RESUMEN
Allograft failure secondary to rejection commonly requires a multimodal treatment, ultimately including mechanical circulatory support. A few case reports have demonstrated the use of Impella-devices due to its assumed favorable safety profile in this fragile cohort. However, this treatment option does not play a role in choice of anti-rejective therapy in clinical routine up to date. We summarize our institutional experiences and literature mini-review on Impella-based treatment strategies in allograft rejection after heart transplantation. In all seven cases, three from our institution and four reported in the literature, Impella-based therapies led to hemodynamic stabilization in allograft failure secondary to rejection. Adverse events included hemolysis, non-fatal bleeding and in one patient a relevant aortic valve insufficiency occurred. All patients showed an improvement of allograft function. Two patients died in context of severe immunosuppression or late secondary organ failure. Based on the limited available data, we propose that Impella-mediated mechanical unloading represents a valuable option for hemodynamic stabilization in severe allograft failure due to rejection, enabling an initiation of causal therapy and thereby potentially representing an opportunity to prevent mortality. Furthermore, we hypothesize it might add to the traditional therapeutic approaches by facilitating recovery by decompressing the myocardium in allograft rejection.
Asunto(s)
Insuficiencia Cardíaca , Trasplante de Corazón , Corazón Auxiliar , Aloinjertos , Rechazo de Injerto , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/cirugía , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: Circulatory efficiency reflects the ratio between total left ventricular work and the work required for maintaining cardiovascular circulation. The effect of severe aortic valve stenosis (AS) and aortic valve replacement (AVR) on left ventricular/circulatory mechanical power and efficiency is not yet fully understood. We aimed to quantify left ventricular (LV) efficiency in patients with severe AS before and after surgical AVR. METHODS: Circulatory efficiency was computed from cardiovascular magnetic resonance (CMR) imaging derived volumetric data, echocardiographic and clinical data in patients with severe AS (n = 41) before and 4 months after AVR and in age and sex-matched healthy subjects (n = 10). RESULTS: In patients with AS circulatory efficiency was significantly decreased compared to healthy subjects (9 ± 3% vs 12 ± 2%; p = 0.004). There were significant negative correlations between circulatory efficiency and LV myocardial mass (r = - 0.591, p < 0.001), myocardial fibrosis volume (r = - 0.427, p = 0.015), end systolic volume (r = - 0.609, p < 0.001) and NT-proBNP (r = - 0.444, p = 0.009) and significant positive correlation between circulatory efficiency and LV ejection fraction (r = 0.704, p < 0.001). After AVR, circulatory efficiency increased significantly in the total cohort (9 ± 3 vs 13 ± 5%; p < 0.001). However, in 10/41 (24%) patients, circulatory efficiency remained below 10% after AVR and, thus, did not restore to normal values. These patients also showed less reduction in myocardial fibrosis volume compared to patients with restored circulatory efficiency after AVR. CONCLUSION: In our cohort, circulatory efficiency is reduced in patients with severe AS. In 76% of cases, AVR leads to normalization of circulatory efficiency. However, in 24% of patients, circulatory efficiency remained below normal values even after successful AVR. In these patients also less regression of myocardial fibrosis volume was seen. Trial Registration clinicaltrials.gov NCT03172338, June 1, 2017, retrospectively registered.
Asunto(s)
Estenosis de la Válvula Aórtica/cirugía , Válvula Aórtica/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Función Ventricular Izquierda , Anciano , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/fisiopatología , Estudios de Casos y Controles , Ecocardiografía Doppler , Femenino , Fibrosis , Prótesis Valvulares Cardíacas , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Humanos , Imagen por Resonancia Cinemagnética , Masculino , Persona de Mediana Edad , Miocardio/patología , Recuperación de la Función , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Remodelación VentricularRESUMEN
Mechanical circulatory support nowadays represents an important option in the treatment of patients with advanced heart insufficiency. Once developed as a bridging to heart transplantation, it is now a valuable option for permanent support in patients for whom a heart transplantation is not possible due to contraindications or a lack of available organs. Furthermore, it can be used as a bridging to myocardial recovery and explantation. The number of implantations of left ventricular assist devices (LVAD) has clearly increased in recent years and approximately one half of these implantations is already carried out in centers not specialized in transplantations. This development necessitates that every practicing physician is aware of the basic principles of mechanical circulatory support and with the possible complications. This article gives a summary of the current state of the technology and treatment of patients with long-term VADs.
