RESUMEN
BACKGROUND: Cell transplantation-based treatments for neurological disease are promising, yet graft rejection remains a major barrier to successful regenerative therapies. Our group and others have shown that long-lasting tolerance of transplanted stem cells can be achieved in the brain with systemic application of monoclonal antibodies blocking co-stimulation signaling. However, it is unknown if subsequent injury and the blood-brain barrier breach could expose the transplanted cells to systemic immune system spurring fulminant rejection and fatal encephalitis. Therefore, we investigated whether delayed traumatic brain injury (TBI) could trigger graft rejection. METHODS: Glial-restricted precursor cells (GRPs) were intracerebroventricularly transplanted in immunocompetent neonatal mice and co-stimulation blockade (CoB) was applied 0, 2, 4, and 6 days post-grafting. Bioluminescence imaging (BLI) was performed to monitor the grafted cell survival. Mice were subjected to TBI 12 weeks post-transplantation. MRI and open-field test were performed to assess the brain damage and behavioral change, respectively. The animals were decapitated at week 16 post-transplantation, and the brains were harvested. The survival and distribution of grafted cells were verified from brain sections. Hematoxylin and eosin staining (HE) was performed to observe TBI-induced brain legion, and neuroinflammation was evaluated immunohistochemically. RESULTS: BLI showed that grafted GRPs were rejected within 4 weeks after transplantation without CoB, while CoB administration resulted in long-term survival of allografts. BLI signal had a steep rise following TBI and subsequently declined but remained higher than the preinjury level. Open-field test showed TBI-induced anxiety for all animals but neither CoB nor GRP transplantation intensified the symptom. HE and MRI demonstrated a reduction in TBI-induced lesion volume in GRP-transplanted mice compared with non-transplanted mice. Brain sections further validated the survival of grafted GRPs and showed more GRPs surrounding the injured tissue. Furthermore, the brains of post-TBI shiverer mice had increased activation of microglia and astrocytes compared to post-TBI wildtype mice, but infiltration of CD45+ leukocytes remained low. CONCLUSIONS: CoB induces sustained immunological tolerance towards allografted cerebral GRPs which is not disrupted following TBI, and unexpectedly TBI may enhance GRPs engraftment and contribute to post-injury brain tissue repair.
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Lesiones Traumáticas del Encéfalo , Rechazo de Injerto/inmunología , Tolerancia Inmunológica/inmunología , Células-Madre Neurales/trasplante , Trasplante de Células Madre/métodos , Aloinjertos , Animales , Anticuerpos Monoclonales/farmacología , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-2/antagonistas & inhibidores , Antígenos CD28/antagonistas & inhibidores , Antígenos CD40/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Neuroglía/trasplanteRESUMEN
Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children, and it is well known for its multifactorial causes which are the manifestation of the disease. Proteinuria is an early consequence of podocyte injury and a typical sign of kidney disease. Steroid-sensitive patients react well with glucocorticoids, but there is a high chance of multiple relapses. CD80, also known as B7-1, is generally expressed on antigen-presenting cells (APCs) in steroid-sensitive MCD patients. Various glomerular disease models associated with proteinuria demonstrated that the detection of CD80 with the increase of urinary CD80 was strongly associated closely with frequent-relapse MCD patients. The role of CD80 in MCD became controversial because one contradicts finding. This review covers the treatment alternatives for MCD with the insight of CD80 as a potential therapeutic target. The promising effectiveness of CD20 (rituximab) antibody and CD80 inhibitor (abatacept) encourages further investigation of CD80 as a therapeutic target in frequent-relapse MCD patients. Therapeutic-based antibody towards CD80 (galiximab) had never been investigated in MCD or any kidney-related disease; hence, the role of CD80 is still undetermined. A new therapeutic approach towards MCD is essential to provide broader effective treatment options besides the general immunosuppressive agents with gruesome adverse effects.
