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1.
Am J Transplant ; 17(8): 2055-2064, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28226413

RESUMEN

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel "cytotopic" agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.


Asunto(s)
Anticoagulantes/farmacología , Coagulación Sanguínea/efectos de los fármacos , Trasplante de Riñón/efectos adversos , Péptidos/farmacología , Microangiopatías Trombóticas/prevención & control , Animales , Humanos , Macaca mulatta , Masculino , Péptidos/sangre , Perfusión , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/patología
2.
Am J Transplant ; 16(9): 2612-23, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-26990829

RESUMEN

Previously, we demonstrated that alemtuzumab induction with rapamycin as sole maintenance therapy is associated with an increased incidence of humoral rejection in human kidney transplant patients. To investigate the role of rapamycin in posttransplant humoral responses after T cell depletion, fully MHC mismatched hearts were transplanted into hCD52Tg mice, followed by alemtuzumab treatment with or without a short course of rapamycin. While untreated hCD52Tg recipients acutely rejected B6 hearts (n = 12), hCD52Tg recipients treated with alemtuzumab alone or in conjunction with rapamycin showed a lack of acute rejection (MST > 100). However, additional rapamycin showed a reduced beating quality over time and increased incidence of vasculopathy. Furthermore, rapamycin supplementation showed an increased serum donor-specific antibodies (DSA) level compared to alemtuzumab alone at postoperation days 50 and 100. Surprisingly, additional rapamycin treatment significantly reduced CD4(+) CD25(+) FoxP3(+) T reg cell numbers during treatment. On the contrary, ICOS(+) PD-1(+) CD4 follicular helper T cells in the lymph nodes were significantly increased. Interestingly, CTLA4-Ig supplementation in conjunction with rapamycin corrected rapamycin-induced accelerated posttransplant humoral response by directly modulating Tfh cells but not Treg cells. This suggests that rapamycin after T cell depletion could affect Treg cells leading to an increase of Tfh cells and DSA production that can be reversed by CTLA4-Ig.


Asunto(s)
Abatacept/farmacología , Formación de Anticuerpos/inmunología , Rechazo de Injerto/inmunología , Trasplante de Corazón , Sirolimus/farmacología , Linfocitos T Reguladores/inmunología , Donantes de Tejidos , Animales , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/metabolismo , Supervivencia de Injerto/inmunología , Inmunosupresores/farmacología , Depleción Linfocítica , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo
3.
Am J Transplant ; 16(1): 137-42, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26561981

RESUMEN

Allocation policies for liver transplantation underwent significant changes in June 2013 with the introduction of Share 35. We aimed to examine the effect of Share 35 on regional variation in posttransplant outcomes. We examined two patient groups from the United Network for Organ Sharing dataset; a pre-Share 35 group composed of patients transplanted between June 17, 2012, and June 17, 2013 (n = 5523), and a post-Share group composed of patients transplanted between June 18, 2013, and June 18, 2014 (n = 5815). We used Kaplan-Meier and Cox multivariable analyses to compare survival. There were significant increases in allocation Model for End-stage Liver Disease (MELD) scores, laboratory MELD scores, and proportions of patients in the intensive care unit and on mechanical, ventilated, or organ-perfusion support at transplant post-Share 35. We also observed a significant increase in donor risk index in this group. We found no difference on a national level in survival between patients transplanted pre-Share 35 and post-Share 35 (p = 0.987). Regionally, however, posttransplantation survival was significantly worse in the post-Share 35 patients in regions 4 and 10 (p = 0.008 and p = 0.04), with no significant differences in the remaining regions. These results suggest that Share 35 has been associated with transplanting "sicker patients" with higher MELD scores, and although no difference in survival is observed on a national level, outcomes appear to be concerning in some regions.


Asunto(s)
Rechazo de Injerto/prevención & control , Fallo Hepático/cirugía , Trasplante de Hígado , Formulación de Políticas , Guías de Práctica Clínica como Asunto/normas , Asignación de Recursos/métodos , Obtención de Tejidos y Órganos/normas , Femenino , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Donantes de Tejidos , Listas de Espera
4.
Am J Transplant ; 16(6): 1726-38, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26705099

