RESUMEN
Calcineurin-inhibitor refractory bronchiolitis obliterans (BO) represents the leading cause of late graft failure after lung transplantation. T helper (Th)2 and Th17 lymphocytes have been associated with BO development. Taking advantage of a fully allogeneic trachea transplantation model in mice, we addressed the pathogenicity of Th cells in obliterative airway disease (OAD) occurring in cyclosporine A (CsA)-treated recipients. We found that CsA prevented CD8(+) T cell infiltration into the graft and downregulated the Th1 response but affected neither Th2 nor Th17 responses in vivo. In secondary mixed lymphocyte cultures, CsA dramatically decreased donor-specific IFN-γ production, enhanced IL-17 production and did not affect IL-13. As CD4(+) depletion efficiently prevented OAD in CsA-treated recipients, we further explored the role of Th2 and Th17 immunity in vivo. Although IL-4 and IL-17 deficient untreated mice developed an OAD comparable to wild-type recipients, a single cytokine deficiency afforded significant protection in CsA-treated recipients. In conclusion, CsA treatment unbalances T helper alloreactivity and favors Th2 and Th17 as coexisting pathways mediating chronic rejection of heterotopic tracheal allografts.
Asunto(s)
Bronquiolitis Obliterante/inducido químicamente , Ciclosporina/toxicidad , Rechazo de Injerto/inducido químicamente , Interleucina-17/fisiología , Trasplante de Pulmón/efectos adversos , Células Th2/inmunología , Tráquea/trasplante , Animales , Western Blotting , Bronquiolitis Obliterante/inmunología , Bronquiolitis Obliterante/patología , Citocinas/metabolismo , Citometría de Flujo , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Técnicas para Inmunoenzimas , Inmunosupresores/toxicidad , Interferón gamma/fisiología , Interleucina-4/fisiología , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tráquea/efectos de los fármacos , Tráquea/inmunología , Trasplante Heterotópico , Trasplante HomólogoRESUMEN
Allograft acceptance and tolerance can be achieved by different approaches including inhibition of effector T cell responses through CD28-dependent costimulatory blockade and induction of peripheral regulatory T cells (Tregs). The observation that Tregs rely upon CD28-dependent signals for development and peripheral expansion, raises the intriguing possibility of a counterproductive consequence of CTLA4-Ig administration on tolerance induction. We have investigated the possible negative effect of CTLA4-Ig on Treg-mediated tolerance induction using a mouse model of single MHC class II-mismatched skin grafts in which long-term acceptance was achieved by short-term administration of IL-2/anti-IL-2 complex. CTLA4-Ig treatment was found to abolish Treg-dependent acceptance in this model, restoring skin allograft rejection and Th1 alloreactivity. CTLA4-Ig inhibited IL-2-driven Treg expansion, and prevented in particular the occurrence of ICOS(+) Tregs endowed with potent suppressive capacities. Restoring CD28 signaling was sufficient to counteract the deleterious effect of CTLA4-Ig on Treg expansion and functionality, in keeping with the hypothesis that costimulatory blockade inhibits Treg expansion and function by limiting the delivery of essential CD28-dependent signals. Inhibition of regulatory T cell function should therefore be taken into account when designing tolerance protocols based on costimulatory blockade.
Asunto(s)
Rechazo de Injerto/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunoconjugados/administración & dosificación , Interleucina-2/administración & dosificación , Linfocitos T Reguladores/inmunología , Abatacept , Animales , Antígenos CD28/metabolismo , Prueba de Histocompatibilidad , Interleucina-2/farmacología , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
Inflammation and cancer are associated with impairment of T-cell responses by a heterogeneous population of myeloid-derived suppressor cells (MDSCs) coexpressing CD11b and GR-1 antigens. MDSCs have been recently implicated in costimulation blockade-induced transplantation tolerance in rats, which was under the control of inducible NO synthase (iNOS). Herein, we describe CD11b+GR-1+MDSC-compatible cells appearing after repetitive injections of lipopolysaccharide (LPS) using a unique mechanism of suppression. These cells suppressed T-cell proliferation and Th1 and Th2 cytokine production in both mixed lymphocyte reaction and polyclonal stimulation assays. Transfer of CD11b+ cells from LPS-treated mice in untreated recipients significantly prolonged skin allograft survival. They produced large amounts of IL-10 and expressed heme oxygenase-1 (HO-1), a stress-responsive enzyme endowed with immunoregulatory and cytoprotective properties not previously associated with MDSC activity. HO-1 inhibition by the specific inhibitor, SnPP, completely abolished T-cell suppression and IL-10 production. In contrast, neither iNOS nor arginase 1 inhibition did affect suppression. Importantly, HO-1 inhibition before CD11b+ cell transfer prevented the delay of allograft rejection revealing a new MDSC-associated suppressor mechanism relevant for transplantation.
Asunto(s)
Endotoxinas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Células Mieloides/citología , Animales , Antígeno CD11b/biosíntesis , Proliferación Celular , Sistema Inmunológico , Interleucina-10/metabolismo , Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores de Quimiocina/biosíntesis , Receptores de Quimiocina/inmunología , Linfocitos T/citología , Células TH1/citología , Células Th2/citologíaRESUMEN
Naturally occurring regulatory T-cells (Tregs) play a critical role in the homeostasis of healthy immune system. A Treg deficiency is responsible for immune system dysregulation, immune hyperreactivity and autoimmunity. Herein, we investigated the role of Tregs, either in the context of antibody-induced transplantation tolerance, mixed donor/recipient chimerism or in models of spontaneous graft acceptance without immunosuppression. We also investigated their capacities to control endotoxin-mediated immune response in the context of lymphopaenia-driven homeostatic T-cell proliferation. Finally, although Tregs adequately control Th1 and Th2 immunity, they are inefficient in regulating IL-17 producing T cells in vitro and in vivo and rather promote them.
