scholarly journals Identification and Characterisation of the CD40-Ligand ofSigmodon hispidus

2018 ◽  
Author(s):  
Marsha S. Russell ◽  
Abenaya Muralidharan ◽  
Louise Larocque ◽  
Jingxin Cao ◽  
Yvon Deschambault ◽  
...  
Keyword(s):  
Animal Model ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Types ◽  
Cd40 Ligand ◽  
Human Pathogens ◽  
Activated T Cells ◽  
Cotton Rat ◽  
Gene And Protein Expression ◽  
Cotton Rats

AbstractCotton rats are an important animal model to study infectious diseases. They have demonstrated higher susceptibility to a wider variety of human pathogens than other rodents and are also the animal model of choice for pre-clinical evaluations of some vaccine candidates. However, the genome of cotton rats remains to be fully sequenced, with much fewer genes cloned and characterised compared to other rodent species. Here we report the cloning and characterization of CD40 ligand, whose human and murine counterparts are known to be expressed on a range of cell types including activated T cells and B cells, dendritic cells, granulocytes, macrophages and platelets and exerts a broad array of immune responses. The cDNA for cotton rat CD40L we isolated is comprised of 1104 nucleotides with an open reading frame (ORF) of 783bp coding for a 260 amino acid protein. The recombinant cotton rat CD40L protein was recognized by an antibody against mouse CD40L. Moreover, it demonstrated functional activities on immature bone marrow dendritic cells by upregulating surface maturation markers (CD40, CD54, CD80, and CD86), and increasing IL-6 gene and protein expression. The availability of CD40L gene identity could greatly facilitate mechanistic research on pathogen-induced-immunopathogenesis and vaccine-elicited immune responses.

Functional domains of HSP70 stimulate generation of cytokines and chemokines, maturation of dendritic cells and adjuvanticity

2004 ◽  
Vol 32 (4) ◽  
pp. 629-632 ◽  
Author(s):  
T. Lehner ◽  
Y. Wang ◽  
T. Whittall ◽  
E. McGowan ◽  
C.G. Kelly ◽  
...  
Keyword(s):  
Amino Acids ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cd40 Ligand ◽  
Interleukin 12 ◽  
Cytokines And Chemokines ◽  
Cc Chemokines ◽  
Factor Α ◽  
Antigen Presenting ◽  
Necrosis Factor

Microbial HSP70 (heat-shock protein 70) consists of three functionally distinct domains: an N-terminal 44 kDa ATPase portion (amino acids 1–358), followed by an 18 kDa peptide-binding domain (amino acids 359–494) and a C-terminal 10 kDa fragment (amino acids 495–609). Immunological functions of these three different domains in stimulating monocytes and dendritic cells have not been fully defined. However, the C-terminal portion (amino acids 359–610) stimulates the production of CC chemokines, IL-12 (interleukin-12), TNFα(tumour necrosis factor α), NO and maturation of dendritic cells and also functions as an adjuvant in the induction of immune responses. In contrast, the ATPase domain of microbial HSP70 mostly lacks these functions. Since the receptor for HSP70 is CD40, which with its CD40 ligand constitutes a major co-stimulatory pathway in the interaction between antigen-presenting cells and T-cells, HSP70 may function as an alternative ligand to CD40L. HSP70–CD40 interaction has been demonstrated in non-human primates to play a role in HIV infection, in protection against Mycobacterium tuberculosis and in conversion of tolerance to immunity.

scholarly journals Myeloid and Plasmacytoid Dendritic Cells and Cancer – New Insights

2019 ◽  
Vol 7 (19) ◽  
pp. 3324-3340 ◽  
Author(s):  
Maya Gulubova ◽  
Koni Vancho Ivanova ◽  
Mehmed Hadzhi ◽  
Dimitur Chonov ◽  
Maria Magdalena Ignatova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Mhc I ◽  
Cross Presentation ◽  
Adaptive Immune ◽  
Histocompatibility Complex ◽  
T Helpers

