RESUMEN
OBJECTIVE: To compare image quality, observer confidence, radiation exposure in the standard-dose (SD-CCTA) and low-dose (LD-CCTA) protocols of coronary CT angiography (CCTA) in patients with atrial fibrillation (AF). MATERIAL AND METHODS: CCTA was performed in 303 patients using a CT scanner with 16-cm coverage (111 scans during sinus rhythm (SR); 192 during AF). LD-CCTA was used in 218 patients; SD-CCTA in 85 patients suspected of having coronary artery disease (CAD). Image quality and observer confidence were evaluated on 5-point scales. Radiation doses were recorded. RESULTS: Image quality was superior in the SD-CCTA compared to the LD-CCTA (SR 1.45±0.40; AF 1.72±0.46; vs. SR 1.83±0.48; AF 1.92±0.50; p < 0.001). Observers were more confident with SD-CCTA than with LD-CCTA (SR 1.38±0.33; AF 1.61±0.43; vs. SR 1.70±0.45; AF 1.82±0.50; p < 0.001). Radiation doses in AF were significantly higher than in the SR (LD-CCTA, 1.68±0.71 mSv; SD-CCTA, 3.72±1.95 mSv; vs. LD-CCTA, 1.3 ±0.52 mSv; SD-CCTA, 2.67±1.47 mSv; p < 0.001). CONCLUSION: Using a low-dose protocol in AF, radiation exposure can be decreased by 50 % at the expense of 20 % impaired image quality. A low-dose CCTA protocol can be considered in young patients, whereas the standard-dose protocol is recommended for older patients and those suspected of having CAD. KEY POINTS: ⢠Whole-heart CT allows visualization of the coronary arteries in atrial fibrillation. ⢠Low-dose CT decreases radiation exposure by 50%, image quality by 20%. ⢠Standard-dose CT seems advantageous when concomitant coronary artery disease is suspected.
Asunto(s)
Fibrilación Atrial/diagnóstico por imagen , Angiografía por Tomografía Computarizada/instrumentación , Angiografía por Tomografía Computarizada/métodos , Angiografía Coronaria/instrumentación , Angiografía Coronaria/métodos , Dosis de Radiación , Femenino , Corazón/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Exposición a la RadiaciónRESUMEN
BACKGROUND: Although the elderly represents a rapidly growing population among transplant recipients, age-specific aspects have not been considered sufficiently in clinical trials. Moreover, age-specific effects of immunosuppressive therapies remain poorly understood. METHODS: Here, we assessed the impact of rapamycin on alloimmune responses in old recipients using a fully major histocompatibility complex-mismatched murine transplantation model. RESULTS: Old untreated recipients displayed a prolonged skin graft survival compared to their young counterparts, an observation that confirmed data of our previous experiments. Rapamycin led to a significant prolongation of graft survival in both young and old recipients. However, graft survival was age-dependent and extended in old versus young recipients (19 days vs 12 days, P = 0.004). This age-specific effect was not linked to changes in frequencies or subset composition of either cluster of differentiation (CD)8 or CD4 T cells. Moreover, antiproliferative effects of rapamycin on CD8 and CD4 T cells as assessed by in vivo bromdesoxyuridine incorporation were comparable and age-independent. In contrast, the systemic production of IL-10 was markedly elevated in old recipients treated with rapamycin. In parallel to this shift in cytokine balance, IFN-γ/IL-10 double-positive regulatory type 1 cells emerged during T helper type 1 differentiation of old T helper cells in presence of rapamycin. Similarly, CD4IFN-γIL-10 cells expanded among Foxp3-negative cells after in vivo treatment of old recipients with rapamycin. CONCLUSIONS: Our results highlight novel aspects of age-dependent immunosuppressive effects of rapamycin, with relevance for age-specific immunosuppressive regimens.