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Antígeno B7-1/antagonistas & inhibidores , Biomarcadores/metabolismo , Enfermedades Renales/tratamiento farmacológico , Nefrosis Lipoidea/tratamiento farmacológico , Animales , Antígeno B7-1/metabolismo , Humanos , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Terapia Molecular Dirigida , Nefrosis Lipoidea/metabolismo , Nefrosis Lipoidea/patología , RecurrenciaRESUMEN
Discovery of the B7 family immune checkpoints such as CTLA-4 (CD152), PD-1 (CD279), as well as their ligands B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), and B7-DC (PD-L2, CD273), has opened new possibilities for cancer immunotherapy using monoclonal antibodies (mAb). The blockade of inhibitory receptors (CTLA-4 and PD-1) with specific mAb results in the activation of cancer patients' T lymphocytes and tumor rejection. However, the use of mAb in clinics has several limitations including side effects and cost of treatment. The development of new low-molecular compounds that block immune checkpoints' functional activity can help to overcome some of these limitations. In this paper, we describe a synthetic peptide (p344) containing 14 amino acids that specifically interact with CTLA-4 protein. A 3D computer model suggests that this peptide binds to the 99MYPPPY104 loop of CTLA-4 protein and potentially blocks the contact of CTLA-4 receptor with B7-1 ligand. Experimental data confirm the peptide-specific interaction with CTLA-4 and its ability to partially block CTLA-4/B7-1 binding. The identified synthetic peptide can be used for the development of novel immune checkpoint inhibitors that can block CTLA-4 functional activity for cancer immunotherapy.
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Antígeno CTLA-4 , Inhibidores de Puntos de Control Inmunológico , Proteínas de Neoplasias , Neoplasias/tratamiento farmacológico , Péptidos , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-1/química , Antígeno B7-1/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/química , Antígeno CTLA-4/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/química , Inhibidores de Puntos de Control Inmunológico/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Neoplasias/química , Neoplasias/metabolismo , Péptidos/química , Péptidos/farmacologíaRESUMEN
The bark of Rhus verniciflua Stokes (RVS) has been used to treat cancer in Korean herbal medicine. When we screened for PD-1 and CTLA-4 immune checkpoint inhibitors (PD-1/PD-L1 CTLA-4/CD80) from around 800 herbal extracts using competitive Enzyme-Linked Immunosorbent Assay (ELISA), we found that RVS blocked both the PD-1/PD-L1 and the CTLA-4/CD80 interactions. To identify the active compounds from RVS, we performed bioactivity-guided fractionation, and the ethyl acetate (EtOAc) fraction of RVS proved to be the most effective at blocking the PD-1/PD-L1 and CTLA-4/CD80 interactions. In addition, we isolated and identified 20 major compounds in the EtOAc fraction of RVS and then examined the blocking effects of these 20 compounds on PD-1/PD-L1 and CTLA-4/CD80. Among them, four compounds [eriodictyol (7) > fisetin (9) > quercetin (18) > liquiritigenin (13)] blocked the interaction of PD-1/PD-L1 on competitive ELISA. In addition, four different compounds [protocatechuic acid (2) > caffeic acid (19) > taxifolin (5) > butin (6)] blocked the interaction of CTLA-4/CD80. Our findings suggest that RVS and its components could be used as a potential immune checkpoint inhibitor blockade and could be developed for immuno-oncological therapeutics.
