholarly journals HIV-1 Env DNA Vaccine plus Protein Boost Delivered by EP Expands B- and T-Cell Responses and Neutralizing Phenotype In Vivo

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e84234 ◽  
Author(s):  
Kar Muthumani ◽  
Megan C. Wise ◽  
Kate E. Broderick ◽  
Natalie Hutnick ◽  
Jonathan Goodman ◽  
...  
Keyword(s):  
T Cell ◽  
Dna Vaccine ◽  
T Cell Responses ◽  
Cell Responses ◽  
Protein Boost ◽  
Hiv 1

scholarly journals HIV-1-Based Virus-like Particles that Morphologically Resemble Mature, Infectious HIV-1 Virions

Viruses ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 507 ◽  
Author(s):  
Christopher A. Gonelli ◽  
Georges Khoury ◽  
Rob J. Center ◽  
Damian F.J. Purcell
Keyword(s):  
T Cell ◽  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Expression Vectors ◽  
Virus Like Particles ◽  
Cell Responses ◽  
Hiv 1

A prophylactic vaccine eliciting both broad neutralizing antibodies (bNAbs) to the HIV-1 envelope glycoprotein (Env) and strong T cell responses would be optimal for preventing HIV-1 transmissions. Replication incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present authentic-structured, virion-associated Env to elicit bNAbs, and also stimulate T cell responses. Here, we optimize our DNA vaccine plasmids as VLP expression vectors for efficient Env incorporation and budding. The original vector that was used in human trials inefficiently produced VLPs, but maximized safety by inactivating RNA genome packaging, enzyme functions that are required for integration into the host genome, and deleting accessory proteins Vif, Vpr, and Nef. These original DNA vaccine vectors generated VLPs with incomplete protease-mediated cleavage of Gag and were irregularly sized. Mutations to restore function within the defective genes revealed that several of the reverse transcriptase (RT) deletions mediated this immature phenotype. Here, we made efficient budding, protease-processed, and mature-form VLPs that resembled infectious virions by introducing alternative mutations that completely removed the RT domain, but preserved most other safety mutations. These VLPs, either expressed from DNA vectors in vivo or purified after expression in vitro, are potentially useful immunogens that can be used to elicit antibody responses that target Env on fully infectious HIV-1 virions.

scholarly journals Cytotoxic T Cell Responses Induced by CS1/CRT Fusion DNA Vaccine in a Human Plasmacytoma Model

2020 ◽  
Vol 10 ◽  
Author(s):  
Xueshi Ye ◽  
Wanli Li ◽  
Jinwen Huang ◽  
Lifei Zhang ◽  
Ye Zhang
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Dna Vaccine ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Myeloma Cells ◽  
Cell Responses ◽  
Incurable Disease ◽  
Cytotoxic T Cell Responses

To date, multiple myeloma remains an incurable disease. Immunotherapy is an encouraging option in the development of multiple myeloma (MM) therapy. CS1 is a specific myeloma antigen, which is highly expressed in myeloma cells. Calreticulin (CRT) is a key determinant of cell death, which can influence antigen presentation and promote cellular phagocytic uptake. In the current study, we constructed a DNA vaccine encoding both CS1 and CRT. Our results show that the PcDNA3.1-CS1/CRT vaccine was able to induce cytotoxic T cell responses against myeloma cells in vivo, and the tumor growth was significantly suppressed in mice immunized with this vaccine. Therefore, our findings indicate that the CS1/CRT fusion DNA vaccine may represent a promising novel myeloma therapy, and the potential for combining the CS1/CRT vaccine with other myeloma treatments.

scholarly journals Enhanced Cellular Immunity in Macaques following a Novel Peptide Immunotherapy

2005 ◽  
Vol 79 (6) ◽  
pp. 3748-3757 ◽  
Author(s):  
S. Chea ◽  
C. J. Dale ◽  
R. De Rose ◽  
I. A. Ramshaw ◽  
S. J. Kent
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
De Novo ◽  
T Cell Responses ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Cell Immunity ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Advances in treating and preventing AIDS depend on understanding how human immunodeficiency virus (HIV) is eliminated in vivo and on the manipulation of effective immune responses to HIV. During the development of assays quantifying the elimination of fluorescent autologous cells coated with overlapping 15-mer simian immunodeficiency virus (SIV) or HIV-1 peptides, we made a remarkable observation: the reinfusion of macaque peripheral blood mononuclear cells, or even whole blood, pulsed with SIV and/or HIV peptides generated sharply enhanced SIV- and HIV-1-specific T-cell immunity. Strong, broad CD4+- and CD8+-T-cell responses could be enhanced simultaneously against peptide pools spanning 87% of all SIV- and HIV-1-expressed proteins—highly desirable characteristics of HIV-specific immunity. De novo hepatitis C virus-specific CD4+- and CD8+-T-cell responses were generated in macaques by the same method. This simple technique holds promise for the immunotherapy of HIV and other chronic viral infections.

