Regulation of Pulmonary Cytotoxic T Lymphocyte Immune Response to Influenza Infection

ABSTRACT The great variability of protein sequences from human immunodeficiency virus (HIV) type 1 (HIV-1) isolates represents a major obstacle to the development of an effective vaccine against this virus. The surface protein (Env), which is the predominant target of neutralizing antibodies, is particularly variable. Here we examine the impact of variability among different HIV-1 subtypes (clades) on cytotoxic T-lymphocyte (CTL) activities, the other major component of the antiviral immune response. CTLs are produced not only against Env but also against other structural proteins, as well as some regulatory proteins. The genetic subtypes of HIV-1 were determined for Env and Gag from several patients infected either in France or in Africa. The cross-reactivities of the CTLs were tested with target cells expressing selected proteins from HIV-1 isolates of clade A or B or from HIV type 2 isolates. All African patients were infected with viruses belonging to clade A for Env and for Gag, except for one patient who was infected with a clade A Env-clade G Gag recombinant virus. All patients infected in France were infected with clade B viruses. The CTL responses obtained from all the African and all the French individuals tested showed frequent cross-reactions with proteins of the heterologous clade. Epitopes conserved between the viruses of clades A and B appeared especially frequent in Gag p24, Gag p18, integrase, and the central region of Nef. Cross-reactivity also existed among Gag epitopes of clades A, B, and G, as shown by the results for the patient infected with the clade A Env-clade G Gag recombinant virus. These results show that CTLs raised against viral antigens from different clades are able to cross-react, emphasizing the possibility of obtaining cross-immunizations for this part of the immune response in vaccinated individuals.

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Dormant Tumor Cell Vaccination: A Mathematical Model of Immunological Dormancy in Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers13020245 ◽

2021 ◽

Vol 13 (2) ◽

pp. 245

Author(s):

Reza Mehdizadeh ◽

Seyed Peyman Shariatpanahi ◽

Bahram Goliaei ◽

Sanam Peyvandi ◽

Curzio Rüegg

Keyword(s):

Breast Cancer ◽

Mathematical Model ◽

Immune Response ◽

Growth Rate ◽

T Lymphocyte ◽

Triple Negative ◽

Cytotoxic T Lymphocyte ◽

Type I ◽

Type I Ifn ◽

Cancer Dormancy

Triple-negative breast cancer (TNBC) is a molecular subtype of breast malignancy with a poor clinical prognosis. There is growing evidence that some chemotherapeutic agents induce an adaptive anti-tumor immune response. This reaction has been proposed to maintain the equilibrium phase of the immunoediting process and to control tumor growth by immunological cancer dormancy. We recently reported a model of immunological breast cancer dormancy based on the murine 4T1 TNBC model. Treatment of 4T1 cells in vitro with high-dose chemotherapy activated the type I interferon (type I IFN) signaling pathway, causing a switch from immunosuppressive to cytotoxic T lymphocyte-dependent immune response in vivo, resulting in sustained dormancy. Here, we developed a deterministic mathematical model based on the assumption that two cell subpopulations exist within the treated tumor: one population with high type I IFN signaling and immunogenicity and lower growth rate; the other population with low type I IFN signaling and immunogenicity and higher growth rate. The model reproduced cancer dormancy, elimination, and immune-escape in agreement with our previously reported experimental data. It predicted that the injection of dormant tumor cells with active type I IFN signaling results in complete growth control of the aggressive parental cancer cells injected at a later time point, but also of an already established aggressive tumor. Taken together, our results indicate that a dormant cell population can suppress the growth of an aggressive counterpart by eliciting a cytotoxic T lymphocyte-dependent immune response.

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Analysis and control of a delayed HIV infection model with cell‐to‐cell transmission and cytotoxic T lymphocyte immune response

Mathematical Methods in the Applied Sciences ◽

10.1002/mma.7147 ◽

2021 ◽

Author(s):

Yu Liu ◽

Xiaolin Lin ◽

Jianquan Li

Keyword(s):

Immune Response ◽

Hiv Infection ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Infection Model ◽

Cell Transmission ◽

Hiv Infection Model ◽

And Control

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Induction of Immune Responses and Clinical Efficacy in a Phase II Trial of IDM-2101, a 10-Epitope Cytotoxic T-Lymphocyte Vaccine, in Metastatic Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2008.16.6462 ◽

2008 ◽

Vol 26 (27) ◽

pp. 4418-4425 ◽

Cited By ~ 65

Author(s):

Minal Barve ◽

James Bender ◽

Neil Senzer ◽

Casey Cunningham ◽

F. Anthony Greco ◽

...

Keyword(s):

Lung Cancer ◽

Immune Response ◽

Small Cell Lung Cancer ◽

Clinical Efficacy ◽

T Lymphocyte ◽

Cell Lung Cancer ◽

Cytotoxic T Lymphocyte ◽

Small Cell ◽

Low Grade ◽

Small Cell Lung

Purpose Generation of broad cytotoxic T-lymphocyte responses against multiple epitopes and tumor-associated antigens (TAAs) may provide effective immunotherapy in patients with cancer. We evaluated a single-vial peptide vaccine consisting of nine HLA-A2 supertype-binding epitopes (two native and seven analog epitopes modified for optimal HLA binding or T-cell receptor stimulation) covering five TAAs and the universal helper pan-DR epitope, formulated as a stable emulsion with incomplete Freund's adjuvant (Montanide ISA 51; Seppic SA, Paris, France). The clinical efficacy, safety, and multiepitope immunogenicity of IDM-2101 was evaluated in patients with stage IIIB or IV non–small-cell lung cancer (NSCLC). Patients and Methods A total of 63 patients were enrolled who were positive for HLA-A2. End points included survival, safety, and immune response. IDM-2101 (previously EP-2101) was administered every 3 weeks for the first 15 weeks, then every 2 months through year 1, then quarterly through year 2, for a total of 13 doses. Epitope-specific cytotoxic and helper T-lymphocyte immunogenic responses were measured by the interferon gamma enzyme-linked immunosorbent spot assay. Results No significant adverse events were noted. Low-grade erythema and pain at the injection site were the most common adverse effects. One-year survival in the treated patients was 60%, and median survival was 17.3 months. One complete and one partial response were identified. Survival was longer in patients demonstrating an immune response to epitope peptides (P < .001). Conclusion IDM-2101 was well tolerated, and evidence of efficacy was suggested.