RESUMEN

We have established a model of sensitization in nonhuman primates and tested two immunosuppressive regimens. Animals underwent fully mismatched skin transplantation, and donor-specific antibody (DSA) response was monitored by flow cross-match. Sensitized animals subsequently underwent kidney transplantation from their skin donor. Immunosuppression included tacrolimus, mycophenolate, and methylprednisolone. Three animals received basiliximab induction; compared with nonsensitized animals, they showed a shorter mean survival time (4.7 ± 3.1 vs. 187 ± 88 days). Six animals were treated with T cell depletion (anti-CD4/CD8 mAbs), which prolonged survival (mean survival time 21.6 ± 19.0 days). All presensitized animals showed antibody-mediated rejection (AMR). In two of three basiliximab-injected animals, cellular rejection (ACR) was prominent. After T cell depletion, three of six monkeys experienced early acute rejection within 8 days with histological evidence of thrombotic microangiopathy and AMR. The remaining three monkeys survived 27-44 days, with mixed AMR and ACR. Most T cell-depleted animals experienced a rebound of DSA that correlated with deteriorating kidney function. We also found an increase in proliferating memory B cells (CD20(+) CD27(+) IgD(-) Ki67(+) ), lymph node follicular helper T cells (ICOS(+) PD-1(hi) CXCR5(+) CD4(+) ), and germinal center (GC) response. Depletion controlled cell-mediated rejection in sensitized nonhuman primates better than basiliximab, yet grafts were rejected with concomitant DSA rise. This model provides an opportunity to test novel desensitization strategies.


Asunto(s)
Modelos Animales de Enfermedad , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Inmunosupresores/uso terapéutico , Isoanticuerpos/inmunología , Trasplante de Riñón/efectos adversos , Trasplante de Piel , Animales , Humanos , Depleción Linfocítica , Macaca mulatta , Masculino , Linfocitos T Colaboradores-Inductores/inmunología
5.
Am J Transplant ; 16(10): 2816-2835, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27273869

RESUMEN

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.


Asunto(s)
Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Isoanticuerpos/inmunología , Trasplante de Hígado/efectos adversos , Aloinjertos , Humanos , Informe de Investigación
6.
Am J Transplant ; 15(3): 815-22, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25675879

RESUMEN

Depletional strategies directed toward achieving tolerance induction in organ transplantation have been associated with an increased incidence and risk of antibody-mediated rejection (AMR) and graft injury. Our clinical data suggest correlation of increased serum B cell activating factor/survival factor (BAFF) with increased risk of antibody-mediated rejection in alemtuzumab treated patients. In the present study, we tested the ability of BAFF blockade (TACI-Ig) in a nonhuman primate AMR model to prevent alloantibody production and prolong allograft survival. Three animals received the AMR inducing regimen (CD3-IT/alefacept/tacrolimus) with TACI-Ig (atacicept), compared to five control animals treated with the AMR inducing regimen only. TACI-Ig treatment lead to decreased levels of DSA in treated animals at 2 and 4 weeks posttransplantation (p < 0.05). In addition, peripheral B cell numbers were significantly lower at 6 weeks posttransplantation. However, it provided only a marginal increase in graft survival (59 ± 22 vs. 102 ± 47 days; p = 0.11). Histological analysis revealed a substantial reduction in findings typically associated with humoral rejection with atacicept treatment. More T cell rejection findings were observed with increased graft T cell infiltration in atacicept treatment, likely secondary to the graft prolongation. We show that BAFF/APRIL blockade using concomitant TACI-Ig treatment reduced the humoral portion of rejection in our depletion-induced preclinical AMR model.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Factor Activador de Células B/inmunología , Trasplante de Riñón , Depleción Linfocítica , Modelos Animales , Proteínas Recombinantes de Fusión/uso terapéutico , Linfocitos T/inmunología , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunología , Animales , Formación de Anticuerpos , Supervivencia de Injerto , Humanos , Macaca mulatta , Masculino
7.
Am J Transplant ; 15(11): 2908-20, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26461968

RESUMEN

Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients, we confirmed our previous finding that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years, although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and that it is a useful monitoring tool in prospective trials.


Asunto(s)
Factor Activador de Células B/genética , Regulación de la Expresión Génica , Memoria Inmunológica/genética , Trasplante de Riñón/efectos adversos , Tolerancia al Trasplante/genética , Adulto , Aloinjertos , Linfocitos B/inmunología , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Rechazo de Injerto/genética , Supervivencia de Injerto/genética , Humanos , Trasplante de Riñón/métodos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pronóstico , Sistema de Registros , Medición de Riesgo , Receptores de Trasplantes , Inmunología del Trasplante/genética , Tolerancia al Trasplante/inmunología , Resultado del Tratamiento
8.
Am J Transplant ; 14(8): 1717-8, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25041120

RESUMEN

The results of the multicenter belatacept liver transplant trial disappoint with respect to safety and efficacy, and new approaches will be required before this agent plays a role in liver transplant immunosuppression. See article by Klintmalm et al on page 1817.


Asunto(s)
Inmunoconjugados/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Hígado , Abatacept , Femenino , Humanos , Masculino
9.
Am J Transplant ; 14(1): 59-69, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24354871

RESUMEN

De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.


