Adoptive transfer of autoimmune splenic dendritic cells to lupus-prone mice triggers a B lymphocyte humoral response.
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ABSTRACT:
SUBMITTER: Sauma D
PROVIDER: S-EPMC5544790 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown cause characterized by expansion of autoreactive lymphocytes. Regulatory T cells (T(regs)) are a component of the normal immune system and contribute to the maintenance of peripheral tolerance. T(reg) abnormalities have been associated with several autoimmune diseases and there is interest in the role of T(regs) in SLE. We previously demonstrated that transfer of expanded CD4(+)CD25(+)CD62L(HI) T(regs) slows the development of lupus in (NZBxNZW)F(1) (B/W) mice. However in the absence of T(reg) specific surface antigens, cell purification remains a compromise between the breadth and purity of the population isolated. Importantly, purified populations always contain Foxp3(-) effector T cells (T(effs)) that theoretically could exacerbate autoimmunity in the recipient. Here we explore the impact of transferring the more comprehensive, but less pure T(reg) subset defined by CD4(+)CD25(+) expression on development of murine lupus. All cells were FACS sorted and expanded prior to adoptive transfer. Development of proteinuria and survival were measured. We found that exogenous expansion of CD4(+)CD25(+) cells produced a population containing 70-85% CD4(+)Foxp3(+)T(regs). Expanded T(regs) had higher CTLA-4 and Foxp3 expression, increased in vitro suppression capacity, and prolonged in vivo survival as compared to freshly isolated cells. Adoptive transfer of expanded CD4(+)CD25(+) T(regs) inhibited the onset of glomerulonephritis and prolonged survival in mice. Importantly the population of T(eff) contained within the adoptively transferred cells had reduced survival and proliferation capacity as compared to either co-transferred T(regs) or transferred T(effs) expanded in the absence of T(regs). These studies demonstrate that adoptive transfer of expanded CD4(+)CD25(+)Foxp3(+)T(regs) has the capacity to inhibit the onset of murine lupus and that this capacity is significant despite transfer of co-cultured T(eff) cells. These data indicate that when co-expanded with regulatory T cells, exogenously activated T(effs) from autoimmune patients may not pose a significant risk of promoting disease.
| S-EPMC2696596 | biostudies-literature
Project description:Adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE) is an inflammatory demyelination that recapitulates in mouse spinal cord (SC) the human multiple sclerosis disease. We now analyze previously reported cDNA array data from age-matched young female adult control and passively myelin antigen-sensitized EAE mice with regard to organizational principles of the SC transcriptome in autoimmune demyelination. Although AT-EAE had a large impact on immune response genes, broader functional and chromosomal gene cohorts were neither significantly regulated nor showed significant changes in expression coordination. However, overall transcriptional control was increased in AT-EAE and the proportions of transcript abundances were perturbed within each cohort. Striking likenesses and oppositions were identified in the coordination profiles of genes related to myelination, calcium signaling, and inflammatory response in controls that were substantially altered in AT-EAE. We propose that up- or down-regulation of genes linked to those targeted by the disease could potentially compensate for the pathological transcriptomic changes.
| S-EPMC2526015 | biostudies-literature
Project description:Fibrocytes are unique, fibroblast-like cells with diverse functions and the potential for immunomodulation, which prompted investigation of their previously unexplored role in sepsis. Specifically, the study goals were to determine if adoptive transfer of fibrocytes would affect outcome in sepsis and to define relevant immunopathologic changes associated with the outcomes. Initial in vitro studies demonstrated that naive T-cell proliferation was significantly increased in cocultures with tissue-derived fibrocytes as compared with culture either alone or with fibroblasts. In vivo, the adoptive transfer of fibrocytes at the time of cecal ligation and puncture significantly improved survival of mice compared with transfer of fibroblasts or saline. Septic mice had lower blood levels of interleukin 6 (IL-6) and markers of organ injury after fibrocyte transfer as well as a reduced bacterial burden. Locally, peritoneal lavage fluid yielded lower bacterial counts, lower IL-6, and reduced inflammatory cell counts when fibrocyte transfer was compared with saline. This was also accompanied by significant increases in splenic CD4(+) and CD8(+) T cells. In vitro stimulation of the splenic T cells demonstrated that, after cecal ligation and puncture and adoptive transfer, the percentages of both CD4(+) and CD8(+) T cells with intracellular interferon ? were increased, whereas those with IL-4 remained similar between the groups. Therefore, it appears the adoptive transfer of fibrocytes improves sepsis survival, lowers bacterial burden, and promotes the proliferation of splenic T cells with a T(H)1 phenotype. These results confirm the immunomodulatory effects of exogenous, tissue-derived fibrocytes in sepsis and suggest their potential in cell therapy.
