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1.
Eur Respir J ; 60(5)2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35798357

RESUMO

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with chronic inflammation and tissue remodelling leading to fibrosis, reduced pulmonary function, respiratory failure and death. Bleomycin (Blm)-induced lung fibrosis in mice replicates several clinical features of human IPF, including prominent lymphoid aggregates of predominantly B-cells that accumulate in the lung adjacent to areas of active fibrosis. We have shown previously a requirement for B-cells in the development of Blm-induced lung fibrosis in mice. To determine the therapeutic potential of inhibiting B-cell function in pulmonary fibrosis, we examined the effects of anti-CD20 B-cell ablation therapy to selectively remove mature B-cells from the immune system and inhibit Blm-induced lung fibrosis. Anti-CD20 B-cell ablation did not reduce fibrosis in this model; however, immune phenotyping of peripheral blood and lung resident cells revealed that anti-CD20-treated mice retained a high frequency of CD19+ CD138+ plasma cells. Interestingly, high levels of CD138+ cells were also identified in the lung tissue of patients with IPF, consistent with the mouse model. Treatment of mice with bortezomib, which depletes plasma cells, reduced the level of Blm-induced lung fibrosis, implicating plasma cells as important effector cells in the development and progression of pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Humanos , Camundongos , Animais , Bleomicina/farmacologia , Plasmócitos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/metabolismo , Doenças Pulmonares Intersticiais/induzido quimicamente
2.
Transplantation ; 107(7): 1502-1512, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36584373

RESUMO

BACKGROUND: During solid organ transplantation, donor leukocytes, including myeloid cells, are transferred within the organ to the recipient. Both tolerogenic and alloreactive roles have been attributed to donor myeloid cells; however, their subset-specific retention posttransplantation has not been investigated in detail. METHODS: Major histocompatibility complex (MHC)-matched and mismatched liver transplants were performed in mice, and the fate of donor and recipient myeloid cells was assessed. RESULTS: Following MHC-matched transplantation, a proportion of donor myeloid cells was retained in the graft, whereas others egressed and persisted in the blood, spleen, and bone marrow but not the lymph nodes. In contrast, after MHC-mismatched transplantation, all donor myeloid cells, except Kupffer cells, were depleted. This depletion was caused by recipient T and B cells because all donor myeloid subsets were retained in MHC-mismatched grafts when recipients lacked T and B cells. Recipient myeloid cells rapidly infiltrated MHC-matched and, to a greater extent, MHC-mismatched liver grafts. MHC-mismatched grafts underwent a transient rejection episode on day 7, coinciding with a transition in macrophages to a regulatory phenotype, after which rejection resolved. CONCLUSIONS: Phenotypic and kinetic differences in the myeloid cell responses between MHC-matched and mismatched grafts were identified. A detailed understanding of the dynamics of immune responses to transplantation is critical to improving graft outcomes.


Assuntos
Transplante de Fígado , Camundongos , Animais , Transplante de Fígado/efeitos adversos , Transplante de Medula Óssea , Transplante Homólogo , Complexo Principal de Histocompatibilidade , Antígenos de Histocompatibilidade , Células Mieloides
3.
Circulation ; 108(20): 2498-504, 2003 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-14581400

RESUMO

BACKGROUND: Chemokines are important mediators of inflammatory cell recruitment that play a significant role in atherosclerosis. Fractalkine (CX3CL1) is an unusual membrane-bound chemokine that mediates chemotaxis through the CX3CR1 receptor. Recently, functional polymorphisms in the human CX3CR1 gene have been described that are associated with coronary artery disease. METHODS AND RESULTS: We investigated the expression of the CX3C chemokine fractalkine and its receptor CX3CR1 in human coronary artery plaques by immunocytometry. We show that a subset of mononuclear cells expresses high levels of fractalkine in human coronary atherosclerotic plaques and that smooth muscle cells within the neointima express the fractalkine receptor CX3CR1. There is a positive correlation between the number of fractalkine-expressing cells and the number of CX3CR1-positive cells in human atherosclerotic plaques (r=0.70, n=15 plaques). Furthermore, we demonstrate that cultured vascular smooth muscle cells express the CX3CR1 receptor and undergo chemotaxis to fractalkine that can be inhibited by G protein inactivation by pertussis toxin. CONCLUSIONS: These results suggest that in human atherosclerosis, fractalkine, rather than mediating inflammatory cell recruitment, can act as a mediator of smooth muscle cell migration.