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Co-expression and Immunity of Legionella pneumophila mip Gene and Immunoadjuvant ctxB Gene

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/37.3.199 ◽

2005 ◽

Vol 37 (3) ◽

pp. 199-204 ◽

Cited By ~ 5

Author(s):

Tao Wang ◽

Jian-Ping Chen ◽

Hong Li ◽

Ke-Qian Zhi ◽

Lei Zhang ◽

...

Keyword(s):

Immune Response ◽

T Lymphocyte ◽

Specific Antibody ◽

Legionella Pneumophila ◽

Cytotoxic T Lymphocyte ◽

Lymphocyte Response ◽

Nih3t3 Cells ◽

Ctxb Gene ◽

Cellular Immune ◽

Cytotoxic T Lymphocyte Response

Abstract The mip gene of Legionella pneumophila and the ctxB gene of Vibrio cholerae were amplified by PCR respectively. The amplified cDNA was ligated to the pcDNA3.1(+) vector. The recombinant plasmids pcDNA3.1-mip and pcDNA3.1-ctxB were identified by restriction analysis and PCR, and further confirmed by sequencing analysis. NIH3T3 cells were transfected with pcDNA3.1-mip and pcDNA3.1-ctxB according to the Lipofection method. Transient and stable products of the co-expression of the mip gene and ctxB gene were detected by immunofluorescence and Western blotting. The results showed that NIH3T3 cells were successfully transfected, and that the transiently and stably co-expressed products can be detected in the transfected cells. To detect the humoral and cellular immune response in immunized mice induced by the coimmunization of the mip and ctxB genes, female BALB/c mice were immunized intramuscularly with pcDNA3.1-mip and pcDNA3.1-ctxB. The results showed that the specific antibody titer and the cytotoxic T-lymphocyte response for pcDNA3.1-mip immunization and co-immunization were increased compared with that of pcDNA3.1(+) immunization. Furthermore, the specific antibody titer and cytotoxic T-lymphocyte response for co-immunization were increased compared with that of pcDNA3.1-mip immunization. Statistical analysis using one-way analysis of variance (ANOVA) showed that there was a significant difference between the groups (P<0.01). The results indicated that the ctxB gene enhanced the humoral and cellular immune response to the mip gene immunization. These findings provide experimental evidence to support the development of the L. pneumophila DNA vaccine.

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Hybrid Cell Vaccination Resolves Leishmania donovani Infection by Eliciting a Strong CD8+ Cytotoxic T-Lymphocyte Response with Concomitant Suppression of Interleukin-10 (IL-10) but Not IL-4 or IL-13

Infection and Immunity ◽

10.1128/iai.00944-07 ◽

2007 ◽

Vol 75 (12) ◽

pp. 5956-5966 ◽

Cited By ~ 26

Author(s):

Rajatava Basu ◽

Suniti Bhaumik ◽

Arun Kumar Haldar ◽

Kshudiram Naskar ◽

Tripti De ◽

...

Keyword(s):

Bone Marrow ◽

Immune Response ◽

T Cell ◽

Visceral Leishmaniasis ◽

T Lymphocyte ◽

Leishmania Donovani ◽

Cytotoxic T Lymphocyte ◽

Hybrid Cell ◽

Cell Depletion ◽

T Cell Depletion

ABSTRACT There is an acute dearth of therapeutic interventions against visceral leishmaniasis that is required to restore an established defective cell-mediated immune response. Hence, formulation of effective immunotherapy requires the use of dominant antigen(s) targeted to elicit a specific antiparasitic cellular immune response. We implemented hybrid cell vaccination therapy in Leishmania donovani-infected BALB/c mice by electrofusing dominant Leishmania antigen kinetoplastid membrane protein 11 (KMP-11)-transfected bone marrow-derived macrophages from BALB/c mice with allogeneic bone marrow-derived dendritic cells from C57BL/6 mice. Hybrid cell vaccine (HCV) cleared the splenic and hepatic parasite burden, eliciting KMP-11-specific major histocompatibility complex class I-restricted CD8+ cytotoxic T-lymphocyte (CTL) responses. Moreover, splenic lymphocytes of HCV-treated mice not only showed the enhancement of gamma interferon but also marked an elevated expression of the Th2 cytokines interleukin-4 (IL-4) and IL-13 at both transcriptional and translational levels. On the other hand, IL-10 production from splenic T cells was markedly suppressed as a result of HCV therapy. CD8+ T-cell depletion completely abrogated HCV-mediated immunity and the anti-KMP-11 CTL response. Interestingly, CD8+ T-cell depletion completely abrogated HCV-induced immunity, resulting in a marked increase of IL-10 but not of IL-4 and IL-13. The present study reports the first implementation of HCV immunotherapy in an infectious disease model, establishing strong antigen-specific CTL generation as a correlate of HCV-mediated antileishmanial immunity that is reversed by in vivo CD8+ T-cell depletion of HCV-treated mice. Our findings might be extended to drug-nonresponsive visceral leishmaniasis patients, as well as against multiple infectious diseases with pathogen-specific immunodominant antigens.

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