| S-EPMC3733111 | biostudies-literature
Project description:BACKGROUNDHIV-infected patients with poor virologic control and multidrug-resistant virus have limited therapeutic options. The current study was undertaken to evaluate the safety, immunologic effects, and antiviral activity of peripheral lymphocytes transferred from an elite controller, whose immune system is able to control viral replication without antiretroviral medications, to an HLA-B*2705-matched progressor.METHODSApproximately 22 billion cells were collected from an elite controller by lymphapheresis and infused within 6 hours into a recipient with a preinfusion CD4+ T cell count of 10 cells/μL (1%) and HIV plasma viral load of 114,993 copies/mL.RESULTSDonor cells were cleared from the recipient's peripheral blood by day 8. A transient decrease in viral load to 58,421 (day 3) was followed by a rebound to 702,972 (day 6) before returning to baseline values by day 8. The decreased viral load was temporally associated with peak levels of donor T cells, including CD8+ T cells that had high levels of expression of Ki67, perforin, and granzyme B. Notably, recipient CD8+ T cells also showed increased expression of these markers, especially in HIV-specific tetramer-positive cells.CONCLUSIONThese results suggest that the adoptive transfer of lymphocytes from an HIV-infected elite controller to an HIV-infected patient with progressive disease may be able to perturb the immune system of the recipient in both positive and negative ways.TRIAL REGISTRATIONClinicalTrials.gov NCT00559416.FUNDINGIntramural Research Programs of the US NIH Clinical Center and the National Institute of Allergy and Infectious Diseases (NIAID); the National Cancer Institute.
| S-EPMC6795294 | biostudies-literature
Project description:Polymorphisms in the SLAM family of leukocyte cell surface regulatory molecules have been associated with lupus-like phenotypes in both humans and mice. The murine Slamf gene cluster lies within the lupus-associated Sle1b region of mouse chromosome 1. Non-autoreactive C57BL/6 (B6) mice that have had this region replaced by syntenic segments from other mouse strains (i.e. 129, NZB and NZW) are B6 congenic strains that spontaneously produce non-nephritogenic lupus-like autoantibodies. We have recently reported that genetic ablation of the SLAM family member CD48 (Slamf2) drives full-blown autoimmune disease with severe proliferative glomerulonephritis (CD48GN) in B6 mice carrying 129 sequences of the Sle1b region (B6.129CD48(-/-)). We also discovered that BALB/c mice with the same 129-derived CD48-null allele (BALB.129CD48(-/-)) have neither nephritis nor anti-DNA autoantibodies, indicating that strain specific background genes modulate the effects of CD48 deficiency. Here we further examine this novel model of lupus nephritis in which CD48 deficiency transforms benign autoreactivity into fatal nephritis. CD48GN is characterized by glomerular hypertrophy with mesangial expansion, proliferation and leukocytic infiltration. Immune complexes deposit in mesangium and in sub-endothelial, sub-epithelial and intramembranous sites along the glomerular basement membrane. Afflicted mice have low-grade proteinuria, intermittent hematuria and their progressive renal injury manifests with elevated urine NGAL levels and with uremia. In contrast to the lupus-like B6.129CD48(-/-) animals, neither BALB.129CD48(-/-) mice nor B6 × BALB/c F1.129CD48(-/-) progeny have autoimmune traits, indicating that B6-specific background genes modulate the effect of CD48 on lupus nephritis in a recessive manner.
