Innate immune response to human bone marrow fibroblastic cell implantation in CB17 scid/beige mice

2006 ◽  
Vol 98 (4) ◽  
pp. 966-980 ◽  
Author(s):  
Zhidao Xia ◽  
Philip R. Taylor ◽  
Rachel M. Locklin ◽  
Siamon Gordon ◽  
Zhanfeng Cui ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Fibroblastic Cell ◽  
Cell Implantation

scholarly journals Hematopoietic Stem and Progenitor Cells as Effectors in Innate Immunity

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Jennifer L. Granick ◽  
Scott I. Simon ◽  
Dori L. Borjesson
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Progenitor Cells ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Phenotypic Characterization ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Stem And Progenitor Cells ◽  
And Function

Recent research has shed light on novel functions of hematopoietic stem and progenitor cells (HSPC). While they are critical for maintenance and replenishment of blood cells in the bone marrow, these cells are not limited to the bone marrow compartment and function beyond their role in hematopoiesis. HSPC can leave bone marrow and circulate in peripheral blood and lymph, a process often manipulated therapeutically for the purpose of transplantation. Additionally, these cells preferentially home to extramedullary sites of inflammation where they can differentiate to more mature effector cells. HSPC are susceptible to various pathogens, though they may participate in the innate immune response without being directly infected. They express pattern recognition receptors for detection of endogenous and exogenous danger-associated molecular patterns and respond not only by the formation of daughter cells but can themselves secrete powerful cytokines. This paper summarizes the functional and phenotypic characterization of HSPC, their niche within and outside of the bone marrow, and what is known regarding their role in the innate immune response.

scholarly journals Role of the Thrombin-PAR-1 Pathway in Coxsackievirus Induced Hepatitis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1470-1470
Author(s):  
Kohei Tatsumi ◽  
Silvio Antoniak ◽  
Nigel Mackman
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Primary Mouse Hepatocytes ◽  
Primary Mouse ◽  
Mouse Hepatocytes ◽  
Transplantation Experiments

Abstract Objective: Coxsackievirus B3 (CVB3) can infect different tissues including the heart and liver. Recently, we found that activation of the coagulation cascade and protease-activated receptor 1 (PAR-1) enhances toll-like receptor-3 (TLR3) mediated interferon-β (IFN-β) expression and protects mice from CVB3-induced myocarditis. Here, we investigated the role of PAR-1 in early anti-viral responses in mice and isolated hepatocytes. Methods: Wild-type (WT) and PAR-1 deficient (PAR-1-/-) mice were infected with CVB3 intraperitoneally. The innate immune response, viral load, liver enzyme plasma levels, and inflammation levels were analyzed. Bone-marrow transplantation experiments with the combination of WT mice PAR-1-/- mice were performed to identify the cellular source of PAR-1 contributing to the innate immune response to CVB3. We also analyzed the effect of the direct thrombin inhibition with dabigatran etexilate on CVB3 hepatitis. In addition, we analyzed the effect of PAR-1 activation on TLR3-dependent interferon (IFN)-β expression in primary mouse hepatocytes and the human hepatocyte cell line PH5CH8 in vitro. Results: PAR-1-/- mice exhibited a reduced early innate immune response in the liver at day 4 after infection, which was associated at later times (day 8) to higher viral titers in the liver, increased alanine transaminase plasma levels and more remarkable inflammation compared to control WT mice. Bone marrow transplantation experiments demonstrated that PAR-1 on non-hematopoietic played the major role in the innate immune response of CVB3 hepatitis. Stimulation of PAR-1 with either thrombin or agonist peptide on primary mouse hepatocytes and human PH5CH8 cells in vitro enhanced the antiviral response to dsRNA by increasing IFN-β and C-X-C motif chemokine 10 (CXCL10) expressions, supporting the results of in vivo experiments. Conclusion: Our results suggest that activation of PAR-1 on hepatocytes enhances the innate immune response to CVB3 in the liver. Disclosures No relevant conflicts of interest to declare.

Aberrant Overexpression Of CD14 In Granulocytes Sensitizes Innate Immune Response In mDia1 Heterozygous Myelodysplastic Syndromes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1557-1557
Author(s):  
Ganesan Keerthivasan ◽  
Baobing Zhao ◽  
Chad E Harris ◽  
Ling Zhang ◽  
Juehua Gao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Innate Immune Response ◽  
Myelodysplastic Syndromes ◽  
Knockout Mice ◽  
Actin Polymerization ◽  
Conflicts Of Interest ◽  
Innate Immune ◽  
Increased Risk ◽  
A Cell