Dendritic cells (DCs) use effective mechanisms to combat antigens and to bring about adaptive immune responses through their ability to stimulate nӓive T cells. At present, four major cell types are categorised as DCs: Classical or conventional (cDCs), Plasmacytoid (pDCs), Langerhans cells (LCs), and monocyte-derived DCs (Mo-DCs). It was suggested that pDCs, CD1c+ DCs and CD141+ DCs in humans are equivalent to mouse pDCs, CD11b+ DCs and CD8α+ DCs, respectively. Human CD141+ DCs compared to mouse CD8α+ DCs have remarkable functional and transcriptomic similarities. Characteristic markers, transcription factors, toll-like receptors, T helpers (Th) polarisation, cytokines, etc. of DCs are discussed in this review. Major histocompatibility complex (MHC) I and II antigen presentation, cross-presentation and Th polarisation are defined, and the dual role of DCs in the tumour is discussed. Human DCs are the main immune cells that orchestrate the immune response in the tumour microenvironment.

Development of CD40L-modified tumor small extracellular vesicles for effective induction of antitumor immune response

Nanomedicine ◽  
2020 ◽  
Vol 15 (17) ◽  
pp. 1641-1652
Author(s):  
Wen Liu ◽  
Yuki Takahashi ◽  
Masaki Morishita ◽  
Makiya Nishikawa ◽  
Yoshinobu Takakura
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Extracellular Vesicles ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Cd40 Ligand ◽  
Further Development

Aim: Tumor-derived small extracellular vesicles (TEVs) are considered for use in inducing tumor antigen-specific immune responses as they contain tumor antigens. The delivery of tumor antigens to the antigen presentation cells (especially dendritic cells [DCs]), and the activation of DCs are the main challenges of TEV therapy. Materials & methods: TEVs were modified with CD40 ligand (CD40L), which can target CD40 expressed on the surface of DCs and can activate them via CD40L-CD40 interactions. Results: It was found that CD40L-TEVs were efficiently taken up by DCs and also activated them. Moreover, tumor antigens were efficiently presented to the T cells by DCs treated with CD40L-TEVs. Conclusion: This study proved that CD40L-modification of TEVs will be helpful for further development of TEV-based tumor vaccination.

scholarly journals The Cotton Rat (Sigmodon hispidus) Is a Permissive Small Animal Model of Human Metapneumovirus Infection, Pathogenesis, and Protective Immunity

2005 ◽  
Vol 79 (17) ◽  
pp. 10944-10951 ◽  
Author(s):  
John V. Williams ◽  
Sharon J. Tollefson ◽  
Joyce E. Johnson ◽  
James E. Crowe
Keyword(s):  
Animal Model ◽  
Respiratory Tract ◽  
Guinea Pigs ◽  
Small Animal ◽  
Human Metapneumovirus ◽  
Small Animal Model ◽  
Cotton Rat ◽  
Nasal Tissue ◽  
Hmpv Infection ◽  
Cotton Rats

ABSTRACT Human metapneumovirus (hMPV) is a newly described paramyxovirus that is an important cause of acute respiratory tract disease. We undertook to develop a small animal model of hMPV infection, pathogenesis, and protection. Hamsters, guinea pigs, cotton rats, and nine inbred strains of mice were inoculated intranasally with hMPV. The animals were sacrificed, and nasal and lung tissue virus yields were determined by plaque titration. None of the animals exhibited respiratory symptoms. The quantity of virus present in the nasal tissue ranged from 4.6 × 102 PFU/gram tissue (C3H mice) to greater than 105 PFU/gram (hamster). The amount of virus in the lungs was considerably less than in nasal tissue in each species tested, ranging from undetectable (<5 PFU/g; guinea pigs) to 1.8 × 105 PFU/gram (cotton rat). The peak virus titer in cotton rat lungs occurred on day 4 postinfection. hMPV-infected cotton rat lungs examined on day 4 postinfection exhibited histopathological changes consisting of peribronchial inflammatory infiltrates. Immunohistochemical staining detected virus only at the luminal surfaces of respiratory epithelial cells throughout the respiratory tract. hMPV-infected cotton rats mounted virus-neutralizing antibody responses and were partially protected against virus shedding and lung pathology on subsequent rechallenge with hMPV. Viral antigen was undetectable in the lungs on challenge of previously infected animals. This study demonstrates that the cotton rat is a permissive small animal model of hMPV infection that exhibits lung histopathology associated with infection and that primary infection protected animals against subsequent infection. This model will allow further in vivo studies of hMPV pathogenesis and evaluation of vaccine candidates.

