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Iron has been implicated in the pathogenesis of age-related retinal diseases, including age-related macular degeneration (AMD). Previous work showed that intravitreal (IVT) injection of iron induces acute photoreceptor death, lipid peroxidation, and autofluorescence (AF). Herein, we extend this work, finding surprising chronic features of the model: geographic atrophy and sympathetic ophthalmia. We provide new mechanistic insights derived from focal AF in the photoreceptors, quantification of bisretinoids, and localization of carboxyethyl pyrrole, an oxidized adduct of docosahexaenoic acid associated with AMD. In mice given IVT ferric ammonium citrate (FAC), RPE died in patches that slowly expanded at their borders, like human geographic atrophy. There was green AF in the photoreceptor ellipsoid, a mitochondria-rich region, 4 h after injection, followed later by gold AF in rod outer segments, RPE and subretinal myeloid cells. The green AF signature is consistent with flavin adenine dinucleotide, while measured increases in the bisretinoid all-trans-retinal dimer are consistent with the gold AF. FAC induced formation carboxyethyl pyrrole accumulation first in photoreceptors, then in RPE and myeloid cells. Quantitative PCR on neural retina and RPE indicated antioxidant upregulation and inflammation. Unexpectedly, reminiscent of sympathetic ophthalmia, autofluorescent myeloid cells containing abundant iron infiltrated the saline-injected fellow eyes only if the contralateral eye had received IVT FAC. These findings provide mechanistic insights into the potential toxicity caused by AMD-associated retinal iron accumulation. The mouse model will be useful for testing antioxidants, iron chelators, ferroptosis inhibitors, anti-inflammatory medications, and choroidal neovascularization inhibitors.
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Compuestos Férricos/administración & dosificación , Atrofia Geográfica/inducido químicamente , Atrofia Geográfica/complicaciones , Inyecciones Intraoculares/métodos , Oftalmía Simpática/inducido químicamente , Oftalmía Simpática/complicaciones , Estrés Oxidativo/efectos de los fármacos , Compuestos de Amonio Cuaternario/administración & dosificación , Animales , Modelos Animales de Enfermedad , Atrofia Geográfica/diagnóstico por imagen , Atrofia Geográfica/metabolismo , Hierro/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Oftalmía Simpática/diagnóstico por imagen , Oftalmía Simpática/metabolismo , Imagen Óptica/métodos , Epitelio Pigmentado de la Retina/diagnóstico por imagen , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patologíaRESUMEN
C-C chemokine receptor type 5 (CCR5) regulates the trafficking of various immune cells to sites of infection. In this study, we showed that expression of CCR5 and its ligands was rapidly increased in the kidney after systemic Candida albicans infection, and infected CCR5-/- mice exhibited increased mortality and morbidity, indicating that CCR5 contributes to an effective defense mechanism against systemic C. albicans infection. The susceptibility of CCR5-/- mice to C. albicans infection was due to impaired fungal clearance, which in turn resulted in exacerbated renal inflammation and damage. CCR5-mediated recruitment of NK cells to the kidney in response to C. albicans infection was necessary for the anti-microbial activity of neutrophils, the main fungicidal effector cells. Mechanistically, C. albicans induced expression of IL-23 by CD11c+ dendritic cells (DCs). IL-23 in turn augmented the fungicidal activity of neutrophils through GM-CSF production by NK cells. As GM-CSF potentiated production of IL-23 in response to C. albicans, a positive feedback loop formed between NK cells and DCs seemed to function as an amplification point for host defense. Taken together, our results suggest that CCR5-mediated recruitment of NK cells to the site of fungal infection is an important step that underlies innate resistance to systemic C. albicans infection.