Assuntos
Arteriosclerose/metabolismo , Quimiocinas CX3C/metabolismo , Quimiotaxia/fisiologia , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/metabolismo , Adulto , Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Arteriosclerose/patologia , Complexo CD3/biossíntese , Contagem de Células , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Quimiocina CX3CL1 , Quimiocinas CX3C/farmacologia , Quimiotaxia/efeitos dos fármacos , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Receptores de Lipopolissacarídeos/biossíntese , Masculino , Proteínas de Membrana/farmacologia , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/patologia , Toxina Pertussis/farmacologia
4.
Iperception ; 3(10): 820-30, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23482297

RESUMO

The scintillating grid illusion is an intriguing stimulus consisting of a grey grid on a black background, with white discs at the grid intersections. Most viewers perceive illusory "scintillating" black discs within the physical white discs, especially at non-fixated locations. Here, we report for the first time that this scintillation percept is stronger when the stimulus is viewed binocularly than when it is presented to only one eye. Further experiments indicate that this is not simply because two monocular percepts combine linearly, but involves a specifically cyclopean contribution (Schrauf & Spillmann, 2000). However, the scintillation percept does not depend on the absolute disparity of the stimulus relative to the screen. In an intriguing twist, although the basic illusion shows more scintillation when viewed binocularly, when the illusion is weakened by shifting the discs away from the grid intersections, scintillation becomes stronger with monocular viewing.

5.
J Immunol ; 178(8): 4975-83, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17404279

RESUMO

In vitro the mannose receptor (MR) mediates Ag internalization by dendritic cells (DC) and favors the presentation of mannosylated ligands to T cells. However, in vivo MR seems to play a role not in Ag presentation but in the homeostatic clearance of endogenous ligands, which could have the secondary benefit of reducing the levels of endogenous Ag available for presentation to the adaptive immune system. We have now observed that while MR(+) cells are consistently absent from T cell areas of spleen and mesenteric lymph nodes (LN), peripheral LN of untreated adult mice contain a minor population of MR(+)MHCII(+) in the paracortex. This novel MR(+) cell population can be readily identified by flow cytometry and express markers characteristic of DC. Furthermore, these MR(+) DC-like cells located in T cell areas can be targeted with MR ligands (anti-MR mAb). Numbers of MR(+)MHCII(+) cells in the paracortex are increased upon stimulation of the innate immune system and, accordingly, the amount of anti-MR mAb reaching MR(+)MHCII(+) cells in T cell areas is dramatically enhanced under these conditions. Our results indicate that the MR can act as an Ag-acquisition system in a DC subpopulation restricted to lymphoid organs draining the periphery. Moreover, the effect of TLR agonists on the numbers of these MR(+) DC suggests that the immunogenicity of MR ligands could be under the control of innate stimulation. In accordance with these observations, ligands highly specific for the MR elicit enhanced humoral responses in vivo only when administered in combination with endotoxin.


Assuntos
Apresentação de Antígeno , Células Dendríticas/fisiologia , Lectinas Tipo C/fisiologia , Lectinas de Ligação a Manose/fisiologia , Receptores de Superfície Celular/fisiologia , Animais , Anticorpos Monoclonais/imunologia , Citometria de Fluxo , Imunidade Inata , Imunização , Imunoglobulina G/biossíntese , Lectinas Tipo C/análise , Lectinas Tipo C/imunologia , Lipopolissacarídeos/farmacologia , Receptor de Manose , Lectinas de Ligação a Manose/análise , Lectinas de Ligação a Manose/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ratos , Receptores de Superfície Celular/análise , Receptores de Superfície Celular/imunologia , Pele/citologia
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