Asunto(s)
Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/farmacología , Interferón gamma/análisis , Interleucina-10/análisis , Sirolimus/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Animales , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Linfocitos T Reguladores/inmunologíaRESUMEN
CD8+ T cells play a cardinal feature in response to alloantigens and are able to generate effector/memory T cells independently from CD4+ T cells. To investigate the impact of aging on CD8 T cells, we used a fully mismatched mouse skin transplant model. Our findings showed a prolonged allograft survival in older recipients associated with a significant increase of CD4+ and CD8+ CD44high CD62Llow effector/memory T cells and a reduced systemic IFNγ production. When reconstituting young CBA Rag-1 mice that lack mature T and B cells with old CD8+ T cells expressing clonal anti-H2K T cell receptor (TCR) alloreactive for MHC I, graft survival was significantly prolonged and comparable to those receiving young CD8+ T cells. Moreover, our data showed that reduced systemic IFNγ levels observed in old recipients had been linked to a compromised expression of the IL-2R ß subunit (CD122) by old CD8+ T cells. In addition, we observed an impaired IFNγ production on IL-2 receptor activation. At the same time, gene profiling analysis of old CD8 T cells demonstrated reduced chemokine ligand-3 and CD40L expression that resulted in compromised CD8+ T cell/dendritic cell communication, leading to impaired migratory and phagocytic activity of CD11c cells.Collectively, our study demonstrated that aging delays allograft rejection. CD8 T cells play a critical role in this process linked to a compromised production of IFNγ, in addition to a defective IL-2 receptor signaling machinery and a defective communication between CD8 T cells and dendritic cells.
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Envejecimiento/inmunología , Linfocitos T CD8-positivos/inmunología , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Transducción de Señal , Trasplante de Piel/efectos adversos , Traslado Adoptivo , Factores de Edad , Envejecimiento/genética , Aloinjertos , Animales , Ligando de CD40/inmunología , Ligando de CD40/metabolismo , Linfocitos T CD8-positivos/metabolismo , Comunicación Celular , Movimiento Celular , Células Cultivadas , Quimiocina CCL3/inmunología , Quimiocina CCL3/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genes Codificadores de los Receptores de Linfocitos T , Rechazo de Injerto/genética , Rechazo de Injerto/metabolismo , Rechazo de Injerto/prevención & control , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Interferón gamma/inmunología , Interferón gamma/metabolismo , Subunidad beta del Receptor de Interleucina-2/inmunología , Subunidad beta del Receptor de Interleucina-2/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Ratones Noqueados , Fagocitosis , Factores de TiempoRESUMEN
BACKGROUND: Organ transplantation has seen an increased use of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplantation outcomes when older donor organs are used represent a growing challenge. METHODS AND RESULTS: Here, we characterize the impact of donor age on solid-organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when older hearts were used. Shorter graft survival of older hearts was independent of organ age per se, because chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c+ dendritic cells augmenting CD4+ and CD8+ T-cell proliferation and proinflammatory cytokine production, particularly that of interleukin-17A. Of note, depletion of donor CD11c+ dendritic cells before engraftment, neutralization of interleukin-17A, or transplantation of older hearts into IL-17A(-/-) mice delayed rejection and reduced alloimmune responses to levels observed when young hearts were transplanted. CONCLUSIONS: These results demonstrate a critical role of old donor CD11c+ dendritic cells in mounting age-dependent alloimmune responses with an augmented interleukin-17A response in recipient animals. Targeting interleukin-17A may serve as a novel therapeutic approach when older organs are transplanted.