Abstract The myelodysplastic syndromes (MDS) are a group of pre-leukemic diseases characterized by increased risk of acute myeloid leukemia (AML). Heterozygous loss of chromosome 5q (5q-) is the most common cytogenetic abnormality in MDS. DIAPH1 is localized to 5q31 and encodes one of the formin family proteins, mDia1, involved in the regulation of linear actin polymerization. Mice with mDia1 deficiency develop hematologic features mimicking human myeloproliferative neoplasm, but its role in the pathogenesis of MDS is unclear. Here we report that mDia1 is largely dispensable for normal hematopoiesis. However, the committed or mature granulocytes in mDia1 heterozygous and knockout mice were activated and showed increased actin polarization. Strikingly, CD14 was aberrantly overexpressed in the bone marrow and peripheral granulocytes of mDia1 heterozygous and knockout mice in a cell-autonomous manner, leading to a hypersensitivity of the innate immune response to lipopolysaccharide (LPS) stimuli through CD14-Toll like receptor 4 (TLR4) signaling. Chronic stimulation with LPS accelerated the occurrence of MDS in mDia1 heterozygous and knockout mice. Similar findings of CD14 overexpression were observed in the bone marrow granulocytes of 5q- MDS patients, but not normal patients or MDS patients without 5q deletion. These patients exhibited relatively frequent infections with long duration of disease. Mechanistically, mDia1 was required for the endocytosis of CD14 upon LPS stimulation. Heterozygosity and loss of mDia1 led to diminished interferon expression that is dependent on CD14 endocytosis. Thus, our study revealed an essential role of the innate immune signaling in the pathogenesis of 5q- MDS. Specifically, heterozygosity or loss of mDia1 leads to a cell autonomous hypersensitivity of innate immune system in the granulocytes that causes myeloid dysplasia. Together with previous reported evidence of dyserythropoiesis due to loss of RPS14, and dysmegakaryopoiesis due to loss of mir-145/146a, these data fully recapitulate the pathogenesis of tri-lineage dysplasia in 5q- MDS. In addition, our study highlighted the significance of the activated CD14/TLR signaling pathway in the pathogenesis of MDS, which could serve as a novel target for therapeutic management. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD38 Controls the Innate Immune Response against Listeria monocytogenes

2013 ◽  
Vol 81 (11) ◽  
pp. 4091-4099 ◽  
Author(s):  
Timo Lischke ◽  
Kira Heesch ◽  
Valéa Schumacher ◽  
Michael Schneider ◽  
Friedrich Haag ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Listeria Monocytogenes ◽  
Innate Immune Response ◽  
Cell Activation ◽  
Cell Types ◽  
Innate Immune ◽  
Infection Model ◽  
Content Type ◽  
Inflammatory Monocytes

ABSTRACTCD38, adenosine-5′-diphosphate-ribosyl cyclase 1, is a multifunctional enzyme, expressed on a wide variety of cell types. CD38 has been assigned diverse functions, including generation of calcium-mobilizing metabolites, cell activation, and chemotaxis. Using a murineListeria monocytogenesinfection model, we found that CD38 knockout (KO) mice were highly susceptible to infection. Enhanced susceptibility was already evident within 3 days of infection, suggesting a function of CD38 in the innate immune response. CD38 was expressed on neutrophils and inflammatory monocytes, and especially inflammatory monocytes further upregulated CD38 during infection. Absence of CD38 caused alterations of the migration pattern of both cell types to sites of infection. We observed impaired accumulation of cells in the spleen but surprisingly similar or even higher accumulation of cells in the liver. CD38 KO and wild-type mice showed similar changes in the composition of neutrophils and inflammatory monocytes in blood and bone marrow, indicating that mobilization of these cells from the bone marrow was CD38 independent.In vitro, macrophages of CD38 KO mice were less efficient in uptake of listeria but still able to kill the bacteria. Dendritic cells also displayed enhanced CD38 expression following infection. However, absence of CD38 did not impair the capacity of mice to prime CD8+T cells againstL. monocytogenes, and CD38 KO mice could efficiently control secondary listeria infection. In conclusion, our results demonstrate an essential role for CD38 in the innate immune response againstL. monocytogenes.

Arg753Gln Polymorphisms in the Toll-Like Receptor 2 Gene are Associated with Cytomegalovirus Infection in Egyptian Bone Marrow Recipients

2020 ◽  
Vol 20 (4) ◽  
pp. 619-624
Author(s):  
Sobhy Hassab El-Nabi ◽  
Samia Sayed ◽  
Mohamed A. Abd-Elhafez ◽  
Mohamed Elfiky ◽  
Ahmed E. Abdel Moneim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Bone Marrow Transplantation ◽  
Innate Immune Response ◽  
Marrow Transplantation ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Cmv Infection ◽  
Tlr2 Gene ◽  
Toll Like Receptor 2