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Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-H1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Rhus/química , Acetatos/química , Benzopiranos/farmacología , Flavanonas/farmacología , Flavonoides/farmacología , Flavonoles , Humanos , Fitoquímicos/química , Fitoterapia/métodos , Quercetina/farmacologíaRESUMEN
INTRODUCTION: Since the approval of belatacept in 2011 for use in the setting of de novo kidney transplantation, this CD80/86 - CD28 co-stimulation blocker has been shown to be a valuable treatment option for maintenance immunosuppression. Areas covered: In this setting, belatacept has been associated with superior glomerular filtration rate as compared to calcineurin inhibitor-based treatments because of the absence of nephrotoxicity. Additionally, belatacept avoids the cardiovascular side effects (e.g. hypertension and dyslipidemia) caused by a CNI-based-regimen. Nevertheless, belatacept-treated recipients have a higher rate of acute rejections and a higher risk of lymphoproliferative disorders. Expert opinion: Data suggest a benefit from early conversion vs. late conversion of belatacept in a conversion setting following CNI-related toxicity. Randomized studies are currently comparing belatacept to tacrolimus, instead of cyclosporine, as was done in the Belatacept Evaluation of Nephroprotection and Efficacy as a First-line Immunosuppression Trial (BENEFIT). The benefits and limitations of belatacept seem to be the same when tacrolimus is used instead of cyclosporine. Finally, we also report in this review on the immunological data available so far that explain belatacept's limitations and the higher rate of acute rejection. The goal is to find the optimal immunosuppressive strategy to improve efficacy and safety at post-transplantation.
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Abatacept/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Riñón/metabolismo , Animales , Antígeno B7-1/antagonistas & inhibidores , Antígenos CD28/antagonistas & inhibidores , Ensayos Clínicos como Asunto , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
The damage and loss of podocytes is a primary hallmark of nephrotic syndrome. In the pursuit of targetable molecules that are involved in podocyte pathophysiology, some studies have identified B7-1 (also known as CD80) as a potential biomarker. Furthermore, B7-1 blockade has been proposed as a podocyte-specific treatment for patients with nephrotic syndrome who have limited therapeutic options, such as those with focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy and lupus nephritis. In this Perspectives article, we describe and compare supporting and contradicting data on the role of podocyte B7-1 in the pathogenesis of various podocytopathies. Moreover, we highlight crucial issues that should be addressed urgently - such as standardization of sample processing time, material conservation and antibody usage in immunohistochemical protocols - as a clinical trial that is investigating the efficacy of B7-1 blockade in treatment-resistant nephrotic syndrome is ongoing.
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Antígeno B7-1/metabolismo , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Podocitos/metabolismo , Podocitos/patología , Abatacept/uso terapéutico , Animales , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-1/inmunología , Biomarcadores/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Renales/patología , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/metabolismo , Nefrosis Lipoidea/tratamiento farmacológico , Nefrosis Lipoidea/metabolismo , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/metabolismoRESUMEN
The cluster of differentiation protein complex, CD80/CD86, regulates Th1/Th2 differentiation in autoimmune disease. In order to establish the effects of CD80/CD86 on Th17 cell differentiation in acute viral myocarditis (VMC), we infected C57BL/6 mice with Coxsackie virus B3 (CVB3) and examined the effects of the treatment with anti-CD80/CD86 monoclonal antibodies (mAbs) on Th17 cell differentiation in vivo. The effects of anti-CD80/CD86 mAbs on Th17 cell differentiation were further evaluated in vitro. The treatment with anti-CD80 mAb induced marked suppression of Th17 cell differentiation and ROR-γt mRNA expression, whereas anti-CD86 mAb alone had no effect, both in vivo and in vitro. Our finding that CD80 regulates Th17 differentiation supports the potential utility of anti-CD80 mAb as an effective new immunotherapeutic target in acute VMC.
