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1.
J Immunol Methods ; 507: 113310, 2022 08.
Article in English | MEDLINE | ID: mdl-35787393

ABSTRACT

Crescentic glomerulonephritis (cGN) is the most aggressive form of glomerulonephritis in humans. A widely studied mouse model is induced by sheep or rabbit antisera raised against murine renal cortical antigens. We here, report that Alpaca readily produce ample amounts of antisera that induces pathology in mice, resembling human disease regarding crescent formation, proteinuria, infiltrating immune cells and a significant Th1, but not Th17 immune response. Alpaca antiserum did not cause end-stage kidney failure, neither in a passive nor in an accelerated experimental setting, which may be advantageous for long term studies of crescentic glomerulonephritis.


Subject(s)
Camelids, New World , Glomerulonephritis , Animals , Glomerulonephritis/etiology , Glomerulonephritis/pathology , Humans , Immune Sera , Mice , Mice, Inbred C57BL , Proteinuria/complications , Rabbits , Sheep
2.
Immunol Cell Biol ; 96(8): 852-862, 2018 09.
Article in English | MEDLINE | ID: mdl-29617057

ABSTRACT

Regulatory T cells (Tregs) maintain self-tolerance and prevent autoimmunity by controlling autoreactive T cells. We recently demonstrated in vivo that Tregs can directly suppress auto-reactive B cells via programmed death ligand 1 (PD-L1) that ligated PD-1 on B cells and caused them to undergo apoptosis. Here, we asked whether this mechanism is utilized by thymus-derived natural Tregs and/or by peripheral lymphoid tissue-induced Tregs. We first demonstrated that antigen-specific PD-L1-expressing Tregs were induced in the draining lymph node of autoantigen-expressing tissue and characterized them by their lack of the transcription factor Helios and of the surface marker Neuropilin-1 (Nrp-1). Next, we established an in vitro co-culture system to study the interaction between B cells and Treg subsets under controlled conditions. We found that Nrp- Treg, but not Nrp+ Treg suppressed autoreactive B cells, whereas both were able to suppress T-helper cells. Such suppression was antigen-specific and was facilitated by PD-L1/PD-1-induced apoptosis. Furthermore, it required physical cell contact and was MHC II-restricted, providing an explanation for the antigen-specificity of peripherally-induced Tregs. These findings identify a role for peripherally induced Helios- Nrp-1- inducible Treg in controlling peripheral B-cell tolerance against tissue auto-antigens.


Subject(s)
B-Lymphocytes/immunology , B7-H1 Antigen/metabolism , T-Lymphocytes, Regulatory/immunology , Animals , Apoptosis , Autoantigens/immunology , Autoimmunity , DNA-Binding Proteins/metabolism , Forkhead Transcription Factors/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuropilin-1/metabolism , Self Tolerance , Transcription Factors/metabolism
3.
Matrix Biol ; 68-69: 280-292, 2018 08.
Article in English | MEDLINE | ID: mdl-29221812

ABSTRACT

Chronic kidney diseases can lead to kidney fibrosis, which can be considered a futile attempt of tissue healing to replaces functional kidney tissue with connective tissue, basically forming a scar. Chronic inflammation is a frequent cause of kidney fibrosis. Classical as well as recently discovered immune cell subsets and their molecular mediators have been intensively investigated for their contribution to kidney fibrosis and their potential as therapeutic targets. Here we review the current knowledge about the role of immune cells in crystal-induced renal fibrosis.


Subject(s)
Kidney/pathology , Lymphocytes/immunology , Myeloid-Derived Suppressor Cells/immunology , Renal Insufficiency, Chronic/immunology , Crystallization , Fibrosis , Humans , Immunity, Innate , Inflammasomes/metabolism , Kidney/immunology , Renal Insufficiency, Chronic/complications
4.
Kidney Int ; 90(3): 525-39, 2016 09.
Article in English | MEDLINE | ID: mdl-27262364

ABSTRACT

Intrarenal crystal formation activates the Nlrp3 inflammasome in myeloid cells and triggers a profound inflammatory response. Here, we studied whether a specific inhibitor of the Nlrp3 inflammasome, CP-456,773, can prevent kidney fibrosis in a murine model of crystal nephropathy induced by diets rich in oxalate or adenine. Inflammasome activation in renal dendritic cells and the resulting interleukin (IL)-1ß and IL-18 production were markedly reduced by CP-456,773 treatment both ex vivo and in vivo. We directly visualized intrarenal inflammasome activation and its inhibition by CP-456,773 in vivo by adoptive transfer of bone marrow cells transduced with interleukin-1ß-Gaussia luciferase, a proteolytic luciferase-based reporter for inflammasome activation, into irradiated mice. CP-456,773 treatment strongly attenuated kidney fibrosis when given early in the genesis of crystal nephropathy, but was unable to reverse established crystal-induced fibrosis. The urinary IL-18 concentration appeared to be a useful noninvasive biomarker for renal inflammasome activation. Finally, NLRP3 inhibition did not compromise adaptive immune responses as previously reported for the global inhibition of IL-1 signaling. Thus, early NLRP3 inhibition by CP-456,773 may be an effective treatment for crystal nephropathy. Use of iGLuc transfected cells introduces a novel imaging technique for inflammasome activation in mice.


Subject(s)
Dendritic Cells/metabolism , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Inflammasomes/drug effects , Kidney/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Nephritis/drug therapy , Sulfones/therapeutic use , Adenine/adverse effects , Adoptive Transfer , Animals , Cells, Cultured , Disease Models, Animal , Fibrosis , Furans , Humans , Immunohistochemistry , Indenes , Inflammasomes/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Kidney/cytology , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Nephritis/chemically induced , Oxalates/adverse effects , Primary Cell Culture , Signal Transduction , Sulfonamides
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