Asunto(s)
Insuficiencia Cardíaca/prevención & control , Corazón Auxiliar , Bombas de Infusión Implantables , Cuidado Terminal/métodos , Disfunción Ventricular Izquierda/terapia , Enfermedad Crónica , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/etiología , Humanos , Diseño de Prótesis , Resultado del Tratamiento , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/diagnósticoRESUMEN
A 57-year-old female lung transplant recipient developed tuberculosis after quadruple maintenance immunosuppression for acute cellular rejection with respiratory compromise. Deteriorating neurological status led to cerebral imaging and lumbar puncture, which showed Mycobacterium tuberculosis. Tuberculous meningitis with elevated intracranial pressure was treated for 2 weeks on a neurosurgical ward, and intensive care therapy was necessary for another 2 weeks. Complete neurological recovery was achieved after 3 months.
Asunto(s)
Trasplante de Pulmón/efectos adversos , Mycobacterium tuberculosis , Tuberculosis Meníngea/diagnóstico por imagen , Tuberculosis Meníngea/diagnóstico , Antituberculosos/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/microbiología , Femenino , Humanos , Hipertensión Intracraneal , Persona de Mediana Edad , Radiografía , Punción Espinal , Tomógrafos Computarizados por Rayos X , Tuberculosis Meníngea/microbiologíaRESUMEN
BACKGROUND: Female gender is a risk factor for early mortality after coronary artery bypass graft surgery (CABG). Yet, the causes for this excess mortality in women have not been fully explained. OBJECTIVES: To analyse gender differences in early mortality (30 days post surgery) after CABG and to identify variables explaining the association between female gender and excess mortality, taking into account preoperative clinical and psychosocial, surgical and postoperative risk factors. METHODS: A total of 1,559 consecutive patients admitted to the German Heart Institute Berlin (2005-2008) for CABG were included in this prospective study. A comprehensive set of prespecified preoperative, surgical and postoperative risk factors were examined for their ability to explain the gender difference in early mortality. RESULTS: Early mortality after CABG was higher in women than in men (6.9 vs. 2.4 %, HR 2.91, 95 % CI 1.70-4.96, P < 0.001). Women were older than men (+4.7 years, P < 0.001), had lower self-assessed preoperative physical functioning (-16 points on a scale from 0 to 100, P < 0.001), and had higher rates of postoperative low cardiac output syndromes (6.6 vs. 3.3 %, P = 0.01), respiratory insufficiency (9.4 vs. 5.3 %, P = 0.006) and resuscitation (5.2 vs. 1.8 %, P = 0.001). The combination of these factors explained 71 % of the gender difference in early mortality; age and physical functioning alone accounted for 61 %. Adjusting for these variables, HR for female gender was 1.36 (95 % CI 0.77-2.41, P = 0.29). CONCLUSIONS: Age, physical function and postoperative complications are key mediators of the overmortality of women after aortocoronary bypass surgery. Self-assessed physical functioning should be more seriously considered in preoperative risk assessment particularly in women.
