RESUMEN
We present this observational study of lung transplant recipients (LTR) treated with carfilzomib (CFZ)-based therapy for antibody-mediated rejection (AMR) of the lung. Patients were considered responders to CFZ if complement-1q (C1q)-fixing ability of their immunodominant (ID) donor-specific anti-human leukocyte antibody (DSA) was suppressed after treatment. Treatment consisted of CFZ plus plasma exchange and immunoglobulins. Fourteen LTRs underwent CFZ for 20 ID DSA AMR. Ten (71.4%) of LTRs responded to CFZ. DSA IgG mean fluorescence intensity (MFI) fell from 7664 (IQR 3230-11 874) to 1878 (653-7791) after therapy (p = 0.001) and to 1400 (850-8287) 2 weeks later (p = 0.001). DSA C1q MFI fell from 3596 (IQR 714-14 405) to <30 after therapy (p = 0.01) and <30 2 weeks later (p = 0.02). Forced expiratory volume in 1s ( FEV1 ) fell from mean 2.11 L pre-AMR to 1.92 L at AMR (p = 0.04). FEV1 was unchanged after CFZ (1.91 L) and subsequently rose to a maximum of 2.13 L (p = 0.01). Mean forced expiratory flow during mid forced vital capacity (25-75) (FEF25-75 ) fell from mean 2.5 L pre-AMR to 1.95 L at AMR (p = 0.01). FEF25-75 rose after CFZ to 2.54 L and reached a maximum of 2.91 L (p = 0.01). Responders had less chronic lung allograft dysfunction or progression versus nonresponders (25% vs. 83%, p = 0.04). No deaths occurred within 120 days and 7 patients died post CFZ therapy of allograft failure. Larger prospective interventional studies are needed to further describe the benefit of CFZ-based therapy for pulmonary AMR.
Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Isoanticuerpos/efectos adversos , Trasplante de Pulmón/efectos adversos , Oligopéptidos/uso terapéutico , Inhibidores de Proteasoma/uso terapéutico , Adulto , Anciano , Aloinjertos , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Pronóstico , Factores de RiesgoRESUMEN
Elevated serum soluble (s) suppressor of tumorigenicity-2 is observed during cardiovascular and inflammatory bowel diseases. To ascertain whether modulated ST2 levels signify heart (HTx) or small bowel transplant (SBTx) rejection, we quantified sST2 in serially obtained pediatric HTx (n = 41) and SBTx recipient (n = 18) sera. At times of biopsy-diagnosed HTx rejection (cellular and/or antibody-mediated), serum sST2 was elevated compared to rejection-free time points (1714 ± 329 vs. 546.5 ± 141.6 pg/mL; p = 0.0002). SBTx recipients also displayed increased serum sST2 during incidences of rejection (7536 ± 1561 vs. 2662 ± 543.8 pg/mL; p = 0.0347). Receiver operator characteristic (ROC) analysis showed that serum sST2 > 600 pg/mL could discriminate time points of HTx rejection and nonrejection (area under the curve [AUC] = 0.724 ± 0.053; p = 0.0003). ROC analysis of SBTx measures revealed a similar discriminative capacity (AUC = 0.6921 ± 0.0820; p = 0.0349). Quantitative evaluation of both HTx and SBTx biopsies revealed that rejection significantly increased allograft ST2 expression. Pathway and Network Analysis of biopsy data pinpointed ST2 in the dominant pathway modulated by rejection and predicted tumor necrosis factor-α and IL-1ß as upstream activators. In total, our data indicate that alloimmune-associated pro-inflammatory cytokines increase ST2 during rejection. They also demonstrate that routine serum sST2 quantification, potentially combined with other biomarkers, should be investigated further to aid in the noninvasive diagnosis of rejection.
Asunto(s)
Biomarcadores/análisis , Rechazo de Injerto/diagnóstico , Trasplante de Corazón/efectos adversos , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Intestino Delgado/trasplante , Complicaciones Posoperatorias , Adolescente , Niño , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Rechazo de Injerto/epidemiología , Rechazo de Injerto/etiología , Supervivencia de Injerto , Cardiopatías/cirugía , Humanos , Incidencia , Proteína 1 Similar al Receptor de Interleucina-1/genética , Enfermedades Intestinales/cirugía , Intestino Delgado/patología , Masculino , Pennsylvania/epidemiología , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.