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Antígeno B7-1/inmunología , Diferenciación Celular , Infecciones por Coxsackievirus/inmunología , Enterovirus Humano B/inmunología , Miocarditis/inmunología , Miocardio/inmunología , Bazo/inmunología , Células Th17/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-1/metabolismo , Antígeno B7-2/inmunología , Antígeno B7-2/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Infecciones por Coxsackievirus/tratamiento farmacológico , Infecciones por Coxsackievirus/metabolismo , Infecciones por Coxsackievirus/virología , Modelos Animales de Enfermedad , Enterovirus Humano B/patogenicidad , Interacciones Huésped-Patógeno , Masculino , Ratones Endogámicos C57BL , Miocarditis/tratamiento farmacológico , Miocarditis/metabolismo , Miocarditis/virología , Miocardio/metabolismo , Miocardio/patología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Transducción de Señal , Bazo/efectos de los fármacos , Bazo/metabolismo , Bazo/virología , Células Th17/efectos de los fármacos , Células Th17/metabolismo , Células Th17/virologíaRESUMEN
Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease. Autoantibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4+ T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co-stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG. The effect of CD28 blockade on lupus nephritis onset, survival, production of anti-ds DNA antibodies and costimulatory molecules was evaluated. CD28 blockade prevented the development of lupus nephritis and prolonged survival during the 3-month treatment and 12 weeks after. Furthermore, the production of anti-ds DNA autoAbs was decreased. Lastly, the protective effect of CD28 blockade was associated with increased intrarenal expression of the immunoregulatory molecule, Indoleamine 2, 3-dioxygenase, of the co-inhibitory receptor programmed cell-Death - 1 (PD-1) and of its ligand programmed death ligand - 1 (PDL-1).In conclusion, CD28 blockade prevented the development of lupus nephritis in NZB/NZW F1 mice. This immunomodulatory strategy is a promising candidate for SLE therapy in humans.
Asunto(s)
Anticuerpos Antinucleares/sangre , Autoanticuerpos/sangre , Antígenos CD28/antagonistas & inhibidores , Inmunoterapia/métodos , Nefritis Lúpica/prevención & control , Animales , Anticuerpos Antinucleares/inmunología , Autoanticuerpos/inmunología , Linfocitos B/inmunología , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-1/inmunología , Antígeno B7-1/metabolismo , Antígeno B7-2/antagonistas & inhibidores , Antígeno B7-2/inmunología , Antígeno B7-2/metabolismo , Antígenos CD28/inmunología , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Femenino , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Riñón/inmunología , Riñón/patología , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Ratones , Ratones Endogámicos NZB , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
OBJECTIVES: CD80/86 blockade to inhibit CD28 costimulation suppressed alloreactive human and murine CD4+ T cells but not alloreactive CD8+ T cells. In contrast, CD28 costimulation augments CD8+ T cell-mediated cell lysis in antigen-nonspecific stimulation. The present study was conducted to discern whether the CD80/86 blockade exerts therapeutic effects on CD8+ T cell-mediated polymyositis (PM) models of mice and whether the effects could be attributable to direct suppression of autoantigen-specific CD8+ T cells. METHODS: C protein-induced myositis (CIM) was induced in mice with intradermal injection of C protein fragments. C protein peptide-induced myositis (CPIM), in which autoaggressive CD8+ T cells are activated without CD4+ T cell help, was induced in mice with intravenous injection of dendritic cells (DCs) loaded with CD8+ T cell-epitope peptides derived from the C protein fragment. The immunised mice were treated with CTLA4-Ig or anti-CD80 and anti-CD86 antibodies (anti-CD80/86 Abs). The muscles were evaluated histologically 21 days after the C protein immunisation or 7 days after the DC injection. RESULTS: CIM was suppressed in the mice treated with CTLA4-Ig or anti-CD80/86 Abs administered prophylactically from the day of immunisation and therapeutically after the disease onset. CPIM was suppressed when CTLA4-Ig was administered concurrently with the DC injection. CONCLUSIONS: The CD80/86 blockade was effective in PM models of mice. Amelioration of CPIM indicates direct suppression of CD8+ T cells by the CD80/86 blockade. CTLA4-Ig should be a potential therapeutic agent of PM and other CD8+T cell-mediated diseases by suppressing both autoantigen-specific CD4+ and CD8+ T cells.
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Abatacept/farmacología , Anticuerpos/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Polimiositis/inmunología , Animales , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-2/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Modelos Animales de Enfermedad , Ratones , Músculo Esquelético/inmunologíaAsunto(s)
Abatacept/uso terapéutico , Antígeno B7-1/antagonistas & inhibidores , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Síndrome Nefrótico/tratamiento farmacológico , Podocitos/inmunología , Proteinuria/tratamiento farmacológico , Animales , Proliferación Celular , Glomeruloesclerosis Focal y Segmentaria/inmunología , Humanos , Ratones , Síndrome Nefrótico/inmunología , Proteinuria/inmunologíaRESUMEN
In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4. Belatacept has been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, that is, no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending.