Asunto(s)
Gasto Cardíaco Bajo/epidemiología , Puente de Arteria Coronaria/mortalidad , Insuficiencia Cardíaca/cirugía , Insuficiencia Respiratoria/epidemiología , Factores de Edad , Anciano , Puente de Arteria Coronaria/métodos , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Resucitación/métodos , Factores de Riesgo , Factores Sexuales , Factores de TiempoRESUMEN
BACKGROUND: Mycophenolate mofetil (MMF) is superior to azathioprine (AZA) in preventing allograft rejections episodes (ARE) early after heart transplantation (HTx). However, long-term efficacy and adverse events are barely known. We evaluated the long-term efficacy and safety, comparing patient outcomes with either MMF or AZA as components of maintenance immunosuppression regimens. METHODS: We evaluated all patients who underwent HTx between January 1994 and May 2003 and received the same induction immunosuppression followed by treatment with cyclosporine (CsA), prednisolone, and with either MMF or AZA. We analyzed the survival, number, and severity of ARE, development of coronary allograft vasculopathy (CAV), and main adverse effects (infections, tumors). RESULTS: Patients receiving MMF (n = 137) showed a lower mortality rate than those treated with AZA (n = 121). There were significant differences between the groups for all parameters evaluated (P < .01). The prevalence of deaths was 18.3% in the MMF group and 47.9% in the AZA group. Biopsy-proven ARE greater than grade 1A and antirejection therapies per patient were lower among the MMF than the AZA group (0.20 vs 0.31 and 0.96 vs 1.24, respectively). Prevalence of coronary stenoses was 11.7% in the MMF group and 24.8% in the AZA group. Rate of extracutaneous and cutaneous malignancies was lower in the MMF than the AZA group (7.3% and 5.8% vs 18.2% and 9.1%, respectively). The prevalence of infections was higher in the MMF group. Patients who were switched during the first post-HTx year from AZA to MMF (n = 97) and thereafter received CsA plus MMF for >1 year also showed significantly better survival than those who remained on AZA treatment. CONCLUSIONS: Among a cohort of patients being followed long term, MMF appeared to be highly efficient to prevent both ARE and the development of coronary artery stenoses. The use of MMF also significantly improved the survival of heart transplant recipients compared with AZA, despite a greater incidence of infections linked to MMF therapy.
Asunto(s)
Trasplante de Corazón/inmunología , Inmunosupresores/uso terapéutico , Ácido Micofenólico/análogos & derivados , Azatioprina/uso terapéutico , Biopsia , Ciclosporina/uso terapéutico , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Rechazo de Injerto/prevención & control , Trasplante de Corazón/mortalidad , Humanos , Ácido Micofenólico/uso terapéutico , Prednisolona/uso terapéutico , Estudios Retrospectivos , Seguridad , Tasa de Supervivencia , Sobrevivientes/estadística & datos numéricos , Factores de Tiempo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Xenograft outcomes are dictated by xenoantigen expression, for example, Gal alpha1, 3Gal (Gal), but might also depend on differing vascular responses. We investigated whether differential vascular gene expression in kidney and cardiac xenografts correlate with development of thrombotic microangiopathy (TM) and consumptive coagulation (CC). Immunosuppressed baboons underwent miniswine or hDAF pig kidney (n = 6) or heart (n = 7), or Gal-transferase gene-knockout (GalT-KO) (thymo)kidney transplantation (n = 14). Porcine cDNA miniarrays determined donor proinflammatory, apoptosis-related and vascular coagulant/fibrinolytic gene expression at defined time points; validated by mRNA, protein levels and immunopathology. hDAF-transgenic and GalT-KO xenografts, (particularly thymokidneys) exhibited prolonged survival. CC was seen with Gal-expressing porcine kidneys (3 of 6), only 1 of 7 baboons postcardiac xenotransplantation and was infrequent following GalT-KO grafts (1 of 14). Protective-type genes (heme oxygenase-I, superoxide dismutases and CD39) together with von Willebrand factor and P-selectin were upregulated in all renal grafts. Transcriptional responses in Gal-expressing xenografts were comparable to those seen in the infrequent GalT-KO rejection. In cardiac xenografts, fibrin deposition was associated with increased plasminogen activator inhibitor-1 expression establishing that gene expression profiles in renal and cardiac xenografts differ in a quantitative manner. These findings suggest that therapeutic targets may differ for renal and cardiac xenotransplants.
