scholarly journals Intranasal Prophylaxis with CpG Oligodeoxynucleotide Can Protect against Yersinia pestis Infection

2013 ◽  
Vol 81 (6) ◽  
pp. 2123-2132 ◽  
Author(s):  
Anthony J. Hickey ◽  
Jr-Shiuan Lin ◽  
Lawrence W. Kummer ◽  
Frank M. Szaba ◽  
Debra K. Duso ◽  
...  
Keyword(s):  
T Cells ◽  
Yersinia Pestis ◽  
Bacterial Growth ◽  
Virulent Strain ◽  
Hepatic Tissue ◽  
Cpg Odn ◽  
Prophylactic Regimen ◽  
Term Survival ◽  
Content Type ◽  
Cpg Oligodeoxynucleotide

ABSTRACTImmunomodulatory agents potentially represent a new class of broad-spectrum antimicrobials. Here, we demonstrate that prophylaxis with immunomodulatory cytosine-phosphate-guanidine (CpG) oligodeoxynucleotide (ODN), a toll-like receptor 9 (TLR9) agonist, confers protection againstYersinia pestis, the etiologic agent of plague. The data establish that intranasal administration of CpG ODN 1 day prior to lethal pulmonary exposure toY. pestisstrain KIM D27 significantly improves survival of C57BL/6 mice and reduces bacterial growth in hepatic tissue, despite paradoxically increasing bacterial growth in the lung. All of these CpG ODN-mediated impacts, including the increased pulmonary burden, are TLR9 dependent, as they are not observed in TLR9-deficient mice. The capacity of prophylactic intranasal CpG ODN to enhance survival does not require adaptive immunity, as it is evident in mice lacking B and/or T cells; however, the presence of T cells improves long-term survival. The prophylactic regimen also improves survival and reduces hepatic bacterial burden in mice challenged intraperitoneally with KIM D27, indicating that intranasal delivery of CpG ODN has systemic impacts. Indeed, intranasal prophylaxis with CpG ODN provides significant protection against subcutaneous challenge withY. pestisstrain CO92 even though it fails to protect mice from intranasal challenge with that fully virulent strain.

scholarly journals Cationic Liposomes Extend the Immunostimulatory Effect of CpG Oligodeoxynucleotide against Burkholderia pseudomallei Infection in BALB/c Mice

2012 ◽  
Vol 19 (5) ◽  
pp. 675-683 ◽  
Author(s):  
Apichaya Puangpetch ◽  
Robert Anderson ◽  
Yan Y. Huang ◽  
Rasana W. Sermswan ◽  
Wanpen Chaicumpa ◽  
...  
Keyword(s):  
Burkholderia Pseudomallei ◽  
Severe Disease ◽  
Antimicrobial Activities ◽  
Cationic Liposomes ◽  
Phagocytic Index ◽  
Cpg Odn ◽  
Content Type ◽  
Cpg Oligodeoxynucleotide ◽  
Alternative Approach ◽  
Lethal Infection

ABSTRACTMelioidosis is a severe disease caused by the Gram-negative bacteriumBurkholderia pseudomallei. Previously we showed that pretreatment of mice with CpG oligodeoxynucleotide (CpG ODN) 2 to 10 days prior toB. pseudomalleichallenge conferred as high as 90% protection, but this window of protection was rather short. In the present study, we therefore aimed to prolong this protective window and to gain further insight into the mechanisms underlying the protection induced by CpG ODN againstB. pseudomalleiinfection. It was found that the CpG ODN incorporated with cationic liposomes (DOTAP) but not zwitterionic liposomes (DOPC) provided complete protection against bacterial challenge. Although marked elevation of gamma interferon (IFN-γ) was found in the infected animals 2 days postinfection, it was significantly lowered by the DOTAP-plus-CpG ODN pretreatment. When appropriately activated, the phagocytic index and oxidative burst responses of neutrophils appeared not to be elevated. However, macrophages from stimulated mice showed higher levels of nitric oxide production and exhibited higher levels of antimicrobial activities, judging from lower numbers of viable intracellular bacteria. Taken together, our results demonstrate that DOTAP can enhance the protective window period of CpG ODN to at least 30 days and provide 100% protection againstB. pseudomalleiinfection. The protective effect of DOTAP plus CpG ODN could provide an alternative approach to preventing this lethal infection, for which no vaccine is yet available.

scholarly journals Factor XI-Deficient Mice Display Reduced Inflammation, Coagulopathy, and Bacterial Growth during Listeriosis