Asunto(s)
Envejecimiento/inmunología , Antígeno CD11c/inmunología , Células Dendríticas/inmunología , Rechazo de Injerto/inmunología , Trasplante de Corazón/efectos adversos , Interleucina-17/inmunología , Envejecimiento/patología , Animales , Células Dendríticas/patología , Rechazo de Injerto/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Trasplante Homólogo/efectos adversosRESUMEN
CD4(+) T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD(+)) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4(+)IFNγ(+)IL-10(+) T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD(+) regulates CD4(+) T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD(+), the frequency of T-bet(-/-) CD4(+)IFNγ(+) T cells was twofold higher than wild-type CD4(+) T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4(+) T-cell differentiation and demonstrate that NAD(+) may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/inmunología , Esclerosis Múltiple/inmunología , Vaina de Mielina/efectos de los fármacos , NAD/farmacología , Regeneración/efectos de los fármacos , Animales , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Homeostasis/efectos de los fármacos , Ratones , Triptófano Hidroxilasa/efectos de los fármacos , Triptófano Hidroxilasa/metabolismoRESUMEN
Donor organ scarcity remains a significant clinical challenge in transplantation. Older organs, increasingly utilized to meet the growing demand for donor organs, have been linked to inferior transplant outcomes. Susceptibility to organ injury, reduced repair capacity, and increased immunogenicity are interrelated and impacted by physiological and pathological aging processes. Insights into the underlying mechanisms are needed to develop age-specific interventional strategies with regards to organ preservation, immunosuppression, and allocation. In this overview, we summarize current knowledge of injury and repair mechanisms and the effects of aging relevant to transplantation.
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Envejecimiento , Trasplante de Órganos/métodos , Donantes de Tejidos/provisión & distribución , Adulto , Factores de Edad , Anciano , Autofagia , Europa (Continente) , Proteínas de Choque Térmico/metabolismo , Humanos , Isquemia/patología , Trasplante de Riñón/normas , Persona de Mediana Edad , Preservación de Órganos/métodos , Trasplante de Órganos/normas , Complejo de la Endopetidasa Proteasomal/metabolismo , Regeneración , Daño por Reperfusión , Obtención de Tejidos y Órganos , Resultado del Tratamiento , Ubiquitina/metabolismo , Adulto JovenRESUMEN
Vascularized composite tissue allotransplantation (VCA) offers treatment options of complex functional deficiencies that cannot be repaired with conventional reconstructive methods. VCAs consist of blocks of functional units comprising different tissue types such as skin, bone, muscle, nerves, blood vessels, tendons, ligaments and others, and are thus substantially different from the composition of organ transplants. The field of VCA has made fascinating progresses in the recent past. Among other VCAs, numerous successful hand, face and limb transplants have been performed in the world. At the same time, specific questions in regard to innate and adaptive immunity, consequences of ischemia/reperfusion injury, immunosuppression, preservation, and regenerative capacity remain. In spite of this, the field is poised to make significant advances in the near future.
RESUMEN
Although Th1, Th2, and Th17 cells are thought to be major effector cells in adaptive alloimmune responses, their respective contribution to allograft rejection remains unclear. To precisely address this, we used mice genetically modified for the Th1 and Th17 hallmark transcription factors T-bet and RORγt, respectively, which allowed us to study the alloreactive role of each subset in an experimental transplant setting. We found that in a fully mismatched heterotopic mouse heart transplantation model, T cells deficient for T-bet (prone to Th17 differentiation) versus RORγt (prone to Th1 differentiation) rejected allografts at a more accelerated rate, indicating a predominance of Th17- over Th1-driven alloimmunity. Importantly, T cells doubly deficient for both T-bet and RORγt differentiated into alloreactive GATA-3-expressing Th2 cells, which promptly induced allograft rejection characterized by a Th2-type intragraft expression profile and eosinophilic infiltration. Mechanistically, Th2-mediated allograft rejection was contingent on IL-4, as its neutralization significantly prolonged allograft survival by reducing intragraft expression of Th2 effector molecules and eosinophilic allograft infiltration. Moreover, under IL-4 neutralizing conditions, alloreactive double-deficient T cells upregulated Eomesodermin (Eomes) and IFN-γ, but not GATA-3. Thus, in the absence of T-bet and RORγt, Eomes may salvage Th1-mediated alloimmunity that underlies IL-4 neutralization-resistant allograft rejection. We summarize that, whereas Th17 cells predictably promote allograft rejection, IL-4-producing GATA-3(+) Th2 cells, which are generally thought to protect allogeneic transplants, may actually be potent facilitators of organ transplant rejection in the absence of T-bet and RORγt. Moreover, Eomes may rescue Th1-mediated allograft rejection in the absence of IL-4, T-bet, and RORγt.