Background: Previous studies have shown that cytomegalovirus (CMV) induced innate immune response via activation of Toll-like receptor 2 (TLR2). The association between CMV among specific single-nucleotide polymorphisms (SNPs) in the TLR2 gene was also investigated. Objective: This study investigated the relationship between specific SNPs in the TLR2 gene (G>A), TLR2-Arg753Gln (rs5743708), and CMV replication after bone marrow transplantation. Methods: The TLR2-Arg753Gln SNP was genotyped in 181 patients after bone marrow transplantation: 83 and 98 patients with and without CMV infection, respectively. CMV load was determined in serially collected blood samples using real-time PCR. Genotyping was performed using specific sequence primer PCR (SSP-PCR), and the results were confirmed by restriction fragment length polymorphism (RFLP) analysis of the PCR-amplified fragments for GG (wild type), GA and AA identification. Results: Roughly, 85% of the patients screened for the presence of the TLR2-Arg753Gln were GG homozygous, and 15% were GA heterozygous; no patients were homozygous for the mutant allele (A). The GA heterozygous allele was more frequent in the CMV-infected group after bone marrow transplantation. Conclusion: To our knowledge, this is a novel observation that supports the notion that the functional missense mutation (TLR2-Arg753Gln polymorphism) is possibly associated with CMV replication after bone marrow transplantation. This suggests a role for TLR2 in the innate immune response of human CMV infection in Egyptian bone marrow recipients..

scholarly journals Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis

Glia ◽  
2009 ◽  
Vol 57 (11) ◽  
pp. 1192-1203 ◽  
Author(s):  
Lianhua Bai ◽  
Donald P. Lennon ◽  
Valerie Eaton ◽  
Kari Maier ◽  
Arnold I. Caplan ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Stem Cells ◽  
Bone Marrow ◽  
Immune Response ◽  
Mesenchymal Stem Cells ◽  
Animal Models ◽  
Human Bone ◽  
Human Bone Marrow

Bone Marrow Cell Rejection by Innate Immune Pathways Is Exclusively Dependent On the TRIF Pathway.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3526-3526
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Lala-Rukh Hussain ◽  
Yiming Huang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Solid Organ ◽  
Allogeneic Bone ◽  
Wild Type ◽  
Donor Chimerism

Abstract Abstract 3526 Poster Board III-463 Research on transplantation rejection, tolerance, and immunosuppressive agents has been directed toward the adaptive immune response as, until now, it has been believed to be the dominant mechanism for alloreactivity. The role of innate immunity in transplantation has not been fully defined. Despite the sentinel role of innate immunity in driving and shaping adaptive immunity, the contribution of innate immunity to bone narrow cells has only recently been identified. TLR4-driven MyD88-dependent immunity has been demonstrated to be critical for allogeneic innate immune responses to solid organ transplants. Whether innate immunity plays a role in BMC rejection has not been defined. In the present studies we tested whether the absence of MyD88 would enhance allogeneic engraftment in bone marrow transplantation (BMT). The core component of TLR signaling is activation of an IL-1-like pathway dependent upon the adapter MyD88. MyD88−/− B6 mice (n=6) were used to study the role of MyD88 signaling in allogeneic BMC rejection. As TRIF is another crucial adapter for TLR3 signaling and responsible for induction of signaling via type 1 IFNs, B6 TRIF−/− mice (n=6) were also investigated. Wild-type B6 (H2b, n=6) mice were used as controls. In the present study, MHC plus minor antigen-disparate BALB/c (H2d) mice served as allogeneic bone marrow donors. Recipients were nonmyeloablatively conditioned with anti-CD154 mAb (day0 and +3) to block CD40:CD154 co-stimulatory pathway and sirolimus (day0 to +4) to block late-stage T cell activation by inhibiting IL-2 responsiveness. Recipients were transplanted with 15 × 106 allogeneic (BALB/c; H2d) marrow cells 4-6 hours following conditioning with 100 cGy total body irradiation (TBI). Allogeneic engraftment was achieved in 33.3% of MyD88−/− recipients at 1 mo after BMT, a percentage similar to that for wild-type B6 mice. Surprisingly, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month after BMT, which was significantly higher than in MyD88−/− (1.8 ± 1.0%; P < 0.0001) or in wild-type B6 mice (1.3 ± 0.8%; P < 0.005) and thereafter through all time points tested (2, 4 and 5 months, P < 0.05). The levels of donor chimerism increased with time and the level of donor chimerism reached 14.7 ± 7.1% TRIF−/− at five months. These results suggest that allogeneic BMC rejection is uniquely independent of the MyD88 pathway but rather involves TRIF signaling. These data suggest that the innate immune response to BMC differs from that for solid organs and may reflect the specificity of BMT compared with other transplants. These findings demonstrate for the first time that BMC elicit an innate immune response via the TRIF pathway and may open the door to novel approaches for immune-based conditioning to promote engraftment. Disclosures: Ildstad: Regenerex: Equity Ownership.

scholarly journals Depletion of Bone Marrow–derived Macrophages Perturbs the Innate Immune Response to Surgery and Reduces Postoperative Memory Dysfunction

2013 ◽  
Vol 118 (3) ◽  
pp. 527-536 ◽  
Author(s):  
Vincent Degos ◽  
Susana Vacas ◽  
Zhenying Han ◽  
Nico van Rooijen ◽  
Pierre Gressens ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Memory Dysfunction
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