Asunto(s)
Rechazo de Injerto/inmunología , Trasplante de Corazón/inmunología , Trasplante de Riñón/inmunología , Trasplante Heterólogo/inmunología , Sistema del Grupo Sanguíneo ABO/inmunología , Enfermedad Aguda , Animales , ADN Complementario/genética , Rechazo de Injerto/mortalidad , Rechazo de Injerto/patología , Supervivencia de Injerto/inmunología , Trasplante de Corazón/mortalidad , Trasplante de Riñón/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Papio , Proteínas/genética , Porcinos/genética , Timo/trasplante , Acondicionamiento Pretrasplante/métodosRESUMEN
Infections with cytomegalovirus (CMV) can induce severe complications after transplantation, particularly in patients resistant to virostatic therapy. Adoptive transfer of CMV-specific T-cell lines has demonstrated promising results in patients after hematopoietic stem cell transplantation. However, the generation of specific T-cell lines ex vivo and their function in vivo is complicated in solid organ transplant (SOT) recipients. Here, we present the successful adoptive transfer of autologous CMV-specific T cells to a lung transplant recipient with ganciclovir-resistant CMV-pneumonia requiring mechanical ventilation. Infused T cells rapidly expanded in vivo and efficiently inhibited viral replication as confirmed by extensive longitudinal immunological monitoring. After full recovery, the patient was released from the clinic. After 4 weeks, the infection reappeared and persisted at a low level even after a second T-cell infusion. Our experimental data indicate that this could be the consequence of the late differentiated phenotype of the infused T cells and therefore their insufficient longevity in vivo. In summary, our report signifies the high therapeutic potential of adoptive immunotherapy in the treatment of SOT recipients when all other measures show no effect. Further studies have to elucidate the most potent strategies to generate antigen-specific T cells with high functional capacity and robust long-term persistence.
Asunto(s)
Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/terapia , Inmunoterapia Adoptiva/métodos , Trasplante de Pulmón/efectos adversos , Trasplante de Pulmón/inmunología , Neumonía Viral/etiología , Neumonía Viral/terapia , Linfocitos T/inmunología , Linfocitos T/trasplante , Secuencia de Aminoácidos , Antígenos Virales/genética , Antivirales/farmacología , Línea Celular , Citomegalovirus/genética , Citomegalovirus/inmunología , Citomegalovirus/fisiología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Farmacorresistencia Viral , Mapeo Epitopo , Ganciclovir/farmacología , Humanos , Interferón gamma/biosíntesis , Masculino , Persona de Mediana Edad , Neumonía Viral/inmunología , Neumonía Viral/virología , Recurrencia , Trasplante Autólogo , Replicación ViralRESUMEN
AIMS: This study investigated the early and mid-term results following valve replacement with the new Shelhigh stentless bioprosthesis made entirely of biological material in patients with active infective endocarditis (AIE). MATERIAL AND METHODS: Between 02/2000 and 12/2004, 164 patients (n = 122 men, mean age 59, 18-85 years) received implantation of an AIE Shelhigh stentless bioprosthesis in the aortic, mitral, tricuspid or pulmonary position. A total of 119 patients (72.6%) had native AIE and 45 (27.4%) prosthetic AIE. A large proportion of the patients reached the operating room in a condition of cardiac decompensation: 37 (22.6%) patients were intubated, 40 (24.4%) had protracted septic shock and 41 (25.0%) required intensive catecholamine treatment. Surgery was regarded as urgent in 94 patients (57.4%) and was performed as an emergency procedure in 70 (42.6%). The mean follow-up time is 1.5 +/- 0.11 years (range, 5 months to 5.2 years). Echocardiographic follow-up examinations were performed early postoperatively and after 12 months. RESULTS: In terms of the operative indication, we found a highly significant difference in the survival rate between patients who were operated on urgently vs in an emergency. In patients who died within 30 days, the main cause of death was septic multiorgan failure (67.6%). Only three patients required reoperation due to reinfection of the Shelhigh bioprostheses; this represents a reinfection rate of 1.8% in relation to the whole cohort. The postoperative echocardiographic examinations showed the Shelhigh valves to have very good hemodynamics without relevant pressure gradients. CONCLUSION: Our experience in the use of Shelhigh bioprostheses in patients with native and prosthetic endocarditis show the early and mid-term results, in particular the low reinfection rate and the good hemodynamics, to be comparable with the results achieved using homografts. Since these prostheses are readily available and their implantation straightforward, they are increasingly being used in patients with endocarditis. These promising results need to verified in the long term.