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Antígenos CD28/antagonistas & inhibidores , Antígenos CD40/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-2/antagonistas & inhibidores , Inhibidores de la Calcineurina/uso terapéutico , HumanosRESUMEN
Blocking of costimulatory CD28/B7 and CD40/CD40L interactions is an experimental approach to immune suppression and tolerance induction. We previously reported that administration of a combination of CTLA-4Ig and MR1 (anti-CD40L mAb) for blockade of these interactions induces tolerance in a fully mismatched allogeneic splenocyte transfer model in mice. We now used this model to study whether regulatory T cells (Tregs) contribute to immune suppression and why both pathways have to be blocked simultaneously. Mice were injected with allogeneic splenocytes, CD4(+) T cells, or CD8(+) T cells and treated with MR1 mAb and different doses of CTLA-4Ig. The graft-versus-host reaction of CD4(+) T cells, but not of CD8(+) T cells, was inhibited by MR1. CTLA-4Ig was needed to cover CD8(+) T cells but had only a weak effect on CD4(+) T cells. Consequently, only the combination provided full protection when splenocytes were transferred. Importantly, MR1 and low-dose CTLA-4Ig treatment resulted in a relative increase in Tregs, and immune suppressive efficacy was abolished in the absence of Tregs. High-dose CTLA-4Ig treatment, in contrast, prevented Treg expansion and activity, and in combination with MR1 completely inhibited CD4(+) and CD8(+) T cell activation in a Treg-independent manner. In conclusion, MR1 and CTLA-4Ig act synergistically as they target different T cell populations. The contribution of Tregs to immune suppression by costimulation blockade depends on the concentration of CTLA-4Ig and thus on the degree of available CD28 costimulation.
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Enfermedad Injerto contra Huésped/inmunología , Tolerancia Inmunológica/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-1/inmunología , Antígenos CD28/antagonistas & inhibidores , Antígenos CD28/inmunología , Antígenos CD40/antagonistas & inhibidores , Antígenos CD40/inmunología , Ligando de CD40/antagonistas & inhibidores , Ligando de CD40/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Terapia de Inmunosupresión , RatonesRESUMEN
Acute brain injuries can activate bidirectional crosstalk between the injured brain and the immune system. The immune system, particularly T lymphocytes and cytokines, has been implicated in the progression of brain injury after intracerebral hemorrhage (ICH). Co-stimulatory molecules B7-1 (CD80)/B7-2 (CD86) binding cognate receptor provides a secondary signaling to T cell activation. The aim of our study was to explore the effects of anti-B7-1 antibody on the development and prognosis of cerebral hemorrhage and to investigate the possible underlying mechanism. Mice were inner canthus veniplex administered with anti-B7-1 antibody at 10 min and 24 h after ICH and sacrificed on the third day after ICH. Immune function was assessed via splenocyte proliferation assay and organism index, respectively. IFN-γ and IL-4 were detected by enzyme-linked immuno sorbent assay. The cerebral edema was evaluated via brain water content. The levels of autophagy and apoptosis related proteins were measured by western blotting analysis. In addition, functional outcome was studied with pole-climbing test and morris water maze. The mice were weighed on 0, 1, 3, 14 and 21 days after ICH. The treatment with anti-B7-1 antibody significantly lowered immune function, and reduced the latency of water maze on 18 and 20 days, the ratio of IFN-γ/IL-4 as well as body weight on day 3 after cerebral hemorrhage. Our study suggests that in the cerebral hemorrhage mice brain anti-B7-1 antibody may reduce long-range brain damage by reversing immune imbalance.
