RESUMEN
Autologous CD117(+) progenitor cells (PC) have been successfully utilized in myocardial infarction and ischemic injury, potentially through the replacement/repair of damaged vascular endothelium. To date, such cells have not been used to enhance solid organ transplant outcome. In this study, we determined whether autologous bone marrow-derived CD117(+) PC could benefit cardiac allograft survival, possibly by replacing donor vascular cells. Autologous, positively selected CD117(+) PC were administered posttransplantation and allografts were assessed for acute rejection. Although significant generation of recipient vascular cell chimerism was not observed, transferred PC disseminated both to the allograft and to peripheral lymphoid tissues and facilitated a significant, dose-dependent prolongation of allograft survival. While CD117(+) PC dramatically inhibited alloreactive T cell proliferation in vitro, this property did not differ from nonprotective CD117(-) bone marrow populations. In vivo, CD117(+) PC did not significantly inhibit T cell alloreactivity or increase peripheral regulatory T cell numbers. Thus, rather than inhibiting adaptive immunity to the allograft, CD117(+) PC may play a cytoprotective role in prolonging graft survival. Importantly, autologous CD117(+) PC appear to be distinct from bone marrow-derived mesenchymal stem cells (MSC) previously used to prolong allograft survival. As such, autologous CD117(+) PC represent a novel cellular therapy for promoting allograft survival.
Asunto(s)
Trasplante de Corazón/inmunología , Proteínas Proto-Oncogénicas c-kit/inmunología , Células Madre/inmunología , Animales , Células de la Médula Ósea/inmunología , Trasplante de Médula Ósea/inmunología , Supervivencia de Injerto/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Linfocitos T/inmunología , Trasplante HomólogoRESUMEN
Recent studies using mouse models demonstrate that CD4(+) T cells are sufficient to mediate acute cardiac allograft rejection in the absence of CD8(+) T cells and B cells. However, the mechanistic basis of CD4-mediated rejection is unclear. One potential mechanism of CD4-mediated rejection is via elaboration of proinflammatory cytokines such as IFN-gamma. To determine whether IFN-gamma is a critical cytokine in CD4-mediated acute cardiac allograft rejection, we studied whether the expression of IFN-gamma receptors on the donor heart was required for CD4-mediated rejection. To investigate this possibility, purified CD4(+) T cells were transferred into immune-deficient mice bearing heterotopic cardiac allografts from IFN-gamma receptor-deficient (GRKO) donors. While CD4(+) T cells triggered acute rejection of wild-type heart allografts, they failed to trigger rejection of GRKO heart allografts. The impairment in CD4-mediated rejection of GRKO hearts appeared to primarily involve the efferent phase of the immune response. This conclusion was based on the findings that GRKO stimulator cells provoked normal CD4 proliferation in vitro and that intentional in vivo challenge of CD4 cells with wild-type donor APC or the adoptive transfer of in vitro primed CD4 T cells failed to provoke acute rejection of GRKO allografts. In contrast, unseparated lymph node cells acutely rejected both GRKO and wild-type hearts with similar time courses, illustrating the existence of both IFN-gamma-dependent and IFN-gamma-independent mechanisms of acute allograft rejection.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Rechazo de Injerto , Trasplante de Corazón/inmunología , Receptores de Interferón/fisiología , Animales , Antígenos CD4/fisiología , Linfocitos T CD8-positivos/inmunología , Femenino , Interferón gamma/fisiología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Trasplante Homólogo , Receptor de Interferón gammaRESUMEN
Heart transplantation has been performed clinically for four decades, and has become the standard of care for end-stage heart disease. Our understanding of the immunobiology of transplantation has made tremendous strides, but our knowledge still lags behind the clinical use. As a result, nonspecific immunosuppression remains the standard therapy. This chapter is a review of our present knowledge of the immunobiology of allotransplantation and xenotransplantation with emphasis on antigen presentation, costimulation, and T-cell activation in the context of transplantation. The molecular events of T-cell activation, with some emphasis on the sites of action of present day immunosuppression, are reviewed. Basic aspects of immunosuppression are reviewed elsewhere in this edition. Given the paucity of allografts, xenografts are being considered as an alternative donor source. This being the case, cellular and humoral response to xenografts is considered and contrasted with our understanding of allograft immunity. Basic mechanisms of tolerance are discussed, with examples of experimental tolerance induction in small and large animals. A brief description of special considerations for the immunology in human neonate/infant recipients is mentioned. Understanding the immunobiology of transplantation is key to making decisions regarding heart transplant recipients today, in addition to developing better protocols and the induction of tolerance in the future.