Asunto(s)
Bioprótesis , Endocarditis/mortalidad , Endocarditis/cirugía , Enfermedades de las Válvulas Cardíacas/mortalidad , Enfermedades de las Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas/estadística & datos numéricos , Prótesis Valvulares Cardíacas/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Endocarditis/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo/métodos , Factores de Riesgo , Stents/estadística & datos numéricos , Análisis de Supervivencia , Tasa de Supervivencia , Resultado del Tratamiento , UltrasonografíaRESUMEN
BACKGROUND: Bronchial arteries are not anastomosed during lung transplantation. We analyzed the occurrence of pulmonary hemorrhage after transplantation. PATIENTS AND METHODS: 235 patients were included. RESULTS: We observed pulmonary bleeding in 4/235 patients (1.7 %). All four cases were due to transplant-specific disorders (arrosion of pulmonary artery in three cases, coagulopathy in one patient). CONCLUSIONS: The analysis shows, that usual pulmonary hemorrhage does not occur in lung transplant recipients. This underlines the role of bronchial arteries in pulmonary hemorrhage of non-LTX-patients.
Asunto(s)
Hemoptisis/etiología , Trasplante de Pulmón/efectos adversos , Hemorragia Posoperatoria/etiología , Adolescente , Adulto , Anciano , Anastomosis Quirúrgica , Bronquios/cirugía , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Troponin T levels have been monitored in baboons (n = 8) undergoing pig heterotopic heart transplantation, and correlated with a decrease in graft contractions and graft survival. Pig heart graft survival was from 12 to 139 days (mean 45, median 33), and graft failure was associated with predominant thrombotic microangiopathy and ischemia, with focal hemorrhage, and edema. An increase in troponin T levels 5 to 6 days before graft failure correlated closely with diminished graft contractions. An increase in troponin T was a reliable indicator that graft dysfunction was occurring.
Asunto(s)
Trasplante de Corazón , Trasplante Heterotópico , Troponina T/metabolismo , Animales , Biomarcadores/sangre , Isquemia Fría , Supervivencia de Injerto/fisiología , Modelos Cardiovasculares , Isquemia Miocárdica/etiología , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatología , Papio , PorcinosRESUMEN
BACKGROUND: ABI793 (ABI) is a human monoclonal antibody (mAb) specific for human CD154. To assess the suitability of ABI for baboon transplantation studies, we carried out in vitro studies to determine ABI's reactivity with baboon cells expressing CD154, performed in vivo pharmacokinetic studies in two baboons, and tested the effect of ABI administration on elicited antibody production in two baboons undergoing either pig hematopoietic progenitor cell (PBPC) or heterotopic heart transplantation. METHODS: In vitro: Baboon peripheral blood mononuclear cells were activated in vitro to upregulate CD154, and binding of ABI to CD154 was measured by flow cytometry. In vivo: Serum levels of ABI were measured immediately before and 15 min after the intravenous administration of ABI (20 mg/kg) to two baboons over 28 days. Subsequently, ABI (25 mg/kg on days 0, 1, 4 and 7, and then 20 mg/kg every 5 days) was included in the immunosuppressive regimen in two pig-to-baboon transplants (PBPC or heart transplantation). RESULTS: In vitro: ABI was almost non-reactive to baboon T cells before stimulation, but bound to activated T cells. In vivo: In the pharmacokinetic study, trough levels of ABI (before the next dose) ranged between 190 and 580 microg/ml, and the estimated half-life was 10-15 days. There was no apparent toxicity. Following pig PBPC or heart transplantation, no elicited antibody was detected while ABI was being administered or during several weeks of follow-up. CONCLUSIONS: ABI functions in baboons, is well-tolerated, and prevents an elicited antibody response to pig antigens.