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Antígeno B7-1/inmunología , Lesiones Encefálicas/inmunología , Antígenos CD28/inmunología , Hemorragia Cerebral/inmunología , Modelos Animales de Enfermedad , Inmunidad Celular/fisiología , Animales , Anticuerpos Antiidiotipos/farmacología , Anticuerpos Antiidiotipos/uso terapéutico , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-1/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Antígenos CD28/antagonistas & inhibidores , Antígenos CD28/metabolismo , Células Cultivadas , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Inmunidad Celular/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/fisiología , Masculino , Ratones , Ratones Endogámicos ICR , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
FSGS is a common glomerular disorder that has a high propensity for recurrence after kidney transplant. The pathophysiology of FSGS is unknown, but podocytes seem to be the target of one or several circulating factors that lead to cytoskeleton reorganization and proteinuria. Research on podocytes has identified B7-1 as an important factor in podocyte biology and a new therapeutic target in renal disease. Indeed, in four patients with recurrent FSGS after transplant, treatment with the B7-1 blocker abatacept was associated with proteinuria remission. Here, we prospectively treated nine patients with recurrent FSGS after transplant using either abatacept or belatacept, a B7-1 blocker with higher affinity, and did not induce proteinuria remission. Furthermore, we did not detect B7-1 expression by immunofluorescence in podocytes of biopsy specimens from these or other kidney grafts or podocytes of native kidney biopsy specimens. In conclusion, B7-1 blockade did not induce FSGS remission after transplant in our study.
Asunto(s)
Abatacept/farmacología , Abatacept/uso terapéutico , Antígeno B7-1/antagonistas & inhibidores , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Síndrome Nefrótico/etiología , Síndrome Nefrótico/prevención & control , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
The aim of the present study was to evaluate the effects of the B7/cluster of differentiation (CD)28 signaling pathway on experimental lupus nephritis and examine the molecular mechanism involved by inhibiting the B7/CD28 signaling pathway. A lupus nephritis model in C57BL/6 J mice was induced via intraperitoneal injection of pristane. A recombinant B71 short hairpin RNA (shRNA) lentivirus vector was constructed by synthesis and splicing. A neutralizing mouse antihuman B71 antibody termed 4E5 was also prepared. The mouse model of lupus nephritis was treated with B71 shRNA and 4E5 via injection through the tail vein. The silencing effects of B71 shRNA lentiviral infection on target molecules were evaluated using immunofluorescence and flow cytometry. The levels of protein in the urine were detected using Albustix test paper each month over 10 months. The concentration of interleukin (IL)4 and interferonγ in the serum was determined using an ELISA. The immune complex (IC) deposits in the kidney were analyzed using direct immunofluorescence. The results demonstrated that the C57BL/6 J mouse lupus nephritis model was successfully constructed with immune cells activated in the spleen of the mice, increases in the concentration of antinuclear antibody (ANA) and antidouble stranded DNA antibodies as well as positive IC formation. Following B71 shRNA lentivirus or 4E5 treatment, CD11b+B71+, CD11c+B71+ and CD21+B71+ cells in the spleen of the mice were significantly reduced. The concentration of ANA and IL4 in the serum was also decreased. The concentration of urine protein was reduced and it was at its lowest level in the 4E5 early intervention group. It was also revealed that the immunofluorescence intensity of the IC deposits was weak in the 4E5 early intervention group. In conclusion, inhibiting the B71/CD28 signaling pathway is able to alleviate experimental lupus nephritis and provides an experimental basis for the therapeutic use of blocking the B71/CD28 signaling pathway in human lupus nephritis and other autoimmune disorders.