| S-EPMC3110600 | biostudies-literature
Project description:ObjectiveTo characterize renal macrophages and dendritic cells (DCs) in 2 murine models of lupus nephritis.MethodsWe used a bead-based enrichment step followed by cell sorting to isolate populations of interest from young mice and nephritic mice. Cell morphology was examined by microscopy. Arginase and nitrite production was examined using biochemical assays. The antigen-presenting functions of the cells were determined using mixed lymphocyte reactions. Selected cytokine, chemokine, and Toll-like receptor (TLR) profiles were examined using real-time quantitative polymerase chain reaction.ResultsWe identified 2 populations of macrophages and 3 populations of DCs in both of our murine models of lupus (NZB/NZW and [NZW × BXSB]F1 mice). F4/80(high) macrophages, which were resident in normal kidneys and found to be increased in number during nephritis, did not produce either arginase or nitrite upon cytokine stimulation and acquired a mixed proinflammatory and antiinflammatory functional phenotype during nephritis that resembles the constitutively activated phenotype of gut F4/80(high) macrophages. The various cell types differed in their expression of chemokine receptors and TLRs, consistent with variability in their renal location. Resident renal CD103+ DCs were the best antigen-presenting cells and could easily be distinguished from CD11c(high) myeloid DCs that accumulated in large numbers during nephritis.ConclusionOur study highlights the heterogeneity of the macrophage/DC infiltrate in chronic lupus nephritis and provides an initial phenotypic and functional analysis of the different cellular components that can now be used to define the role of each cell subset in nephritis progression or amelioration. Of note, the dominant macrophage population that accumulates during nephritis has an acquired phenotype that is neither M1 nor M2 and may reflect failure of resolution of inflammation.
| S-EPMC4547797 | biostudies-literature
Project description:BACKGROUND:Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies. This disease causes disabling neuropsychiatric symptoms even in the absence of apparent inflammation in the central nervous system (CNS), but the mechanisms involved remain unknown. Innate immune-mediated inflammation has attracted attention as a pathogenic mechanism in neuropsychiatric diseases. METHODS:We investigated the CNS of lupus-prone mice focusing on innate immunity. Three strains of lupus-prone mice, FcγRIIB-/-Yaa, an F1 hybrid of NZB and NZW (NZB/NZW) mice, and MRL/Faslpr (MRL/lpr) mice were used to analyze CNS immunopathology. RESULTS:Flow cytometry analysis demonstrated the numbers of brain CD45+ cells were increased compared with controls in lupus-prone mice. Upregulation of MHC class I and PDCA1 was observed in microglia and CD11b+ myeloid cells of lupus-prone mice, indicating they were activated in response to interferons (IFN). Microglial gene expression analysis of FcγRIIB-/-Yaa mice revealed the upregulation of IFN-responsive genes and inflammation-related genes including Axl, Clec7a, and Itgax, which were previously reported in neurodegenerative conditions and primed conditions. Upregulated chemokine gene expressions including Ccl5 and Cxcl10 were concurrent with increased numbers of T cells and monocytes, especially Ly6Clo monocytes in the CNS. Upregulation of Axl, Clec7a, Itgax, Ccl5, and Cxcl10 was also observed in NZB/NZW mice, indicating common lupus pathology. The primed status of microglia in FcγRIIB-/-Yaa mice was also demonstrated by morphological changes such as enlarged cell bodies with hypertrophic processes, and hyperreactivity to lipopolysaccharide. Immunohistochemistry of FcγRIIB-/-Yaa mice indicated reactive responses of astrocytes and vascular endothelium. Behavioral studies of FcγRIIB-/-Yaa mice revealed depressive-like behavior and heat hyperalgesia in the forced swim test and the tail-flick test, respectively. CONCLUSIONS:Our data indicated that microglia in lupus exhibit a unique primed phenotype characterized by the upregulated expressions of neurodegeneration-related genes and IFN-responsive genes. Interaction with peripheral cells and brain resident cells was presumed to orchestrate neuroinflammation. Targeting innate immune cells, such as microglia and monocytes, may be a promising therapeutic approach for neuropsychiatric SLE.