2011 ◽  
Vol 80 (1) ◽  
pp. 91-99 ◽  
Author(s):  
Deyan Luo ◽  
Frank M. Szaba ◽  
Lawrence W. Kummer ◽  
Lawrence L. Johnson ◽  
Erik I. Tucker ◽  
...  
Keyword(s):  
Bacterial Growth ◽  
Hepatic Necrosis ◽  
Host Responses ◽  
Hepatic Tissue ◽  
Bacterial Burden ◽  
Wild Type ◽  
Factor Xi ◽  
Content Type ◽  
High Doses ◽  
Deficient Mice

ABSTRACTIn mice infected sublethally withListeria monocytogenes, fibrin is deposited at low levels within hepatic tissue, where it functions protectively by limiting bacterial growth and suppressing hemorrhagic pathology. Here we demonstrate that mice infected with lethal doses ofL. monocytogenesproduce higher levels of fibrin and display evidence of systemic coagulopathy (i.e., thrombocytopenia, fibrinogen depletion, and elevated levels of thrombin-antithrombin complexes). When the hepatic bacterial burden exceeds 1 × 106CFU, levels of hepatic fibrin correlate with the bacterial burden, which also correlates with levels of hepatic mRNA encoding the hemostatic enzyme factor XI (FXI). Gene-targeted FXI-deficient mice show significantly improved survival upon challenge with high doses ofL. monocytogenesand also display reduced levels of hepatic fibrin, decreased evidence of coagulopathy, and diminished cytokine production (interleukin-6 [IL-6] and IL-10). While fibrin limits the bacterial burden during sublethal listeriosis in wild-type mice, FXI-deficient mice display a significantly improved capacity to restrain the bacterial burden during lethal listeriosis despite their reduced fibrin levels. They also show less evidence of hepatic necrosis. In conjunction with suboptimal antibiotic therapy, FXI-specific monoclonal antibody 14E11 improves survival when administered therapeutically to wild-type mice challenged with high doses ofL. monocytogenes.Together, these findings demonstrate the utility of murine listeriosis as a model for dissecting qualitative differences between protective and pathological host responses and reveal novel roles for FXI in exacerbating inflammation and pathogen burden during a lethal bacterial infection.

scholarly journals CpG Oligodeoxynucleotide 2006 and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis

2011 ◽  
Vol 55 (7) ◽  
pp. 3461-3464 ◽  
Author(s):  
Suman Gupta ◽  
Shraddha A. Sane ◽  
Nishi Shakya ◽  
Preeti Vishwakarma ◽  
W. Haq
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Inhibitory Effect ◽  
Rational Approach ◽  
Host Use ◽  
Cpg Odn ◽  
Content Type ◽  
Cpg Oligodeoxynucleotide ◽  
Class B ◽  
Different Doses

ABSTRACTIn view of the severe immunosuppression in visceral leishmaniasis (VL), a rational approach to effectively combat the parasitic scourge would be to enhance the immune status of the host. Use of CpG oligodeoxynucleotide (CpG-ODN) against leishmaniasis has previously been reported, especially as an immunomodulator and adjuvant with various immunogens. In the present study, experiments were carried out with BALB/c mice and hamsters infected withLeishmania donovani. Immunostimulating class B bacterial CpG-ODN namely, ODN-2006, was administered at various doses by the intraperitoneal (i.p.) route. The dose of CpG-ODN-2006 (1 nM/single dose) showing the most antileishmanial activity was given as free and liposomal forms with different doses of miltefosine, namely, 5 and 10 mg/kg of body weight, for 5 days in mice and hamsters, respectively. Among the various groups, mice coadministered liposomal CpG-ODN and miltefosine (5 mg/kg) showed the best inhibitory effect (97% parasite inhibition) compared with free CpG-ODN plus miltefosine and miltefosine, free CpG-ODN, and liposomal CpG-ODN given separately. Similar responses were observed in the case of hamsters, where the combination of liposomal CpG-ODN with miltefosine (10 mg/kg) gave 96% parasite inhibition. Promising antileishmanial efficacy was observed in animals treated with liposomal CpG-ODN and miltefosine.

scholarly journals Essential Engagement of Toll-Like Receptor 2 in Initiation of Early Protective Th1 Response against Rough Variants of Mycobacterium abscessus

2015 ◽  
Vol 83 (4) ◽  
pp. 1556-1567 ◽  
Author(s):  
Jong-Seok Kim ◽  
Min-Jung Kang ◽  
Woo Sik Kim ◽  
Seung Jung Han ◽  
Hong Min Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Protective Immunity ◽  
Mycobacterium Abscessus ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Term Survival ◽  
Content Type ◽  
Specific Manner ◽  
Toll Like Receptor 2