Asunto(s)
Trasplante de Corazón/inmunología , Inmunología del Trasplante , Trasplante Heterólogo/inmunología , Trasplante Homólogo/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Presentación de Antígeno/inmunología , Rechazo de Injerto/inmunología , Histocompatibilidad/inmunología , Humanos , Inmunosupresores/uso terapéutico , Lactante , Recién Nacido , Células Asesinas Naturales/inmunología , Ratones , Ratas , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: An outbreak of Kawasaki disease (KD) in Colorado between November, 1997, and June, 1998, provided the opportunity to study inflammatory indices and coronary artery abnormalities. METHODS: Medical records of the 33 patients diagnosed with KD at The Children's Hospital during the outbreak were reviewed. Demographic and clinical information, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and echocardiogram results were recorded. Traditional abnormalities (dilatation, aneurysm, ectasia), as well as "prominence" of the coronary arteries were noted. RESULTS: Twenty-five patients had CRP and ESR performed on the day of admission; 11 of 25 (44%) had a discrepancy between the height of the ESR and CRP values (high ESR and low CRP or low ESR and high CRP). The mean CRP was higher in patients who presented in <10 days than in patients who presented in > or =10 days: 13.9 mg/dl vs. 5.2 mg/dl (P = 0.01). The ESR value did not correlate with the day of illness. Age, gender or presence of coronary artery abnormalities did not correlate with the height of CRP or ESR elevation. Thirty percent of patients had at least one abnormality on their initial echocardiogram (dilatation, aneurysm, ectasia). An additional 24% of patients displayed prominence as the only finding on their initial echocardiogram. Of the 33 patients 7 (21.2%) had coronary artery aneurysms. CONCLUSIONS: Many patients with KD have discrepancies in the degree of elevation of CRP and ESR. Physicians should consider obtaining both tests in patients with KD. This outbreak was associated with a high degree of coronary artery abnormalities. The finding of coronary artery prominence is an observation that deserves further study.
Asunto(s)
Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Anomalías de los Vasos Coronarios/epidemiología , Brotes de Enfermedades , Síndrome Mucocutáneo Linfonodular/sangre , Síndrome Mucocutáneo Linfonodular/epidemiología , Niño , Preescolar , Colorado/epidemiología , Anomalías de los Vasos Coronarios/complicaciones , Femenino , Humanos , Lactante , Masculino , Registros Médicos , Síndrome Mucocutáneo Linfonodular/complicaciones , Prevalencia , Estudios Retrospectivos , Factores de TiempoRESUMEN
Numerous studies indicate that CD4 T cells are required for acute cardiac allograft rejection. However, the precise role for CD4 T cells in this response has remained ambiguous owing to the multipotential properties of this T-cell subpopulation. In the current study, we demonstrate the capacity of CD4 T cells to serve as direct effector cells of cardiac allograft rejection. We show that CD4 T cells are both necessary and sufficient for acute graft rejection, as indicated by adoptive transfer experiments in immune-deficient SCID and rag1(-/-) recipients. We have analyzed the contribution of direct (donor MHC class II restricted) and indirect (host MHC class II restricted) antigen recognition in CD4-mediated rejection. Acute CD4 T cell-mediated rejection required MHC class II expression by the allograft, indicating the importance of direct graft recognition. In contrast, reciprocal experiments indicate that CD4 T cells can acutely reject allogeneic cardiac allografts established in rag1(-/-) hosts that were also MHC class II deficient. This latter result indicates that indirect presentation of donor antigens by host MHC class II is not required for acute CD4-mediated rejection. Taken together, these results indicate that CD4 T cells can serve as effector cells for primary acute cardiac allograft rejection, predominantly via direct donor antigen recognition and independent of indirect reactivity.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Genes MHC Clase II , Rechazo de Injerto/inmunología , Trasplante de Corazón/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Enfermedad Aguda , Animales , Antígenos H-2 , Trasplante de Corazón/mortalidad , Isoanticuerpos , Prueba de Cultivo Mixto de Linfocitos , Depleción Linfocítica , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones SCID/inmunología , Trasplante HomólogoRESUMEN