scholarly journals Readministration of Adenovirus Vector in Nonhuman Primate Lungs by Blockade of CD40-CD40 Ligand Interactions

2000 ◽  
Vol 74 (7) ◽  
pp. 3345-3352 ◽  
Author(s):  
Narendra Chirmule ◽  
Steven E. Raper ◽  
Linda Burkly ◽  
David Thomas ◽  
John Tazelaar ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rhesus Monkeys ◽  
Neutralizing Antibodies ◽  
Interleukin 2 ◽  
Adenovirus Vector ◽  
Cd40 Ligand ◽  
Adenoviral Vectors ◽  
Immunoglobulin M ◽  
Long Term Effects ◽  
Activated T Cells

ABSTRACT The interaction between CD40 on B cells and CD40 ligand (CD40L) on activated T cells is important for B-cell differentiation in T-cell-dependent humoral responses. We have extended our previous murine studies of CD40-CD40L in adenoviral vector-mediated immune responses to rhesus monkeys. Primary immune responses to adenoviral vectors and the ability to readminister vector were studied in rhesus monkeys in the presence or absence of a transient treatment with a humanized anti-CD40 ligand antibody (hu5C8). Adult animals were treated with hu5C8 at the time vector was instilled into the lung. Immunological analyses demonstrated suppression of adenovirus-induced lymphoproliferation and cytokine responses (interleukin-2 [IL-2], gamma interferon, IL-4, and IL-10) in hu5C8-treated animals. Animals treated with hu5C8 secreted adenovirus-specific immunoglobulin M (IgM) levels comparable to control animals, but did not secrete IgA or develop neutralizing antibodies; consequently, the animals could be readministered with adenovirus vector expressing alkaline phosphatase. A second study was designed to examine the long-term effects on immune functions of a short course of hu5C8. Acute hu5C8 treatment resulted in significant and prolonged inhibition of the adenovirus-specific humoral response well beyond the time hu5C8 effects were no longer significant. These studies demonstrate the potential of hu5C8 as an immunomodulatory regimen to enable administration of adenoviral vectors, and they advocate testing this model in humans.

scholarly journals Microbial Community Structure and Composition is Associated With Host Species and Sex in Sigmodon Cotton Rats

2020 ◽  
Author(s):  
Britton Strickland ◽  
Mira Patel ◽  
Meghan H. Shilts ◽  
Helen H. Boone ◽  
Arash Kamali ◽  
...  
Keyword(s):  
Animal Model ◽  
Microbial Communities ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Small Animal ◽  
Rrna Gene ◽  
Small Animal Model ◽  
Cotton Rat ◽  
Cotton Rats ◽  
The Impact

Abstract Background: The cotton rat (genus Sigmodon) is an essential small animal model for the study of human infectious disease and viral therapeutic development. However, the impact of the host microbiome on infection outcomes has not been explored in this model, partly due to the lack of a comprehensive characterization of microbial communities across different cotton rat species. Understanding the dynamics of their microbiome could significantly help to better understand its role during when modeling viral infections in this small animal model.Results: We examined the bacterial communities of the gut and three external sites (skin, ear, and nose) of two inbred species of cotton rats commonly used in research (S. hispidus and S. fulviventer) by using 16S rRNA gene sequencing, constituting the first comprehensive catalog of the cotton rat microbiome. We showed that S. fulviventer maintained higher alpha diversity and richness than S. hispidus at external sites (skin, ear, nose), but there were no differentially abundant genera. However, S. fulviventer and S. hispidus had distinct fecal microbiomes composed of several significantly differentially abundant genera. Whole metagenomic shotgun sequencing of fecal samples identified species-level differences between S. hispidus and S. fulviventer, as well as different metabolic pathway functions as a result of differential host microbiome contributions. Furthermore, the microbiome composition of the external sites showed significant sex-based differences while fecal communities were not largely different. Conclusions: Our study shows that host genetic background potentially exerts homeostatic pressures, resulting in distinct microbiomes for two different inbred cotton rat species. Because of the numerous studies that have uncovered strong relationships between host microbiome, viral infection outcomes, and immune responses, our findings represent a strong contribution for understanding the impact of different microbial communities on viral pathogenesis. Furthermore, we provide novel cotton rat microbiome data as a springboard to uncover the full therapeutic potential of the microbiome against viral infections.