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Bioactive herbicidal compounds produced by soil microorganisms might be used to creating a bioherbicide for biological weed control. A total of 1,300 bacterial strains were isolated and screened for herbicidal activity against grass and broadleaf weeds. Among primarily selected 102 strains, the herbicidal activity of bacterial fermentation broths from the following three isolates strain-101, strain-128, and strain-329 reduced the growth of D. sanguinalis by 66.7%, 78.3%, and 100%, respectively as compared with control. Phylogenetic analysis of 16S rRNA gene sequencing determined that the strain-329 has 99% similarity to Streptomyces anulatus (HBUM 174206). The potential bioherbicidal efficacy of Streptomyces strain-329 was tested on grass and broadleaf weeds for phytotoxic activity through pre- and post-emergence applications. At pre-emergence application, the phytotoxic efficacy to D. sanguinalis and S. bicolor on seed germination were 90.4% and 81.3%, respectively at the 2x concentration, whereas in the case of Solanum nigrum, 85.2% phytotoxic efficacy was observed at the 4x concentration. The efficacy of Streptomyces strain-329 was substantially higher at post-emergence application, presenting 100% control of grass and broadleaf weeds at the 1x concentration. Two herbicidal compounds coded as 329-C1 and 329-C3 were extracted and purified by column chromatography and high-performance liquid chromatography methods. The active compound 329-C3 slightly increased leaf electrolytic leakage and MDA production as concentration-dependent manner. These results suggest that new Streptomyces sp. strain-329 produced bioherbicidal metabolites and may provide a new lead molecule for production an efficient bioherbicide to regulate grass and broadleaf weeds.
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Fermentación , Herbicidas/metabolismo , Malezas/crecimiento & desarrollo , Poaceae/genética , Streptomyces/química , Cromatografía Líquida de Alta Presión , Herbicidas/aislamiento & purificación , Herbicidas/farmacología , Filogenia , Malezas/clasificación , Malezas/efectos de los fármacos , Poaceae/clasificación , Poaceae/efectos de los fármacos , ARN Ribosómico 16S/genética , Especificidad de la Especie , Streptomyces/clasificación , Streptomyces/genética , Control de Malezas/métodosRESUMEN
High mobility group box 1 (HMGB1) has been proposed as crucial in the pathogenesis of many diseases including sepsis. Acetylation of HMGB1 prevents its entry into the nucleus and leads to its secretion from the cell where it can trigger inflammation. We hypothesized that histone deacetylase 4 (HDAC4) controls the acetylation of HMGB1 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells via the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. The results showed that LPS treatment promoted the degradation of HDAC4 in a proteasome-dependent manner, which led to HMGB1 acetylation. In LPS-activated RAW264.7 cells, treatment with TAK-242 (a toll like receptor 4 inhibitor) and pyridone 6 (a JAK inhibitor) significantly inhibited HDAC4 degradation and acetylation of HMGB1, and thus prevented secretion of HMGB1. Decreased phosphorylation of STAT1 was also observed. Interestingly, HDAC4 overexpression significantly prevented the acetylation and secretion of HMGB1 in both RAW264.7 cells and isolated murine peritoneal macrophages. We conclude that HDAC4 might be a useful target for the treatment of sepsis.
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Susceptibility to systemic Candida albicans infection is determined by immune resistance, as well as by the ability to control Candida-induced immunopathologies. We showed previously that exogenous IL-33 can increase resistance to peritoneal C. albicans infection by regulating multiple steps of the neutrophil anti-Candida response. In this study, using a mouse model of systemic candidiasis, we observed that IL-33 administration limited fungal burden and inflammation and increased survival. In kidneys, IL-33 seemed to directly act on neutrophils and CD4(+) T cells: IL-33 administration enhanced fungal clearance by increasing neutrophil phagocytic activity without which Candida proliferation was uncontrollable. In contrast, IL-33 stimulated CD4(+) T cells to produce IL-13, which, in turn, drove the polarization of macrophages toward the M2 type. Furthermore, the absence of IL-13 abolished IL-33-mediated polarization of M2 macrophages and renal functional recovery. In addition, IL-33 and IL-13 acted synergistically to increase M2 macrophage polarization and its phagocytic activity. Overall, this study identifies IL-33 as a cytokine that is able to induce resistance and tolerance and suggests that targeting resistance and tolerance simultaneously with therapeutic IL-33 may benefit patients with systemic candidiasis.