Asunto(s)
Antígeno B7-1/metabolismo , Antígenos CD28/metabolismo , Nefritis Lúpica/patología , Animales , Anticuerpos Antinucleares/sangre , Autoanticuerpos/sangre , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-1/genética , Línea Celular , Modelos Animales de Enfermedad , Femenino , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Células HEK293 , Humanos , Interferón gamma/sangre , Interleucina-4/sangre , Células K562 , Riñón/metabolismo , Riñón/patología , Riñón/ultraestructura , Lentivirus/genética , Nefritis Lúpica/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Interferencia de ARN , Transducción de Señal , Bazo/citología , Bazo/metabolismo , Terpenos/químicaRESUMEN
Prostaglandin E2 (PGE2) favors multiple aspects of tumor development and immune evasion. Therefore, microsomal prostaglandin E synthase (mPGES-1/-2), is a potential target for cancer therapy. We explored whether inhibiting mPGES-1 in human and mouse models of breast cancer affects tumor-associated immunity. A new model of breast tumor spheroid killing by human PBMCs was developed. In this model, tumor killing required CD80 expression by tumor-associated phagocytes to trigger cytotoxic T cell activation. Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE2, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression. Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice. Macrophages of mPGES-1(-/-) PyMT mice indeed expressed elevated levels of CD80 compared to their wildtype counterparts. CD80 expression in tumor-spheroid infiltrating mPGES-1(-/-) macrophages translated into antigen-specific cytotoxic T cell activation. In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth. We propose that mPGES-1 inhibition in combination with immune cell activation might be part of a therapeutic strategy to overcome the immunosuppressive tumor microenvironment.
Asunto(s)
Antígeno B7-1/antagonistas & inhibidores , Neoplasias de la Mama/metabolismo , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Macrófagos/metabolismo , Animales , Antígeno B7-1/biosíntesis , Antígeno B7-1/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Dinoprostona/metabolismo , Femenino , Humanos , Oxidorreductasas Intramoleculares/metabolismo , Células MCF-7 , Macrófagos/inmunología , Ratones , Ratones Noqueados , Prostaglandina-E Sintasas , Transducción de Señal , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Microambiente TumoralRESUMEN
The care of patients with rheumatoid arthritis (RA) has been revolutionized since the 1990s. Strict monitoring and disease control based on measurement of signs and symptoms towards a target of low disease activity have improved outcome of patients enormously. As a result of treatment strategies based upon individualized measurement of disease activity, the clinical view of RA has changed from a destructive autoimmune disease (with a median joint damage of >10 Sharp units per year) to a condition in which significant damage can be prevented in the majority of patients. Moreover, a large number of targeted therapies (tumour necrosis factor, IL6, CD80/CD86 and CD20 inhibitors) have become available to better treat the underlying disease process. However, identification of the underlying pathways that drive the disease process in an individual patient has been relatively unsuccessful, implying that no predictive factors have been identified to guide the choice of a specific treatment. Distinct subsets of RA patients have been identified, based on the presence or absence of anticitrullinated protein antibodies (ACPAs). These two subsets are associated with different environmental and genetic risk factors, histology and disease outcome (a more destructive disease course with more persistent joint inflammation is observed when ACPAs are present). Therefore, it is recommended that treatment should be guided towards a more consistently low level of disease activity in the presence of ACPAs than in the absence of the antibodies.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/terapia , Autoanticuerpos/sangre , Medicina de Precisión , Algoritmos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Artritis Reumatoide/inmunología , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-2/antagonistas & inhibidores , Citrulina/inmunología , Medicina Basada en la Evidencia , Humanos , Infliximab , Interleucina-6/antagonistas & inhibidores , Factores de Riesgo , Rituximab , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND: Atherosclerosis is based on a chronic inflammatory process including the innate and adaptive immune response. Costimulatory molecules and their receptors provide decisive signals for antigen-specific cell activation. The contribution of B7-related pathways to atherosclerosis has hardly been explored. METHODS: In the present study, we investigated the contribution of B7-1 to inflammation and tissue injury in the human plaque microenvironment in order to identify possible target structures of future therapeutic agents ex vivo and in vitro. RESULTS: Carotid artery plaque stimulation with lipopolysaccharides (LPS) could be significantly inhibited by RhuDex(®), a specific inhibitor of the costimulatory molecule B7-1 ex vivo (P<0.001). Coculture of antigen-presenting cells with T-cells demonstrated that the inhibitory effects of RhuDex(®) derived from reduced T-cell activation. In addition, incubation of monocytes/macrophages with LPS and RhuDex(®) resulted in an inhibitory negative feedback on antigen-presenting cells. Signaling pathways affected by RhuDex(®) seem to be nuclear transcription factor kappa B, activator protein-1, and extracellular signal-regulated kinase 1/2. CONCLUSION: The present data support B7-1 alone as an important costimulatory molecule in the context of LPS-mediated inflammation in atherosclerotic lesions. Due to its marked inhibitory effects, RhuDex(®) may be a useful therapy to modulate the inflammatory milieu in atherosclerosis.