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Ligando de CD40/inmunología , Trasplante de Corazón/inmunología , Papio , Porcinos , Trasplante Heterólogo/inmunología , Animales , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Ligando de CD40/sangre , Ligando de CD40/metabolismo , Citometría de Flujo , Expresión Génica , Células Madre Hematopoyéticas/inmunología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Papio/inmunología , Porcinos/inmunologíaRESUMEN
To investigate the specificity of anti-Galalpha1,3Gal (Gal) antibodies (Abs) with respect to Gal oligosaccharides of types 2 and 6, eight baboons received an intravenous infusion of either a poly-l-lysine conjugate of Gal type 2 (n = 5) or type 6 (n = 3), followed 48 h later by the alternative Gal type 6 or 2 conjugate, respectively. IgM Abs reactive to Gal type 2 were depleted by 80 to 89% by either Gal conjugate. IgM reactive to Gal type 6 was less efficiently depleted by the Gal type 2 conjugate (57% depletion) than the Gal type 6 (82% depletion). Gal-reactive IgG was depleted more slowly and less efficiently by either glycoconjugate (initially by only 28 to 54%). Our results indicate that the Gal type 6 conjugate depletes most anti-Gal IgM, but the Gal type 2 conjugate is less efficient in depleting anti-Gal IgM reactive with type 6. There remain small fractions of antibody that are unadsorbed, particularly of IgG, probably due to their low affinity and distribution in both the intra- and extra-vascular compartments.
Asunto(s)
Disacáridos/inmunología , Galactosa , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Polilisina/farmacología , Trisacáridos/farmacología , Animales , Ensayo de Inmunoadsorción Enzimática , Epítopos/inmunología , Inyecciones Intravenosas , Papio , Polilisina/administración & dosificación , Trisacáridos/administración & dosificaciónRESUMEN
BACKGROUND: Spleen transplantation (Tx) between some strains of rodents can lead to donor-specific tolerance either spontaneously or after a short course of immunosuppression. This study developed a surgical technique for spleen Tx in miniature swine to investigate its immunologic impact in a large animal model. METHODS: The preferred surgical technique of spleen Tx (n=8) involved excision of the donor spleen with its vascular pedicle to the aorta and portal vein. Carrel patches of donor aorta and portal vein were anastomosed to the abdominal aorta and inferior vena cava, respectively, of the (splenectomized) recipient. The results in four major histocompatibility complex-matched pairs that were mismatched for the porcine allelic antigen are reported. Two recipients were untreated, one received a 12-day course of cyclosporine A (CsA) alone, and one received thymic irradiation (700 cGy) and CsA. Hematopoietic cell chimerism was followed by fluorescence-activated cell sorter, and graft survival was assessed by histology. RESULTS: Spleen Tx was technically successful. In two untreated pigs, chimerism was detected in the blood (maximum 5% for 17 and 25 days) and lymph nodes (maximum 6% for 28 and 56 days), but both grafts showed histologic rejection by day 28. In two treated pigs, chimerism was present in the blood for 47 and 57 days, and rejection was prevented, with follow-up for 57 and 217 days, respectively. CONCLUSION: Spleen Tx in major histocompatibility complex-matched pairs treated with CsA+/-thymic irradiation results in prolonged chimerism and is associated with the development of in vivo unresponsiveness to the transplanted spleen.