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Linfocitos T CD4-Positivos/inmunología , Candida albicans/inmunología , Candidiasis/inmunología , Tolerancia Inmunológica/inmunología , Interleucina-13/inmunología , Interleucinas/inmunología , Animales , Modelos Animales de Enfermedad , Citometría de Flujo , Interleucina-13/biosíntesis , Interleucina-33 , Enfermedades Renales/inmunología , Enfermedades Renales/microbiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Depletion of alloreactive T-lymphocytes from allogeneic bone marrow transplants may prevent graft-versus-host disease (GVHD) without impairing donor cell engraftment, immunity, and the graft-versus-leukemia (GVL) effect. Alloreactive T-cells may be identified by their expression, upon activation, of CD137, a costimulatory receptor and putative surrogate marker for antigen-specific effector T-cells. In this context, we tested the use of anti-CD137-saporin immunotoxin to selectively deplete mouse and human alloreactive T-cells. Anti-CD137 antibodies were internalized by cells within 4 h of binding to the cell surface CD137, and anti-CD137-saporin immunotoxin effectively killed polyclonally activated T-cells or antigen-stimulated T-cells. Transfer of donor T-cells after allodepletion with anti-CD137-saporin immunotoxin failed to induce any evident expression of GVHD; however, a significant GVL effect was observed. Targeting of CD137 with an immunotoxin was also effective in killing polyclonally activated or alloreactive human T-cells. Our results indicate that anti-CD137-saporin immunotoxin may be used to deplete alloreactive T-cells prior to bone marrow transplantation and thereby prevent GVHD and the relapse of leukemia.
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Inmunotoxinas/toxicidad , Depleción Linfocítica/métodos , Proteínas Inactivadoras de Ribosomas Tipo 1/toxicidad , Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Endocitosis/efectos de los fármacos , Femenino , Factores de Transcripción Forkhead/metabolismo , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia/inmunología , Leucemia/patología , Activación de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Ratones , Unión Proteica/efectos de los fármacos , Saporinas , Linfocitos T/efectos de los fármacos , Trasplante Homólogo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
Mutations in the inverted formin-2 (INF2) gene were recently identified in patients with autosomal dominant intermediate Charcot-Marie-Tooth (DI-CMT) disease and focal segmental glomerulosclerosis (FSGS). Here, we identified a novel p.L132P INF2 mutation in a Korean family with DI-CMT and FSGS by whole-exome sequencing. This mutation was cosegregated with affected individuals in the family and was not found in the 300 controls. The two affected members exhibited juvenile onset sensorimotor polyneuropathy and FSGS. Nerve conduction studies showed an intermediate range of motor nerve conduction velocities. We report a novel INF2 mutation in a family with DI-CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS.
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Enfermedad de Charcot-Marie-Tooth/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Proteínas de Microfilamentos/genética , Mutación/genética , Adolescente , Pueblo Asiatico/genética , Enfermedad de Charcot-Marie-Tooth/complicaciones , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Forminas , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Humanos , Persona de Mediana EdadRESUMEN
Kidney ischemia-reperfusion injury (IRI) occurs as a result of complex interactions of kidney parenchymal cells and immune cells that are initiated by hypoxic damage of parenchymal cells. In particular, tubular epithelial cells (TECs) not only are susceptible to ischemia but also have an auto-loop system to amplify renal inflammation caused by ischemia and reperfusion. Since endogenous TLR2 ligands released from TECs trigger renal inflammation leading to kidney IRI in an autocrine manner, we hypothesized that local infusion of TLR2 blockers would prevent kidney IRI. In this study, we demonstrated that injection of antagonist anti-TLR2 mAb through the renal vein after cross-clamping significantly reduced the recruitment of NK cells to the kidney after IRI, a phenomenon that is governed by TLR2 signaling in TECs. In addition, intrarenal blocking of TLR2 signaling was shown to inhibit NK cell-mediated neutrophil infiltration and subsequent renal damage. Overall, our simple experiment system will be of help in testing the efficacy of candidate blockers targeting kidney parenchymal cells in inhibition of kidney IRI.