Asunto(s)
Linfocitos T Reguladores/inmunología , Tolerancia al Trasplante/inmunología , Trasplante Homólogo/inmunología , Animales , Antígenos CD/inmunología , Humanos , Quimera por Trasplante/inmunologíaRESUMEN
Spontaneous rupture of a liver haemangioma is a rare but life-threatening acute clinical situation following haemorrhage within the liver, the subcapsular space and the peritoneal cavity in cases of capsular rupture. Rupture of a liver haemangioma has been reported to occur spontaneously in the majority of cases. In the past, prompt surgical treatment was recommended but was associated with high morbidity and mortality. Currently, conservative management and, in cases of recurrent haemorrhage, delayed surgery may be proposed. We report a case of spontaneous rupture of hepatic haemangioma treated by arterial embolisation and conservative means. The literature is also reviewed.
Asunto(s)
Hemangioma/terapia , Neoplasias Hepáticas/terapia , Embolización Terapéutica , Femenino , Hemangioma/irrigación sanguínea , Hemangioma/diagnóstico por imagen , Hemangioma/cirugía , Arteria Hepática/diagnóstico por imagen , Humanos , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Persona de Mediana Edad , Rotura Espontánea , Tomografía Computarizada por Rayos XRESUMEN
A 64-year-olf woman has been treated by chemotherapy for a uterine cervical carcinoma with known pathological lymph nodes in the abdomen and in the thorax. She is admitted in our Intensive Care Unit for fever and cardiac tamponade attributed to a large pericardial effusion. No diagnostic could be concluded from the analysis of the liquid or the pericardial biopsy. Complementary investigations are performed and the differential diagnosis of pericardial effusion is discussed in the context of a neoplastic disease.
Asunto(s)
Derrame Pericárdico/complicaciones , Neoplasias del Cuello Uterino/complicaciones , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Carboplatino/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Derrame Pericárdico/diagnóstico por imagen , Derrame Pericárdico/patología , Tomografía Computarizada por Rayos X , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
We report the case of a 74-year-old woman admitted to the emergency unit for resting dyspnea. Clinical presentation, cardiac MRI and echocardiography were consistent with cardiac tamponade requiring emergency pericardiocentesis. Cytologic examination of the pericardial fluid revealed the presence of CD68pos CD1aneg S100neg foamy histiocytes (Fig. 1). Additional investigations complied with the diagnosis of Erdheim-Chester histiocytosis. Treatment with αIFN was initiated but the patient developed severe neutropenia that contraindicated further administration. The detection of BRAFV600E mutation on histiocytes isolated from the pericardial liquid and CNS involvement (cerebral masses) prompted the administration of vemurafenib, a selective BRAFV600E kinase inhibitor. Four months after the initiation of low-dose vemurafenib, pericarditis almost resolved and cerebral masses decreased by 50% (Fig. 2). To our knowledge, analysis of pericardial fluid allowing the diagnosis of Erdheim-Chester disease and the detection of the BRAFV600E mutation has in fact been rarely described in the literature. This case report and the successful evolution under vemurafenib also support the use of BRAFV600E inhibitors in αIFN-intolerant patients with BRAFV600E mutation, particularly in case of heart and central nervous system involvement.
Asunto(s)
Enfermedad de Erdheim-Chester/diagnóstico , Líquido Pericárdico/citología , Anciano , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Enfermedad de Erdheim-Chester/patología , Femenino , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , VemurafenibAsunto(s)
Disnea/diagnóstico , Fiebre/diagnóstico , Leishmaniasis Visceral/complicaciones , Leishmaniasis Visceral/diagnóstico , Síndrome de Activación Macrofágica/diagnóstico , Anciano , Diagnóstico Diferencial , Disnea/etiología , Fiebre/etiología , Humanos , Leishmaniasis Visceral/inmunología , Síndrome de Activación Macrofágica/etiología , MasculinoRESUMEN
The impact of in vivo regulatory T cells (Treg) expansion using short-term injections of interleukin-2 (IL-2) coupled to a specific anti-IL-2 antibody was examined in various allogeneic combinations of murine skin transplantations. In a model of a single major histocompatibility complex (MHC) class II disparity, the IL-2-expanded Tregs infiltrated the transplanted skin, inhibited Th1 alloreactivity, and prevented acute graft rejection. However, in the presence of increased load of CD4-recognized alloantigens, exogenous IL-2 only moderately prolonged graft survival as attested by CD8 T cell-depletion in full minor plus major mismatched recipients treated with IL-2. If direct CD8 alloreactivity remained intact, the IL-2/anti-IL-2-mediated Tregs expansion failed to delay allograft rejection. This observation was confirmed by the inability of expanded Tregs to delay rejection of multiple minor disparate (MHC matched) skin allografts. Altogether, these results warn that cross-reactive CD8(+) T cells represent an important hurdle to Treg-based tolerance induction.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Proliferación Celular/efectos de los fármacos , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Interleucina-2/administración & dosificación , Trasplante de Piel/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Animales , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Reacciones Cruzadas , Rechazo de Injerto/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Inyecciones Intraperitoneales , Interleucina-2/inmunología , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Factores de Tiempo , Tolerancia al Trasplante/efectos de los fármacosRESUMEN
T and B memory cells are critical for host defences against pathogens. However, converging lines of evidence indicate that alloreactive memory T cells can play a detrimental role in the transplantation setting. This emergence of memory cells seems to be facilitated by several induction therapies and immunosuppressive agents, which lead to T cell loss. Herein, we briefly review some clinical and experimental observations from the literature, highlighting the immunological risk associated with enhanced T-cell memory responses.