| S-EPMC6936062 | biostudies-literature
Project description:ObjectiveTolerogenic dendritic cells (tDCs) are immunosuppressive cells with potent tolerogenic ability and are promising immunotherapeutic tools for treating rheumatoid arthritis (RA). However, it is currently unknown whether allogeneic tDCs (allo-tDCs) induce tolerance in RA, and whether the numbers of adoptively transferred allo-tDCs, or the requirement for pulsing with relevant auto-antigens are important.MethodstDCs were derived from bone marrow precursors of C57BL/B6 mice, which were induced in vitro by GM-CSF, IL-10 and TGF-β1. Collagen-induced arthritis (CIA) was modeled in D1 mice by immunization with type II collagen (CII) to test the therapeutic ability of allo-tDCs against CIA. Clinical and histopathologic scores, arthritic incidence, cytokine and anti-CII antibody secretion, and CD4(+)Th subsets were analyzed.ResultstDCs were characterized in vitro by a stable immature phonotype and a potent immunosuppressive ability. Following adoptive transfer of low doses (5×10(5)) of CII-loaded allo-tDCs, a remarkable anti-arthritic activity, improved clinical scores and histological end-points were found. Serological levels of inflammatory cytokines and anti-CII antibodies were also significantly lower in CIA mice treated with CII-pulsed allo-tDCs as compared with allo-tDCs. Moreover, treatment with allo-tDCs altered the proportion of Treg/Th17 cells.ConclusionThese findings suggested that allo-tDCs, especially following antigen loading, reduced the severity of CIA in a dose-dependent manner. The dampening of CIA was associated with modulated cytokine secretion, Treg/Th17 polarization and inhibition of anti-CII secretion. This study highlights the potential therapeutic utility of allo-tDCs in autoimmune arthritis and should facilitate the future design of allo-tDC immunotherapeutic strategies against RA.
| S-EPMC3812020 | biostudies-literature
Project description:Each year, up to one fifth of the United States population is infected with influenza virus. Although mortality rates are low, hundreds of thousands are hospitalized each year in the United States. Specific high risk groups, such as those with suppressed or dysregulated immune systems, are at greater danger for influenza complications. Respiratory infections are a common cause of hospitalizations and early mortality in patients with systemic lupus erythematosus (SLE); however, whether this increased infection risk is a consequence of the underlying dysregulated immune background and/or immunosuppressing drugs is unknown. To evaluate the influenza immune response in the context of lupus, as well as assess the effect of infection on autoimmune disease in a controlled setting, we infected lupus-prone MRL/MpJ-Fas(lpr) mice with influenza virus A PR/8/34 H1N1. Interestingly, we found that Fas(lpr) mice generated more influenza A virus specific T cells with less neutrophil accumulation in the lung during acute infection. Moreover, Fas(lpr) mice produced fewer flu-specific IgG and IgM antibodies, but effectively cleared the virus. Further, increased extrinsic apoptosis during influenza infection led to a delay in autoimmune disease pathology with decreased severity of splenomegaly and kidney disease. Following primary influenza A infection, Fas(lpr) mice had severe complications during the contraction and resolution phase with widespread severe pulmonary inflammation. Our findings suggest that influenza infection may not exacerbate autoimmune pathology in mice during acute infection as a direct result of virus induced apoptosis. Additionally, autoimmunity drives an enhanced antigen-specific T cell response to clear the virus, but persisting pulmonary inflammation following viral clearance may cause complications in this lupus animal model.
| S-EPMC4324011 | biostudies-literature
Project description:BXD2 mice spontaneously develop autoantibodies and subsequent glomerulonephritis, offering a useful animal model to study autoimmune lupus. Although initial studies showed a critical contribution of IL-17 and Th17 cells in mediating autoimmune B cell responses in BXD2 mice, the role of follicular helper T (Tfh) cells remains incompletely understood. We found that both the frequency of Th17 cells and the levels of IL-17 in circulation in BXD2 mice were comparable to those of wild-type. By contrast, the frequency of PD-1+ CXCR5+ Tfh cells was significantly increased in BXD2 mice compared with wild-type mice, while the frequency of PD-1+ CXCR5+ Foxp3+ follicular regulatory T (Tfr) cells was reduced in the former group. The frequency of Tfh cells rather than that of Th17 cells was positively correlated with the frequency of germinal center B cells as well as the levels of autoantibodies to dsDNA. More importantly, CXCR5+ CD4+ T cells isolated from BXD2 mice induced the production of IgG from naïve B cells in an IL-21-dependent manner, while CCR6+ CD4+ T cells failed to do so. These results together demonstrate that Tfh cells rather than Th17 cells contribute to the autoimmune germinal center reactions in BXD2 mice.
| S-EPMC4358919 | biostudies-literature