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Anticuerpos Bloqueadores/administración & dosificación , Riñón/irrigación sanguínea , Células Asesinas Naturales/efectos de los fármacos , Daño por Reperfusión/inmunología , Daño por Reperfusión/terapia , Receptor Toll-Like 2/antagonistas & inhibidores , Animales , Anticuerpos Bloqueadores/efectos adversos , Movimiento Celular/efectos de los fármacos , Femenino , Humanos , Infusiones Intravenosas , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Modelos AnimalesRESUMEN
Damage-associated molecular patterns released from damaged kidney cells initiate postischemic inflammation, an essential step in the progression of kidney ischemia-reperfusion injury (IRI). However, the mechanism that coordinates this highly specific process in ischemic kidneys remains to be clarified. Previously, we demonstrated that CD137 from NK cells specifically stimulates CD137 ligand (CD137L) on tubular epithelial cells (TECs) such that TECs produced the high CXCR2 chemokine levels required for neutrophil chemotaxis. We report in the present study that endogenous TLR2 ligands released from ischemic TECs induce CCR5 chemokine expression, which is critical to promoting NK cell recruitment. By implanting CD137L(-/-) TECs into the kidney capsule of TLR2(-/-) mice, we further showed that TLR2-mediated NK cell recruitment is an uncoupled event that can occur independently of CD137L signaling in TECs, which is responsible for recruiting neutrophils. Therefore, our findings identify TECs as both a target for kidney damage and also as a master regulator that actively modulates stepwise signaling, leading to the initiation and amplification of acute sterile inflammation that inflicts kidney IRI. Being clinically important, the signaling pathway of innate receptors in epithelial cells may therefore be a good target to block acute sterile inflammation resulting from tissue damage, including kidney IRI.
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Quimiotaxis de Leucocito/fisiología , Túbulos Renales/metabolismo , Células Asesinas Naturales/inmunología , Daño por Reperfusión/metabolismo , Transducción de Señal , Receptor Toll-Like 2/metabolismo , Ligando 4-1BB/inmunología , Ligando 4-1BB/metabolismo , Animales , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Citometría de Flujo , Inmunohistoquímica , Túbulos Renales/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Daño por Reperfusión/inmunología , Transducción de Señal/fisiología , Receptor Toll-Like 2/inmunologíaRESUMEN
BACKGROUND: A surgical robot (the da Vinci system) was developed to overcome the disadvantages of laparoscopic surgery, and applications of this system have been widely used. In this study, we present our standardized technique of robotic right colectomy with lymphadenectomy and intracorporeal anastomosis, with an assessment of feasibility in a series of 15 patients. METHODS: All robotic right colectomies with lymphadenectomy were performed by a single surgeon between April 2009 and March 2010. Robotic assistance was used for the colonic mobilization, lymphadenectomy, and bowel reconstruction. Patient demographics, perioperative clinical outcomes, and pathologic results were reviewed. RESULTS: Robotic-assisted right colectomy was successfully performed on 15 patients with colon cancer. The total operative time was 201.4 ± 8.1 minutes, with a mean robotic time of 114.4 ± 7.5 minutes. No patient required conversion to conventional surgery. The median time to clear liquid intake was 3 days, and the median length of stay after surgery was 8 days. The mean tumor diameter was 3.0 ± 0.3 cm, and the mean number of harvested lymph nodes was 24.2 ± 15.5. Tumors were diagnosed as stage I in 7 patients, stage II in 5, and stage III in 3. CONCLUSIONS: Robotic right colectomy with lymphadenectomy can be performed successfully and safely. The robotic system was safe and feasible for the following steps: accurate node dissection, suturing for intracorporeal anastomosis, and natural orifice specimen extraction. Further comparative studies must be performed to verify the advantages of robotic surgery over conventional laparoscopic surgery.