Lack of endogenous TRIM5α-mediated restriction in rhesus macaque dendritic cells

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3772-3776 ◽  
Author(s):  
Nathalie J. Arhel ◽  
Sébastien Nisole ◽  
Laetitia Carthagena ◽  
Frédéric Coutant ◽  
Philippe Souque ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Rhesus Macaque ◽  
Rhesus Macaques ◽  
Cell Types ◽  
Primary Cells ◽  
Adaptive Immune ◽  
Trim Protein ◽  
Tripartite Motif ◽  
Hiv 1

Rhesus macaques are resistant to infection by HIV-1 as a result of an innate cellular restriction mechanism attributable to the expression of rhTRIM5α, a member of the large tripartite motif (TRIM) protein family. TRIM5α-mediated restriction, which occurs before reverse transcription through targeting of the HIV-1 capsid, has been identified in a number of macaque primary cells and cell lines and is thought to occur in all macaque cell types. We report, however, that rhesus macaque dendritic cells (DCs) lack TRIM5α-mediated restriction and are equally permissive to HIV-1 infection as human DCs. Evidence suggests that, although TRIM5α RNA levels are normal in these cells, the protein may be dysfunctional. We propose that abrogation of TRIM5α-mediated restriction in DCs, although still operative in cells that replicate HIV-1 (macrophages, T lymphocytes), illustrates the need for innate mechanisms to not inhibit adaptive immune responses to ensure an optimal fight against pathogens.

Combination of monocyte-derived dendritic cells and activated T cells which express CD40 ligand: a new approach to cancer immunotherapy

2004 ◽  
Vol 53 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Takami Sato ◽  
Mizue Terai ◽  
Rie Yasuda ◽  
Ryuko Watanabe ◽  
David Berd ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cancer Immunotherapy ◽  
Cd40 Ligand ◽  
Activated T Cells ◽  
New Approach

scholarly journals Microbial community structure and composition is associated with host species and sex in Sigmodon cotton rats

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Britton A. Strickland ◽  
Mira C. Patel ◽  
Meghan H. Shilts ◽  
Helen H. Boone ◽  
Arash Kamali ◽  
...  
Keyword(s):  
Animal Model ◽  
Microbial Communities ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Rrna Gene ◽  
Cotton Rat ◽  
Cotton Rats ◽  
The Impact ◽  
Comprehensive Characterization

Abstract Background The cotton rat (genus Sigmodon) is an essential small animal model for the study of human infectious disease and viral therapeutic development. However, the impact of the host microbiome on infection outcomes has not been explored in this model, partly due to the lack of a comprehensive characterization of microbial communities across different cotton rat species. Understanding the dynamics of their microbiome could significantly help to better understand its role when modeling viral infections in this animal model. Results We examined the bacterial communities of the gut and three external sites (skin, ear, and nose) of two inbred species of cotton rats commonly used in research (S. hispidus and S. fulviventer) by using 16S rRNA gene sequencing, constituting the first comprehensive characterization of the cotton rat microbiome. We showed that S. fulviventer maintained higher alpha diversity and richness than S. hispidus at external sites (skin, ear, nose), but there were no differentially abundant genera. However, S. fulviventer and S. hispidus had distinct fecal microbiomes composed of several significantly differentially abundant genera. Whole metagenomic shotgun sequencing of fecal samples identified species-level differences between S. hispidus and S. fulviventer, as well as different metabolic pathway functions as a result of differential host microbiome contributions. Furthermore, the microbiome composition of the external sites showed significant sex-based differences while fecal communities were not largely different. Conclusions Our study shows that host genetic background potentially exerts homeostatic pressures, resulting in distinct microbiomes for two different inbred cotton rat species. Because of the numerous studies that have uncovered strong relationships between host microbiome, viral infection outcomes, and immune responses, our findings represent a strong contribution for understanding the impact of different microbial communities on viral pathogenesis. Furthermore, we provide novel cotton rat microbiome data as a springboard to uncover the full therapeutic potential of the microbiome against viral infections.

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