Asunto(s)
Complejo Mayor de Histocompatibilidad/inmunología , Bazo/trasplante , Esplenectomía/métodos , Animales , Biopsia , Ciclosporina/farmacología , Citometría de Flujo , Rechazo de Injerto/mortalidad , Rechazo de Injerto/patología , Células Madre Hematopoyéticas/citología , Prueba de Histocompatibilidad , Inmunosupresores/farmacología , Complicaciones Posoperatorias , Trasplante de Piel/inmunología , Bazo/patología , Porcinos Enanos , Donantes de Tejidos , Quimera por TrasplanteRESUMEN
BACKGROUND: Arsenic trioxide (As2O3) is an anticancer drug that has been reported to induce apoptosis and inhibit differentiation in human plasmacytoma and normal plasma/B cells without significant myelosuppression. We assessed the ability of As2O3 as single therapy or in combination with an anti-CD20 monoclonal antibody (mAb) and whole body irradiation (WBI) to deplete B and plasma cells, both in vitro and in vivo, and to reduce the level of anti-alphaGal1-3Gal antibody (anti-Gal Ab) in baboons. METHODS: In vitro the effect of As2O3 on antibody secretion (anti-Gal IgM, total IgG and IgM) was measured by enzyme-linked immunospot assay (ELISPOT). Its inhibition of proliferation of baboon splenocytes and the NCI-H929 human plasmacytoma cell line was measured by tritiated thymidine uptake. In vivo: all baboons (n=7) had undergone splenectomy. The effects of As2O3 (0.18 to 0.36 mg/kg) on B/plasma cell depletion and anti-Gal Ab production were assessed in three baboons. For comparison, three baboons received either WBI (2 x 150 cGy) or anti-CD20 mAb (20 mg/kg x 4 doses), or both WBI and anti-CD20 mAb. A final baboon received As2O3 + WBI (150 cGy) + anti-CD20 mAb. Anti-Gal Ab levels were measured daily by ELISA. Depletion of B cells from blood and bone marrow (BM) was monitored by flow cytometry and by histology of lymph nodes (LN). Autopsy was performed in three baboons. RESULTS: In vitro: As2O3 (at 5 x 10-6 mol/l) reduced anti-Gal IgM and total IgM secretors by 76% (P=0.53) and 95% (P < 0.001), respectively, but did not reduce total IgG secretors. As2O3 inhibited in a dose-dependent manner the proliferation of activated splenocytes and of the NCI-H929 plasmacytoma cell line; complete inhibition was achieved at a dose of 1 x 10-5 mol/l. In vivo: As2O3 was found to be toxic at the doses given and was associated with the deaths of two of the four baboons that received it. Daily intravenous therapy with As2O3 alone reduced B cells (CD20+) in the blood (by 50 to 90%), BM (40%) and LN (20 to 30%), but anti-Gal Ab levels were not significantly decreased. Anti-CD20 mAb therapy alone or WBI alone depleted B cells by 100% in the blood and BM, and 80 to 100% in the LN. The combination of anti-CD20 mAb + WBI led to depletion of B cells in blood, BM and LN for 3 months, but reduction of anti-Gal Ab remained marginal. The combination of As2O3 + anti-CD20 mAb + WBI did not reduce anti-Gal Ab levels further. At autopsy in the latter baboon, B cells remained present in Peyer's patches and tonsils. CONCLUSIONS: In vitro: As2O3 reduced B/plasma cell numbers and suppressed IgM secretors, but not IgG secretors. In vivo: As2O3 was not as effective as either anti-CD20 mAb or WBI in depleting B/plasma cells, and was largely ineffective in reducing anti-Gal Ab levels. Its administration was associated with considerable toxicity. Autopsy in one baboon suggested that B cells in Peyer's patches and tonsils may be resistant to therapy and remain a source of continuing production of anti-Gal Ab.