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Colectomía/métodos , Colon/cirugía , Neoplasias del Colon/cirugía , Laparoscopía/métodos , Escisión del Ganglio Linfático/métodos , Robótica/métodos , Anastomosis Quirúrgica/métodos , Neoplasias del Colon/secundario , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Renal ischemia-reperfusion injury (IRI) after kidney transplantation is a major cause of delayed graft function. Even though IRI is recognized as a highly coordinated and specific process, the pathways and mechanisms through which the innate response is activated are poorly understood. In this study, we used a mouse model of acute kidney IRI to examine whether the interactions of costimulatory receptor CD137 and its ligand (CD137L) are involved in the early phase of acute kidney inflammation caused by IRI. We report here that the specific expressions of CD137 on natural killer cells and of CD137L on tubular epithelial cells (TECs) are required for acute kidney IRI. Reverse signaling through CD137L in TECs results in their production of the chemokine (C-X-C motif) receptor 2 ligands CXCL1 and CXCL2 and the subsequent induction of neutrophil recruitment, resulting in a cascade of proinflammatory events during kidney IRI. Our findings identify an innate pathogenic pathway for renal IRI involving the natural killer cell-TEC-neutrophil axis, whereby CD137-CD137L interactions provide the causal contribution of epithelial cell dysregulation to renal IRI. The CD137L reverse signaling pathway in epithelial cells therefore may represent a good target for blocking the initial stage of inflammatory diseases, including renal IRI.
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Ligando 4-1BB/inmunología , Células Epiteliales/inmunología , Inflamación/patología , Túbulos Renales/inmunología , Túbulos Renales/patología , Células Asesinas Naturales/inmunología , Transducción de Señal/inmunología , Ligando 4-1BB/deficiencia , Traslado Adoptivo , Animales , Quimiocina CXCL1/biosíntesis , Quimiocina CXCL2/biosíntesis , Quimiotaxis , Células Epiteliales/trasplante , Inflamación/complicaciones , Inflamación/inmunología , Células Asesinas Naturales/trasplante , Ratones , Ratones Endogámicos C57BL , Neutrófilos/citología , Receptores Fc/inmunología , Daño por Reperfusión/complicaciones , Daño por Reperfusión/inmunología , Daño por Reperfusión/patologíaRESUMEN
PURPOSE: In comparison to temporal lobe epilepsy (TLE) patients with hippocampal sclerosis (TLE-HS), TLE patients without HS (TLE-NH) have a similar clinical course but may result in worse surgical outcome. We investigated whether the clinical features related to the lack of HS in TLE patients (TLE-NH) can be explained by water diffusion abnormalities throughout diffusion tensor imaging (DTI) by voxel-based analysis. METHODS: Nineteen patients with TLE-HS (left/right TLE 12:7), 18 patients with TLE-NH (left/right TLE 10:8), and 20 controls were included in the study. By statistical parametric mapping (SPM2), the diffusion properties specific to disease characteristics (TLE-HS vs. TLE-NH) were analyzed. RESULTS: In TLE-HS, we found the areas of increased mean diffusivity (MD) in their ipsilateral temporal and extratemporal areas including the hippocampus, parahippocampal, and frontoparietal regions. Left TLE-HS showed a characteristic MD increase in the ipsilateral posterior cingulum, isthmus of corpus callosum, and contralateral occipital and temporal regions, which was not observed in right TLE-HS group. In left TLE-NH, two regions of increased MD were observed in the ipsilateral posterior fornix (within fusiform gyrus) and posterior cingulum. Right TLE-NH did not show any increased MD. DISCUSSION: In left TLE-NH, we could find the water diffusion change along the posterior cingulum, which was quite different from the extensive abnormality from TLE-HS. In addition, there was a lesion-side-specific distribution (left predominant) of pathology in mesial TLE. This provides a possibility that TLE-NH is a heterogeneous or entity different from TLE-HS.