Asunto(s)
Centro Germinal/inmunología , Rechazo de Injerto/prevención & control , Inmunoconjugados/uso terapéutico , Trasplante de Riñón , Abatacept , Alefacept , Animales , Anticuerpos , Linfocitos B/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Rechazo de Injerto/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Macaca mulatta , Masculino , Proteínas Recombinantes de Fusión/uso terapéutico , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Tacrolimus/uso terapéutico
10.
Am J Transplant ; 14(4): 779-87, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24580828

RESUMEN

The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.


Asunto(s)
Rechazo de Injerto/inmunología , Antígenos HLA/inmunología , Isoanticuerpos/inmunología , Hepatopatías/inmunología , Trasplante de Hígado , Guías de Práctica Clínica como Asunto , Donantes de Tejidos , Humanos , Hepatopatías/cirugía , Pronóstico , Informe de Investigación
11.
Clin Exp Immunol ; 174(3): 364-71, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23981074

RESUMEN

While there have been significant advances in our understanding of the autoimmune responses and the molecular nature of the target autoantigens in primary biliary cirrhosis (PBC), unfortunately these data have yet to be translated into new therapeutic agents. We have taken advantage of a unique murine model of autoimmune cholangitis in which mice expressing a dominant negative form of transforming growth factor ß receptor II (dnTGFßRII), under the control of the CD4 promoter, develop an intense autoimmune cholangitis associated with serological features similar to human PBC. CD40-CD40 ligand (CD40L) is a major receptor-ligand pair that provides key signals between cells of the adaptive immune system, prompting us to determine the therapeutic potential of treating autoimmune cholangitis with anti-CD40L antibody (anti-CD40L; MR-1). Four-week-old dnTGFßRII mice were injected intraperitoneally with either anti-CD40L or control immunoglobulin (Ig)G at days 0, 2, 4 and 7 and then weekly until 12 or 24 weeks of age and monitored for the progress of serological and histological features of PBC, including rigorous definition of liver cellular infiltrates and cytokine production. Administration of anti-CD40L reduced liver inflammation significantly to 12 weeks of age. In addition, anti-CD40L initially lowered the levels of anti-mitochondrial autoantibodies (AMA), but these reductions were not sustained. These data indicate that anti-CD40L delays autoimmune cholangitis, but the effect wanes over time. Further dissection of the mechanisms involved, and defining the events that lead to the reduction in therapeutic effectiveness will be critical to determining whether such efforts can be applied to PBC.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Autoinmunes/terapia , Ligando de CD40/inmunología , Colangitis/terapia , Mitocondrias/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Antígenos CD4/genética , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Ligando de CD40/metabolismo , Colangitis/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Genotipo , Hígado/citología , Hígado/metabolismo , Cirrosis Hepática Biliar/inmunología , Ratones , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/genética , Receptores de Factores de Crecimiento Transformadores beta/inmunología
12.
Am J Transplant ; 12(10): 2641-51, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22759336

RESUMEN

Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Formación de Anticuerpos , Linfocitos B/inmunología , Rechazo de Injerto , Trasplante de Corazón , Isoanticuerpos/inmunología , Alemtuzumab , Animales , Enfermedad Crónica , Citometría de Flujo , Inmunohistoquímica , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos C57BL
13.
Am J Transplant ; 12(9): 2395-405, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22776408

RESUMEN

Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in transplantation, with mounting evidence associating alloantibodies with the development of chronic rejection. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing or eliminating, highlighting the need for a nonhuman primate model of antibody-mediated rejection. In this report, we demonstrate that depletion using anti-CD3 immunotoxin (IT) combined with maintenance immunosuppression that included tacrolimus with or without alefacept reliably prolonged renal allograft survival in rhesus monkeys. In these animals, a preferential skewing toward CD4 repopulation and proliferation was observed, particularly with the addition of alefacept. Furthermore, alefacept-treated animals demonstrated increased alloantibody production (100%) and morphologic features of antibody-mediated injury. In vitro, alefacept was found to enhance CD4 effector memory T cell proliferation. In conclusion, alefacept administration after depletion and with tacrolimus promotes a CD4+memory T cell and alloantibody response, with morphologic changes reflecting antibody-mediated allograft injury. Early and consistent de novo alloantibody production with associated histological changes makes this nonhuman primate model an attractive candidate for evaluating targeted therapeutics.