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Aloinjertos/inmunología , Rechazo de Injerto/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Proteínas de Dominio T Box/metabolismo , Células Th2/inmunología , Traslado Adoptivo , Animales , Diferenciación Celular , Eosinófilos/inmunología , Factor de Transcripción GATA3/biosíntesis , Trasplante de Corazón/efectos adversos , Interferón gamma/biosíntesis , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/deficiencia , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Proteínas de Dominio T Box/biosíntesis , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genéticaRESUMEN
Increasing numbers of elderly transplant recipients and a growing demand for organs from older donors impose pressing challenges on transplantation medicine. Continuous and complex modifications of the immune system in parallel to aging have a major impact on transplant outcome and organ quality. Both, altered alloimmune responses and increased immunogenicity of organs present risk factors for inferior patient and graft survival. Moreover, a growing body of knowledge on age-dependent modifications of allorecognition and alloimmune responses may require age-adapted immunosuppression and organ allocation. Here, we summarize relevant aspects of immunosenescence and their possible clinical impact on organ transplantation.
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Envejecimiento/inmunología , Rechazo de Injerto/epidemiología , Rechazo de Injerto/inmunología , Trasplante de Órganos/tendencias , Inmunología del Trasplante , Anciano , Humanos , Factores de RiesgoRESUMEN
Obesity has become an increasing problem in healthcare worldwide with far-reaching consequences. More obese patients with irreversible end-stage organ failure undergo organ transplantation, and organs from obese donors are more frequently used. A growing body of evidence suggests more frequent postoperative complications and inferior patient and graft survival linked to obesity. More recently, adipose tissue has been linked to chronic inflammatory processes potentially impacting alloimmune responses and graft quality.
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Rechazo de Injerto/inmunología , Isoanticuerpos/inmunología , Obesidad/inmunología , Inmunología del Trasplante , Trasplante , Rechazo de Injerto/epidemiología , Supervivencia de Injerto/inmunología , Humanos , Obesidad/epidemiología , PrevalenciaRESUMEN
Aging affects all compartments of the immune response and has a major impact on transplant outcome and organ quality. Although clinical trials in the aging transplant population remain rare, our current understanding of immunosenescence provides a basis for an age-adapted immunosuppression and organ allocation with the goal to optimize utilization and to improve outcomes in older recipients. From a more general perspective, understanding the mechanisms and consequences of immunosenescence will have a broad impact on immune therapies in and beyond transplantation.
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Envejecimiento/inmunología , Inmunidad Innata/fisiología , Trasplante de Órganos/métodos , Inmunología del Trasplante/inmunología , Factores de Edad , Anciano , Envejecimiento/fisiología , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Tolerancia Inmunológica , Terapia de Inmunosupresión , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/inmunología , Trasplante de Riñón/métodos , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/inmunología , Trasplante de Hígado/métodos , Donadores Vivos , Persona de Mediana Edad , Trasplante de Órganos/efectos adversos , Pronóstico , Medición de Riesgo , Donantes de Tejidos , Inmunología del Trasplante/fisiologíaRESUMEN
PURPOSE OF REVIEW: The roles of adaptive immune cells in transplant models have been extensively studied, but very little is known about the role of innate immune cells in the allograft response, especially in tolerance induction. In this review, we summarized the latest developments in the study of the role of natural killer cells in mediating graft rejection and tolerance induction. RECENT FINDINGS: Natural killer cells are potent cytolytic cells; they also induce tissue inflammation by producing powerful proinflammatory cytokines. Thus, natural killer cells can act as effector cells in transplant rejection. Recent studies, however, have demonstrated additional roles for natural killer cells in the induction of transplant tolerance. We found that natural killer cells control survival of graft-derived donor cells and killing of donor dendritic cells by host natural killer cells inhibits direct priming of alloreactive T cells. Natural killer cells are also shown directly to suppress the activation of T cells. In other models, natural killer cells are found to regulate the induction of regulatory T cells. These new findings may have important clinical implications in tolerance induction. SUMMARY: Natural killer cells are involved in both graft rejection and tolerance induction; such opposing effects may be mediated by differences in the activation status of natural killer cells. We believe that natural killer cells can be therapeutically modified for the induction of transplant tolerance.