Asunto(s)
Antineoplásicos/toxicidad , Disacáridos/inmunología , Óxidos/toxicidad , Células Plasmáticas/efectos de los fármacos , Trasplante Heterólogo/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Antígenos CD20/inmunología , Arsénico/sangre , Trióxido de Arsénico , Arsenicales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Técnicas In Vitro , Ganglios Linfáticos/citología , Papio , Células Plasmáticas/inmunología , Bazo/citología , Irradiación Corporal TotalAsunto(s)
Transfusión de Leucocitos , Oligosacáridos/administración & dosificación , Oligosacáridos/inmunología , Animales , Anticuerpos Heterófilos/sangre , Anticuerpos Heterófilos/aislamiento & purificación , Infusiones Intravenosas , Papio , Esplenectomía , Porcinos , Trasplante Heterólogo/inmunologíaRESUMEN
The immunologic barriers to xenotransplantation are summarized and approaches to overcome them briefly reviewed. Intensive investigation is being directed to the problem of acute humoral xenograft rejection, which is the major current barrier. Although the induced antibody response appears to be prevented by combination therapy with an anti-CD154 monoclonal antibody and mycophenolate mofetil, deposition of natural anti-Gal antibody on the graft endothelial cells appears to be sufficient to lead to rejection or a state of consumptive coagulopathy. Approaches towards the induction of tolerance are described. The potential microbiologic risks and physiologic incompatibilities of pig-to-human organ transplantation are also briefly discussed.
Asunto(s)
Trasplante Heterólogo/inmunología , Animales , Endotelio Vascular/citología , Ingeniería Genética , Rechazo de Injerto , Trasplante de Células Madre Hematopoyéticas , Humanos , Terapia de Inmunosupresión/métodos , Porcinos , Timo/trasplante , Quimera por TrasplanteRESUMEN
BACKGROUND: Anti-Galalpha 1-3Gal (Gal) antibodies (Ab) play a key role in the rejection of pig cells or organs transplanted into primates. A course of extracorporeal immunoadsorption (EIA) of anti-Gal Ab using an immunoaffinity column of a Gal type 6 oligosaccharide depletes Ab successfully, but Ab returns during the next few days. Although therapy with an anti-CD154 monoclonal antibody (mAb) prevents an induced Ab response to Gal or non-Gal epitopes, T cell-independent natural anti-Gal IgM and IgG return to baseline (pretransplant) levels. We have investigated the capacity of continuous i.v. infusion of bovine serum albumin conjugated to Gal type 6 oligosaccharide (BSA-Gal) to deplete or maintain depletion of circulating anti-Gal Ab. METHODS: Porcine peripheral blood mobilized progenitor cells (PBPC) obtained by leukapheresis from MHC-inbred miniature swine (n=6) were transplanted into baboons. Group 1 baboons (n=4) underwent whole body (300 cGy) and thymic (700 cGy) irradiation, T cell depletion with antithymocyte globulin, complement depletion with cobra venom factor, short courses of anti-CD154 mAb therapy (20 mg/kg i.v. on alternate days), cyclosporine (CyA) (in two baboons only), mycophenolate mofetil, and porcine hematopoietic growth factors. Anti-Gal Ab depletion by EIA was carried out before transplantation of high doses (2-4x 1010 cells/kg) of PBPC. Group 2 baboons (n=3) received the group 1 regimen (including CyA) plus a continuous i.v. infusion of BSA-Gal. To prevent sensitization to BSA, anti-CD154 mAb therapy was continued until BSA-Gal administration was discontinued. RESULTS: In group 1, Gal-reactive Ab returned to pre-PBPC transplant levels within 15-21 days, but no induced Ab to Gal or non-Gal determinants developed while anti-CD154 mAb therapy was being administered. In group 2, anti-Gal Ab was either not measurable or minimally measurable while BSA-Gal was being administered. After discontinuation of BSA-Gal, Ab did not return to pre-PBPC transplant level for more than 40-60 days, and no sensitization developed even when all therapy was discontinued. In one baboon, however, Ab to Gal type 2, but not type 6, returned during BSA-Gal therapy. CONCLUSIONS: Prevention of the induced humoral response to Gal and non-Gal epitopes by anti-CD154 mAb therapy has been reported previously by our group, but our studies are the first to demonstrate a therapy that resulted in an absence of natural anti-Gal Ab for a prolonged period. The combination of BSA-Gal and T cell costimulatory blockade may facilitate survival of pig cells and organs transplanted into primates. The return in one baboon of Ab reactive with the Gal type 2 oligosaccharide, but not type 6, indicates some polymorphism of anti-Gal Ab and suggests that, to be effective in all cases, the infusion of a combination of type 6 and type 2 BSA-Gal may be required.