Asunto(s)
Antígenos HLA/inmunología , Prueba de Histocompatibilidad , Tolerancia Inmunológica , Inmunología del Trasplante , Alelos , Autoanticuerpos/inmunología , Antígenos HLA/genética , Humanos , Donantes de TejidosRESUMEN
Local immunological injury caused by acute lung rejection leads to fibroblast proliferation. Hyaluronate is a product of activated fibroblasts and possibly an indicator of fibroblast proliferation. One hundred thirty-six bronchoalveolar lavage and plasma hyaluronate assays were performed in 57 lung transplant recipients. Pulmonary endothelial cell function was assessed by measuring bronchoalveolar lavage levels of purine nucleoside phosphorylase. Presence of acute cellular rejection was monitored by transbronchial biopsy histologic evaluation and was classified as minimal to mild (acute rejection I, II) and moderate to severe (acute rejection III, IV). Infection was confirmed by bronchoalveolar lavage culture and antibiotic sensitivity. Bronchoalveolar lavage hyaluronate levels in clinically stable recipients were 33.5 +/- 4.69 micrograms/L and were significantly higher than with clinically stable recipients (p = 0.0001), infection (p = 0.008), or mild rejection (p = 0.001). Levels were highest in recipients with diffuse alveolar damage (392.4 +/- 60.6 micrograms/L). Diffuse alveolar damage also resulted in significant elevations of plasma HA as compared with stable recipients (p = 0.001) and mild rejection. We conclude that clinically significant injury to the allograft from rejection or diffuse alveolar damage can be assessed by bronchoalveolar lavage hyaluronate assays and suggest that the source of hyaluronate in these instances are activated fibroblasts.
Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Rechazo de Injerto/diagnóstico , Ácido Hialurónico/análisis , Infecciones/diagnóstico , Trasplante de Pulmón , Complicaciones Posoperatorias/diagnóstico , Enfermedad Aguda , Femenino , Humanos , Ácido Hialurónico/sangre , Infecciones/etiología , Enfermedades Pulmonares/diagnóstico , Masculino , Purina-Nucleósido Fosforilasa/análisisRESUMEN
Microchimerism in lung allograft recipients was studied in the autopsies of nine female recipients of male lung grafts who had survived for more than 1 month after transplantation. Using a Y chromosome-specific probe tissues were studied for the presence of donor cells that had migrated beyond the graft itself. They were quantitated by cell counting to give absolute numbers of cells per organ volume. While donor cells were disseminated throughout the body, their numbers were small. These absolute numbers should be studied in a larger group of recipients to determine if they correlate with prognosis and the development of bronchiolitis obliterans.
Asunto(s)
Quimera , Leucocitos/citología , Trasplante de Pulmón/patología , Inmunología del Trasplante/genética , Trasplante Homólogo/patología , Cromosoma Y , Adulto , Sondas de ADN , Femenino , Humanos , Hibridación in Situ , Masculino , Persona de Mediana EdadRESUMEN
We have previously reported data from clinical and laboratory animal observations which suggest that organ tolerance after transplantation depends on a state of balanced lymphodendritic cell chimerism between the host and donor graft. We have sought further evidence to support this hypothesis by investigating HLA-mismatched liver allograft recipients. 9 of 9 female recipients of livers from male donors had chimerism in their allografts and extrahepatic tissues, according to in-situ hybridisation and molecular techniques 10 to 19 years posttransplantation. In 8 women with good graft function, evidence of the Y chromosome was found in the blood (6/8), skin (8/8), and lymph nodes (7/8). A ninth patient whose transplant failed after 12 years from recurrent chronic viral hepatitis had chimerism in her lymph nodes, skin, jejunum, and aorta at the time of retransplantation. Although cell migration is thought to take place after all types of transplantation, the large population of migratory cells in, and the extent of their seeding from, hepatic grafts may explain the privileged tolerogenicity of the liver compared with other organs.