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Rechazo de Injerto/inmunología , Supervivencia de Injerto , Inmunidad Innata , Células Asesinas Naturales/inmunología , Trasplante de Órganos/efectos adversos , Tolerancia al Trasplante , Animales , Células Dendríticas/inmunología , Humanos , Inflamación/inmunología , Activación de Linfocitos , Linfocitos T Reguladores/inmunología , Trasplante HomólogoRESUMEN
Transplant rejection is mediated primarily by adaptive immune cells such as T cells and B cells. The T and B cells are also responsible for the specificity and memory of the rejection response. However, destruction of allografts involves many other cell types including cells in the innate immune system. As the innate immune cells do not express germline-encoded cell surface receptors that directly recognize foreign Ags, these cells are thought to be recruited by T cells to participate in the rejection response. In this study, we examined the alloreactivity of the innate NK cells in Rag(-/-) mice using a stringent skin transplant model and found that NK cells at a resting state readily reject allogeneic cells, but not the skin allografts. We also found that IL-15, when preconjugated to its high affinity IL-15Ralpha-chain, is remarkably potent in stimulating NK cells in vivo, and NK cells stimulated by IL-15 express an activated phenotype and are surprisingly potent in mediating acute skin allograft rejection in the absence of any adaptive immune cells. Furthermore, NK cell-mediated graft rejection does not show features of memory responses. Our data demonstrate that NK cells are potent alloreactive cells when fully activated and differentiated under certain conditions. This finding may have important clinical implications in models of transplantation and autoimmunity.
Asunto(s)
Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Inmunidad Innata , Interleucina-15/fisiología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Proliferación Celular , Citotoxicidad Inmunológica/genética , Genes RAG-1 , Rechazo de Injerto/genética , Supervivencia de Injerto/genética , Supervivencia de Injerto/inmunología , Proteínas de Homeodominio/genética , Inmunidad Innata/genética , Memoria Inmunológica/genética , Células Asesinas Naturales/citología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Trasplante de Piel/inmunologíaRESUMEN
BACKGROUND: Leukocyte recruitment to sites of intestinal inflammation is a crucial multi-step process, leading ultimately to the accumulation of cells in the inflamed tissue. These interactions in the gut are critically dependent on the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on endothelial cells within the mesenteric lymph nodes and the lamina propria of the intestine. Here, we investigate the pathophysiologic role of MAdCAM-1 in the intestinal microcirculation in vivo. METHODS: Using a standard mouse model, chronic colitis was established after four cycles of dextran sodium sulfate (DSS) application. MAdCAM-1 expression was investigated by immunohistochemistry and Western blotting, as well as real-time polymerase chain reaction (PCR). Intravital microscopy was used to study the role of MAdCAM-1 on leukocyte-endothelium interactions and leukocyte extravasation. RESULTS: Significant changes in MAdCAM-1 were observed in mice with chronic DSS-induced colitis. Upregulation of MAdCAM-1 expression in chronic colitis was demonstrated on a protein and messenger ribonucleic acid (mRNA) level. Anti-MAdCAM-1 treatment lead to a marked reduction (>60%) of leukocyte sticking and extravasation in vivo, compared to the controls. This was parallelled by a significant reduction (45%) of intestinal inflammation, as measured by the histologic grading score. CONCLUSION: These in vivo results demonstrate a distinct role of MAdCAM-1 in inflammatory intestinal diseases, and suggest that therapeutic strategies targeting this adhesion molecule could be useful in the treatment of chronic colitis.