Kawasaki syndrome (KS) is the major cause of acquired heart disease in children. Although acute myocarditis is observed in most patients with KS, its pathogenesis is unknown. Because antimyosin autoantibodies are present in autoimmune myocarditis and rheumatic carditis, the purpose of the current study was to determine whether anticardiac myosin Abs might be present during the acute stage of KS. Sera from KS patients as well as age-matched febrile controls and normal adults were compared for reactivity with human cardiac myosin in ELISAs and Western blot assays. A total of 5 of 13 KS sera, as compared with 5 of 8 acute rheumatic fever sera, contained Ab titers to human cardiac myosin that were significantly higher than those found in control sera. Both cardiac and skeletal myosins were recognized in the ELISA by KS sera, although stronger reactivity was observed to human cardiac myosin. Only IgM antimyosin Abs from KS sera were significantly elevated relative to control sera. KS sera containing antimyosin Abs recognized synthetic peptides from the light meromyosin region of the human cardiac myosin molecule and had a different pattern of reactivity than acute rheumatic fever sera, further supporting the association of antimyosin Ab with KS. These Abs may contribute to the pathogenesis of acute myocarditis found in patients with KS.
Asunto(s)
Autoanticuerpos/sangre , Síndrome Mucocutáneo Linfonodular/inmunología , Miocardio/inmunología , Miosinas/inmunología , Adulto , Secuencia de Aminoácidos , Animales , Especificidad de Anticuerpos , Autoanticuerpos/toxicidad , Western Blotting , Línea Celular , Niño , Pruebas Inmunológicas de Citotoxicidad , Ensayo de Inmunoadsorción Enzimática , Humanos , Sueros Inmunes/toxicidad , Datos de Secuencia Molecular , Miocardio/citología , Subfragmentos de Miosina/inmunología , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/inmunología , RatasRESUMEN
Studies from a number of centers have documented the growth and success of pediatric heart transplantation. The 1st year of life is the period of greatest mortality from congenital heart disease and has now become the single most frequent age of pediatric heart transplantation. Appropriately, congenital heart disease is the most common diagnosis leading to heart transplantation. Early mortality is still greatest in recipients who undergo transplantation during the 1st year of life. The patients at greatest risk are being identified and new maneuvers to lower early mortality are emerging. Long-term follow-up continues to indicate excellent late survival with low morbidity. This review focuses on key advances in knowledge reported in the last year.
Asunto(s)
Trasplante de Corazón , Niño , Estudios de Seguimiento , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/tratamiento farmacológico , Cardiopatías Congénitas/mortalidad , Cardiopatías Congénitas/cirugía , Humanos , Inmunosupresores/uso terapéutico , Lactante , Cuidados Posoperatorios , Análisis de SupervivenciaRESUMEN
Kawasaki disease (KD) is the leading cause of acquired heart disease in children in the United States. The etiology is unknown. Data regarding the presence of T cell activation and its potential role in the pathogenesis of the disease have been conflicting. Expansion of T cells bearing V beta 2 and V beta 8 has recently been reported in the acute phase of KD, which suggests that a superantigen may mediate the disease process. To further assess the potential role of T cells in KD, T cell phenotypes were evaluated by using flow cytometry in a large series of patients, acutely and during convalescence. Included in this analysis were assessments of changes in the percentage of T cells bearing TCR V beta 2, V beta 5.1, V beta 6.7, V beta 8, V beta 12.1, and V beta 19 over time; the percentage of each V beta family bearing the activation markers HLA-DR and IL-2R; and the percentage of each V beta family bearing the memory marker, CD45RO. No expansion of any V beta family was present acutely, nor were increases in HLA-DR and IL-2R observed. However, a significant increase was observed during convalescence in the percentage of cells bearing CD45RO in the CD8+, but not the CD4+, population. CD45RO expression was also increased on V beta 2, V beta 8, and V beta 19 CD8+ T cells in a subset of patients. These data suggest that one or more conventional Ags drive the T cell immune response in KD, and argue against a role for superantigens in the disease process.