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Imagen de Difusión por Resonancia Magnética/métodos , Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/patología , Hipocampo/patología , Procesamiento de Imagen Asistido por Computador/métodos , Lóbulo Temporal/patología , Adolescente , Adulto , Lobectomía Temporal Anterior , Atrofia , Encéfalo/patología , Encéfalo/fisiopatología , Mapeo Encefálico/métodos , Imagen de Difusión Tensora/métodos , Dominancia Cerebral/fisiología , Epilepsia del Lóbulo Temporal/fisiopatología , Epilepsia del Lóbulo Temporal/cirugía , Femenino , Hipocampo/fisiopatología , Hipocampo/cirugía , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Esclerosis , Programas Informáticos , Lóbulo Temporal/fisiopatología , Lóbulo Temporal/cirugía , Adulto JovenRESUMEN
In the DBA/2 --> unirradiated (C57BL/6 x DBA/2)F(1) model of chronic graft-vs-host disease (cGVHD), donor CD4(+) T cells play a critical role in breaking host B cell tolerance, while donor CD8(+) T cells are rapidly removed and the remaining cells fall into anergy. Previously we have demonstrated that in vivo ligation of GITR (glucocorticoid-induced TNF receptor-related gene) can activate donor CD8(+) T cells, subsequently converting the disease pattern from cGVHD to an acute form. In this study, we investigated the effect of an agonistic mAb against CD40 on cGVHD. Treatment of anti-CD40 mAb inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis. The inhibition of cGVHD occurred because anti-CD40 mAb prevented donor CD8(+) T cell anergy such that subsequently activated donor CD8(+) T cells deleted host CD4(+) T cells and host B cells involved in autoantibody production. Additionally, functionally activated donor CD8(+) T cells induced full engraftment of donor hematopoietic cells and exhibited an increased graft-vs-leukemia effect. However, induction of acute GVHD by donor CD8(+) T cells seemed to be not so apparent. Further CTL analysis indicated that there were lower levels of donor CTL activity against host cells in mice that received anti-CD40 mAb, compared with mice that received anti-GITR mAb. Taken together, our results suggest that a different intensity of donor CTL activity is required for removal of host hematopoietic cells, including leukemia vs induction of acute GVHD.
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Antígenos CD40/antagonistas & inhibidores , Linfocitos T CD8-positivos/inmunología , Anergia Clonal/inmunología , Enfermedad Injerto contra Huésped/inmunología , Animales , Anticuerpos Antinucleares/sangre , Anticuerpos Antinucleares/inmunología , Anticuerpos Monoclonales/inmunología , Autoantígenos/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Enfermedad Crónica , Citotoxicidad Inmunológica , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Efecto Injerto vs Leucemia/inmunología , Inmunohistoquímica , Ratones , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D2-->Balb/c (H-2(d)) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4(+) T-cell cytokines and increased apoptosis of donor CD4(+) T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4(+) T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD.
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Trasplante de Médula Ósea/inmunología , Enfermedad Injerto contra Huésped/terapia , Inmunoterapia , Trasplante de Células Madre/efectos adversos , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Enfermedad Injerto contra Huésped/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Ratones Endogámicos , Trasplante HomólogoRESUMEN
In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8+ T cells rapidly fall into anergy to host cells, while donor CD4+ T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8+ T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8+ T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4+CD25+ regulatory T cells (Treg cells) are critical in maintaining the donor CD8+ T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of Treg cells in determining cGVHD versus aGVHD.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Anergia Clonal/fisiología , Enfermedad Injerto contra Huésped/inmunología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Enfermedad Crónica , Femenino , Tolerancia Inmunológica/fisiología , Ratones , Ratones Endogámicos DBARESUMEN
In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD toward aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cell anergy. Functionally active donor CD8+ T cells produced high levels of IFN-gamma and had an elevated CTL activity against host Ags. In in vitro MLR, anergic responder CD8+ T cells were generated, and DTA-1 stimulated the activation of these anergic CD8+ T cells. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, were responsible for the DTA-1-mediated conversion of cGVHD to aGVHD. These results indicate that donor CD8+ T cell anergy is a restriction factor in the development of aGVHD and that in vivo ligation of GITR prevents CD8+ T cell anergy by activating donor CD8+ T cells that otherwise become anergic. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD vs aGVHD and as a target for therapeutic intervention in a variety of related diseases.