Asunto(s)
Aterosclerosis/patología , Antígeno B7-1/antagonistas & inhibidores , Inflamación/prevención & control , Aterosclerosis/inmunología , Antígeno B7-1/fisiología , Quimiocinas/biosíntesis , Citocinas/biosíntesis , Humanos , Inflamación/etiología , Lipopolisacáridos/farmacología , Activación de Linfocitos/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
We report a 17-yr-old boy who developed a microangiopathic hemolytic anemia presumed secondary to tacrolimus shortly following a living-related donor renal transplant. This was initially managed by plasmapheresis. Reinstitution of calcineurin inhibition using cyclosporine led to recurrence of hemolysis, so an alternative agent was needed. He was commenced on monthly intravenous belatacept, with no further recurrence of the hemolysis, and subsequent stable graft function. Modulation via CTLA-4 offers an alternative immunosuppressive tactic if current regimens produce graft threatening adverse effects. The method of administration and frequency of dosage of belatacept also lends itself well to the high-risk period of adolescence and transition. We propose that belatacept may therefore also have utility in difficult cases complicated by poor concordance, common in the adolescent age group.
Asunto(s)
Anemia Hemolítica/tratamiento farmacológico , Calcineurina/química , Inmunoconjugados/uso terapéutico , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Complicaciones Posoperatorias/prevención & control , Abatacept , Adolescente , Anemia Hemolítica/etiología , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-2/antagonistas & inhibidores , Antígeno CTLA-4/metabolismo , Rechazo de Injerto , Hemólisis , Humanos , Terapia de Inmunosupresión/métodos , Donadores Vivos , Masculino , Plasmaféresis , Recurrencia , Tacrolimus/efectos adversos , Resultado del TratamientoRESUMEN
Mycoplasma arthritidis is a natural pathogen of rodents causing arthritis, toxic shock and necrotizing fasciitis. It secretes a potent superantigen (SAg), MAM, that differentially affects the immune system depending upon presence or absence of TLR4, thus potentially influencing disease outcomes. Here, we establish that antibody to co-stimulatory molecule B7-1(CD80) enhances arthritis in wild-type C3H/HeSnJ (TLR2+4+) mice but suppresses arthritis in TLR4-defect C3H/HeJ (TLR2+4-) mice. Also, blockade of the B7-1/CD28 co-stimulatory pathway in C3H/HeSnJ mice resulted in a marked increase in an alternative co-stimulatory pathway ICOS/ICOSL that was associated with elevation of the IL-17/Th17cascade with enhanced IL-23, IL-6, and the RORγt and STAT3 transcriptional factors on CD4+ T cells. Anti- B7-1 also increased inflammatory chemokines and the stress protein HMGB1 that promotes cellular infiltration to joints. Using a MAM-deficient strain of M. arthritidis, a monoclonal antibody to TLR4 and a TLR4-defective mouse strain, we established that both MAM and TLR4 are required for the systemic and local joint triggering of the Th17/IL-17 cascade in mice treated with anti-B7-1 antibody. Importantly, blocking of IL-17 with anti-IL-17 antibody suppressed the elevated arthritis in M. arthritidis-infected mice treated with anti-B7-1 antibody. Thus, this unique model of arthritis illustrates how microbial agonists can bridgeinnate and adaptive immune responses to redirect signalling pathways, thus promoting chronic inflammatory and autoimmune disease.