AlthoughMycobacterium abscessus(M. abscessus) is becoming more prevalent in patients without overt immunodeficiency, little is known about the factors that contribute to disease susceptibility. This study was undertaken to investigate how Toll-like receptor 2 (TLR2) functionally contributes to the generation of protective immunity againstM. abscessusin a morphotype-specific manner. We found thatTlr2−/−mice were extremely susceptible to an intravenous (i.v.) model of infection byM. abscessusrough variants, displaying uncontrolled infection in the lungs and a significantly lower survival rate than with wild-type (WT) mice. This uncontrolled infection resulted from failures in the following processes: (i) production of the crucial cytokines gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 12p70 (IL-12p70); (ii) early infiltration of neutrophils, monocytes, and dendritic cells (DCs) in the lungs ofTlr2−/−mice; (iii) rapid influx of CD4+and CD8+T cells; and (iv) the expansion of memory/effector T cells. Notably, systemic administration ofM. abscessusculture filtrate-treated syngeneic DCs from WT mice greatly strengthened immune primingin vivo, resulting in a dramatic reduction in bacterial growth and improved long-term survival inTlr2−/−mice, with a recovery of protective immunity. Our findings demonstrate that TLR2 is an essential contributor to instructive and effector immunity duringM. abscessusinfection in a morphotype-specific manner.

scholarly journals Role of γδ T Cells in Immunopathology of Pulmonary Mycobacterium avium Infection in Mice

1998 ◽  
Vol 66 (11) ◽  
pp. 5508-5514 ◽  
Author(s):  
Bernadette M. Saunders ◽  
Anthony A. Frank ◽  
Andrea M. Cooper ◽  
Ian M. Orme
Keyword(s):  
T Cells ◽  
Mycobacterium Avium ◽  
Bacterial Growth ◽  
Virulent Strain ◽  
Γδ T Cells ◽  
Inflammatory Cells ◽  
Wild Type ◽  
Bacterial Strains ◽  
Avium Infection

ABSTRACT Several studies have shown that γδ T cells influence granuloma development after infection with intracellular pathogens. The role of γδ T cells in controlling the influx of inflammatory cells into the lung after Mycobacterium avium infection was therefore examined with gene-disrupted mice (K/O). The mice were infected with either M. avium 724, a progressively replicating highly virulent strain of M. avium, or with M. avium2-151 SmT, a virulent strain that induces a chronic infection. γδ-K/O mice infected with M. avium 2-151 SmT showed early enhanced bacterial growth within the lung compared to the wild-type mice, although granuloma formation was similar in both strains. γδ-K/O mice infected with M. avium 724 showed identical bacterial growth within the lung compared to the wild-type mice, but they developed more-compact lymphocytic granulomas and did not show the extensive neutrophil influx and widespread tissue necrosis seen in wild-type mice. These data support the hypothesis that isolates of M. avium that induce protective T-cell-specific immunity are largely unaffected by the absence of γδ T cells. Whereas with bacterial strains that induce poor protective immunity, the absence of γδ T cells led to significant reductions in both the influx of neutrophils and tissue damage within the lungs of infected mice.

CpG-A and CpG-B oligonucleotides differentially enhance human peptide–specific primary and memory CD8+ T-cell responses in vitro

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2162-2169 ◽  
Author(s):  
Simon Rothenfusser ◽  
Veit Hornung ◽  
Maha Ayyoub ◽  
Stefanie Britsch ◽  
Andreas Towarowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Interferon Α ◽  
Cpg Odn ◽  
Cell Responses ◽  
Cpg Oligodeoxynucleotide ◽  
Memory Cd8 T Cell

Abstract Two distinct types of CpG oligodeoxynucleotide (ODN) have been identified that differ in their capacity to stimulate antigen-presenting cells: CpG-A induces high amounts of interferon-α (IFN-α) and IFN-β in plasmacytoid dendritic cells (PDCs), whereas CpG-B induces PDC maturation and is a potent activator of B cells but stimulates only small amounts of IFN-α and IFN-β. Here we examined the ability of these CpG ODNs to enhance peptide-specific CD8+ T-cell responses in human peripheral blood mononuclear cells (PBMCs). The frequency of influenza matrix–specific “memory” CD8+ T cells was increased by both types of CpG ODN, whereas the frequency of Melan-A specific “naive” CD8+ T cells increased on stimulation with CpG-B but not with CpG-A. The presence of PDCs in PBMCs was required for this CpG ODN-mediated effect. The expanded cells were cytotoxic and produced IFN-γ on peptide restimulation. Soluble factors induced by CpG-A but not CpG-B increased the granzyme-B content and cytotoxicity of established CD8+ T-cell clones, each of which was IFN-α/-β dependent. In conclusion, CpG-B seems to be superior for priming CD8+ T-cell responses, and CpG-A selectively enhances memory CD8+ T-cell responses and induces cytotoxicity. These results demonstrate distinct functional properties of CpG-A and CpG-B with regard to CD8 T cells.