Asunto(s)
Quimera , Trasplante de Hígado/inmunología , Sistema del Grupo Sanguíneo ABO/inmunología , Adulto , Preescolar , Sondas de ADN , Femenino , Prueba de Histocompatibilidad , Humanos , Leucocitos/inmunología , Ganglios Linfáticos/inmunología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Piel/inmunología , Donantes de Tejidos , Trasplante Homólogo , Cromosoma YRESUMEN
In this study, experimental otitis media was created in the chinchilla by direct middle ear challenge with Escherichia coli endotoxin, Streptococcus pneumoniae, Haemophilus influenzae, or Pseudomonas aeruginosa. The effusions recovered from the chinchillas in all four challenge groups were shown to inhibit the lymphoproliferative response of chinchilla peripheral blood lymphocytes to stimulation with phytohemagglutinin. The effect was dose dependent, and for effusions of infectious origin, the degree of inhibition was directly related to the duration of infection. Presence of the inhibitor in plasma was undocumented, suggesting a local production within the middle ear. Lymphocytes from middle ears infected with bacteria but not middle ears challenged with endotoxin were hyporesponsive or nonresponsive to stimulation with phytohemagglutinin. These results confirm the presence of an inhibitor of the lymphoproliferative response in experimental otitis media of different etiologies.
Asunto(s)
Activación de Linfocitos/fisiología , Otitis Media con Derrame/inmunología , Animales , Supervivencia Celular , Chinchilla , FitohemaglutininasRESUMEN
Previous studies have shown that the interleukin-2-induced propagation of lymphocytes from endomyocardial biopsy specimens, an indicator of cellular rejection, is associated with the development of graft coronary disease in heart transplant patients. To further investigate the concept of cell-mediated immune responses in graft coronary disease, we have applied the methodologies of interleukin-2-induced propagation of lymphocytes from arterial tissues. In a group of 23 patients, which included 6 heart, 6 kidney, and 11 liver transplant recipients, we observed that arterial lymphocyte growth was significantly associated with obliterative vasculopathy (p less than 0.03). T-cell phenotyping analysis of coronary artery-derived lymphocyte cultures from three heart transplant patients with graft coronary disease showed significant numbers of CD4, CD8 double-negative T cells and T-cell receptor-gamma delta cells, especially when the cultures were established with relatively high doses of 400 U/ml of interleukin-2. These data suggest that the subset of CD4-CD8-, T cell receptor-gamma delta+ T cells may play a role in the pathogenesis and progression of graft coronary disease.
Asunto(s)
Relación CD4-CD8 , Enfermedad Coronaria/inmunología , Trasplante de Corazón , Complicaciones Posoperatorias/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Células Cultivadas , Enfermedad Coronaria/patología , HumanosAsunto(s)
Antibacterianos/administración & dosificación , Inmunosupresores/administración & dosificación , Trasplante de Riñón/inmunología , Trasplante de Hígado/inmunología , Animales , Perros , Femenino , Supervivencia de Injerto/efectos de los fármacos , Inmunidad Celular/efectos de los fármacos , Inyecciones Intramusculares , Prueba de Cultivo Mixto de Linfocitos , TacrolimusAsunto(s)
Antibacterianos/farmacología , División Celular/efectos de los fármacos , Animales , Células Cultivadas , Ciclosporinas/farmacología , ADN/biosíntesis , Relación Dosis-Respuesta a Droga , Factor de Crecimiento Epidérmico/farmacología , Técnicas In Vitro , Hígado/citología , Regeneración Hepática/efectos de los fármacos , Índice Mitótico/efectos de los fármacos , Ratas , TacrolimusRESUMEN
FK 506 was tested in unrelated baboons submitted to renal transplantation and bilateral native nephrectomy. Untreated baboons died after 9.2 +/- 4.0 SD days. When FK 506 was given orally for 90 days, survival with the optimum dose was 74.6 +/- 28.9 days; this allowed maximum credit for each individual animal of 90 days. A 3-day course of intramuscular FK 506 started on postoperative day 4 allowed 1- to 2-month survival. Delayed rejection in these baboons as well as in those treated daily for 90 days with FK could sometimes be reversed temporarily with a second 3-day course. The doses required for a good therapeutic effect were 10 times greater in baboons than in dogs, a finding that may reflect a species difference of lymphocyte sensitivity to this drug. FK appeared to be relatively nontoxic in subhuman primates, and it remains a promising drug for clinical trial.