scholarly journals Neutrophil subtypes shape HIV-specific CD8 T-cell responses after vaccinia virus infection

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Mauro Di Pilato ◽  
Miguel Palomino-Segura ◽  
Ernesto Mejías-Pérez ◽  
Carmen E. Gómez ◽  
Andrea Rubio-Ponce ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
Adaptive Immune System ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Adaptive Immune

AbstractNeutrophils are innate immune cells involved in the elimination of pathogens and can also induce adaptive immune responses. Nα and Nβ neutrophils have been described with distinct in vitro capacity to generate antigen-specific CD8 T-cell responses. However, how these cell types exert their role in vivo and how manipulation of Nβ/Nα ratio influences vaccine-mediated immune responses are not known. In this study, we find that these neutrophil subtypes show distinct migratory and motility patterns and different ability to interact with CD8 T cells in the spleen following vaccinia virus (VACV) infection. Moreover, after analysis of adhesion, inflammatory, and migration markers, we observe that Nβ neutrophils overexpress the α4β1 integrin compared to Nα. Finally, by inhibiting α4β1 integrin, we increase the Nβ/Nα ratio and enhance CD8 T-cell responses to HIV VACV-delivered antigens. These findings provide significant advancements in the comprehension of neutrophil-based control of adaptive immune system and their relevance in vaccine design.

scholarly journals Analysis of CD4+ T-Cell Responses to Human Papillomavirus (HPV) Type 11 L1 in Healthy Adults Reveals a High Degree of Responsiveness and Cross-Reactivity with Other HPV Types

2002 ◽  
Vol 76 (15) ◽  
pp. 7418-7429 ◽  
Author(s):  
O. Martin Williams ◽  
Keith W. Hart ◽  
Eddie C. Y. Wang ◽  
Colin M. Gelder
Keyword(s):  
Human Papillomavirus ◽  
T Cell ◽  
In Vitro Selection ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Cross Reactivity ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Hpv Types

ABSTRACT Human papillomavirus type 11 (HPV-11) infection causes genital warts and recurrent respiratory papillomatosis. While there is compelling evidence that CD4+ T cells play an important role in immune surveillance of HPV-associated diseases, little is known about human CD4+ T-cell recognition of HPV-11. We have investigated the CD4+ T-cell responses of 25 unrelated healthy donors to HPV-11 L1 virus-like particles (VLP). CD4+ T-cell lines from 21 of 25 donors were established. Cell sorting experiments carried out on cells from six donors demonstrated that the response was located in the CD45RAlow CD45ROhigh memory T-cell population. To determine the peptide specificity of these responses, epitope selection was analyzed by using 95 15-mer peptides spanning the entire HPV-11 L1 protein. No single region of L1 was immunodominant; responders recognized between 1 and 10 peptides, located throughout the protein, and peptide responses fell into clear HLA class II restricted patterns. Panels of L1 peptides specific for skin and genital HPV were used to show that the L1 CD4+ T-cell responses were cross-reactive. The degree of cross-reactivity was inversely related to the degree of L1 sequence diversity between these viruses. Finally, responses to HPV-11 L1 peptides were elicited from ex vivo CD45RO+ peripheral blood mononuclear cells, demonstrating that recognition of HPV-11 was a specific memory response and not due to in vitro selection during tissue culture. This is the first study of CD4+ T-cell responses to HPV-11 in healthy subjects and demonstrates marked cross-reactivity with other skin and genital HPV types. This cross-reactivity may be of significance for vaccine strategies against HPV-associated clinical diseases.

scholarly journals Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

2011 ◽  
Vol 19 (1) ◽  
pp. 84-95 ◽  
Author(s):  
Jin Huk Choi ◽  
Joe Dekker ◽  
Stephen C. Schafer ◽  
Jobby John ◽  
Craig E. Whitfill ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Transduction Efficiency ◽  
Virus Antibody ◽  
Cell Responses

ABSTRACTThe immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity.In vitroandin vivoassays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 × 1011adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND50) elicited strong virus- and transgene-specific T cell responses. The 0.05-ND50formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P= 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 ± 5.2% proliferation versus 7.7 ± 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND50) of antibody did not improve cellular and humoral responses in naïve animals, they did promote strong cellular (0.005 ND50) and humoral (0.0005 ND50) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naïve individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.

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