Increased frequencies of activated effector CD4+ T cells in the peripheral blood and hepatic tissue of patients with NAFL and NASH

2014 ◽  
Vol 52 (08) ◽  
Author(s):  
M Rau ◽  
AK Schilling ◽  
J Meertens ◽  
I Hering ◽  
T Kudlich ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Hepatic Tissue

Dual-isotope single-photon emission computerized tomography scanning in patients with glioblastoma multiforme: association with patient survival and histopathological characteristics of tumor after high-dose radiotherapy

1998 ◽  
Vol 89 (1) ◽  
pp. 60-68 ◽  
Author(s):  
Richard B. Schwartz ◽  
B. Leonard Holman ◽  
Joseph F. Polak ◽  
Basem M. Garada ◽  
Marc S. Schwartz ◽  
...  
Keyword(s):  
Survival Rate ◽  
Glioblastoma Multiforme ◽  
Single Photon ◽  
Photon Emission ◽  
High Dose ◽  
Term Survival ◽  
Content Type ◽  
Dual Isotope ◽  
Fine Print

Object. The study was conducted to determine the association between dual-isotope single-photon emission computerized tomography (SPECT) scanning and histopathological findings of tumor recurrence and survival in patients treated with high-dose radiotherapy for glioblastoma multiforme. Methods. Studies in which SPECT with 201Tl and 99mTc-hexamethypropyleneamine oxime (HMPAO) were used were performed 1 day before reoperation in 47 patients with glioblastoma multiforme who had previously been treated by surgery and high-dose radiotherapy. Maximum uptake of 201Tl in the lesion was expressed as a ratio to that in the contralateral scalp, and uptake of 99mTc-HMPAO was expressed as a ratio to that in the cerebellar cortex. Patients were stratified into groups based on the maximum radioisotope uptake values in their tumor beds. The significance of differences in patient gender, histological characteristics of tissue at reoperation, and SPECT uptake group with respect to 1-year survival was elucidated by using the chi-square statistic. Comparisons of patient ages and time to tumor recurrence as functions of 1-year survival were made using the t-test. Survival data at 1 year were presented according to the Kaplan—Meier method, and the significance of potential differences was evaluated using the log-rank method. The effects of different variables (tumor type, time to recurrence, and SPECT grouping) on long-term survival were evaluated using Cox proportional models that controlled for age and gender. All patients in Group I (201Tl ratio < 2 and 99mTc-HMPAO ratio < 0.5) showed radiation changes in their biopsy specimens: they had an 83.3% 1-year survival rate. Group II patients (201T1 ratio < 2 and 99mTc-HMPAO ratio of ≥ 0.5 or 201Tl ratio between 2 and 3.5 regardless of 99mTc-HMPAO ratio) had predominantly infiltrating tumor (66.6%); they had a 29.2% 1-year survival rate. Almost all of the patients in Group III (201Tl ratio > 3.5 and 99mTc-HMPAO ratio ≥ 0.5) had solid tumor (88.2%) and they had a 6.7% 1-year survival rate. Histological data were associated with 1-year survival (p < 0.01); however, SPECT grouping was more closely associated with 1-year survival (p < 0.001) and was the only variable significantly associated with long-term survival (p < 0.005). Conclusions. Dual-isotope SPECT data correlate with histopathological findings made at reoperation and with survival in patients with malignant gliomas after surgical and high-dose radiation therapy.

Tumor recurrence and survival following gamma knife surgery for brain metastases

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 287-288 ◽  
Author(s):  
Thomas Mindermann
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Gamma Knife ◽  
Tumor Recurrence ◽  
Patient Survival ◽  
Gamma Knife Surgery ◽  
Recurrence Rates ◽  
Term Survival ◽  
Content Type ◽  
Fine Print

Object. The authors evaluated prognostic factors for tumor recurrence and patient survival following gamma knife surgery (GKS) for brain metastasis. Methods. A retrospective review of 101 patient charts was undertaken for those patients treated with GKS for brain metastases from 1994 to 2001. Recurrence rates of brain metastasis following GKS depended on the duration of patient survival. Long-term survival was associated with a higher risk of tumor recurrence and shorter-term survival was associated with a lower risk. The duration of survival following GKS for brain metastases seems to be characteristic of the primary disease rather than the cerebral disease. Conclusions. Recurrence rates of brain metastasis following GKS are related to duration of survival, which is in turn mostly dependent on the nature and course of the primary tumor.

Sign in / Sign up

Export Citation Format

Share Document