Asunto(s)
Rechazo de Injerto/inmunología , Supervivencia de Injerto/inmunología , Isoanticuerpos/inmunología , Animales , Inmunohistoquímica , Memoria Inmunológica , Inmunosupresores/uso terapéutico , Depleción Linfocítica , Macaca mulatta , Masculino
15.
Am J Transplant ; 16(7): 1949-50, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26792650
16.
Am J Transplant ; 11(4): 841-7, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21446981

RESUMEN

For patients with chronic renal and liver diseases, simultaneous liver and kidney transplantation (SLKT) is the best therapeutic option. The role of a pretransplant donor-specific antibody (DSA) in SLKT is unclear. We report the results of a retrospective review from 7/08 to 10/09 of SLKT at our institution. Monitoring of DSA was performed using single antigen bead assay. Between 7/08 and 10/09, there were six SLKT who had preformed DSA and positive XM (four class I and II DSA, one class I DSA only, one class II only). One-year patient and renal graft survival was 83%. Death-censored liver allograft survival was 100%. Acute humoral rejection (AHR) of the kidney occurred in 66% (three with both class I and II DSA and one with only class II DSA) of patients. In those with AHR, class I antibodies were rapidly cleared (p < 0.01) while class II antibodies persisted (p = 0.25). All patients who had humoral rejection of their kidney had preformed anticlass II antibodies. Liver allografts may not be fully protective of the renal allograft, especially with pre-existing MHC class II DSA. Long-term and careful follow-up will be critical to determine the impact of DSA on both allografts.


Asunto(s)
Genes MHC Clase II/inmunología , Genes MHC Clase I/inmunología , Rechazo de Injerto/inmunología , Isoanticuerpos/inmunología , Trasplante de Riñón/inmunología , Trasplante de Hígado/inmunología , Donantes de Tejidos , Especificidad de Anticuerpos , Supervivencia de Injerto , Prueba de Histocompatibilidad , Humanos , Estudios Retrospectivos , Trasplante Homólogo
17.
Nat Med ; 5(6): 686-93, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10371508

RESUMEN

CD154 is the ligand for the receptor CD40. This ligand-receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Rechazo de Injerto/tratamiento farmacológico , Trasplante de Riñón , Glicoproteínas de Membrana/inmunología , Animales , Formación de Anticuerpos , Ligando de CD40 , Rechazo de Injerto/inmunología , Humanos , Inmunosupresores/farmacología , Interleucinas/genética , Interleucinas/metabolismo , Riñón/metabolismo , Selectina L/genética , Selectina L/metabolismo , Recuento de Leucocitos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Macaca mulatta , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacología , ARN/análisis , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Tacrolimus/farmacología , Resultado del Tratamiento
19.
Am J Transplant ; 9(8): 1835-45, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19522878

RESUMEN

Alemtuzumab is a monoclonal antibody that depletes T and B cells and is used as induction therapy for renal transplant recipients. Without long-term calcineurin inhibitor (CNI) therapy, alemtuzumab-treated patients have a propensity to develop alloantibody and may undergo antibody-mediated rejection (AMR). In pursuit of a mechanistic explanation, we analyzed peripheral B cells and serum of these patients for BAFF (Blys) and BAFF-R, factors known to be integral for B-cell activation, survival, and homeostasis. Serum BAFF levels of 22/24 alemtuzumab-treated patients were above normal range, with average levels of 1967 pg/mL compared to 775 pg/mL in healthy controls (p = 0.006). BAFF remained elevated 2 years posttransplant in 78% of these patients. BAFF-R on CD19(+) B cells was significantly downregulated, suggesting ligand/receptor engagement. BAFF mRNA expression was increased 2-7-fold in CD14(+) cells of depleted patients, possibly linking monocytes to the BAFF dysregulation. Addition of recombinant BAFF to mixed lymphocyte cultures increased B-cell activation to alloantigen, as measured by CD25 and CD69 coexpression on CD19(+) cells. Of note, addition of sirolimus (SRL) augmented BAFF-enhanced B-cell activation whereas CNIs blocked it. These data suggest associations between BAFF/BAFF-R and AMR in alemtuzumab-treated patients.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Factor Activador de Células B/sangre , Rechazo de Injerto/prevención & control , Trasplante de Riñón/patología , Adolescente , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/farmacología , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Antígeno de Maduración de Linfocitos B/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Estudios de Casos y Controles , Femenino , Rechazo de Injerto/patología , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Lectinas Tipo C , Masculino , Persona de Mediana Edad , Linfocitos T/efectos de los fármacos , Linfocitos T/patología , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Adulto Joven
20.
Am J Transplant ; 9(5): 1087-98, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19344431

RESUMEN

Alemtuzumab induction with 60 days of tacrolimus treatment and continuous sirolimus treatment prevented acute rejection in nine of 10 consecutive renal allograft recipients. All patients are alive with a functioning kidney graft at 27-39 months of follow-up. Extensive immune monitoring was performed in all patients. Alloantibody detection, cytokine kinetics assay (CKA), and trans vivo delayed-type hypersensitivity (DTH) assay were performed every 6 months showing correlation with clinical evolution. Despite alloantibody presence in five patients, eight patients remain without the need for specific treatment and only sirolimus monotherapy in decreasing dosage. Four patients take only 1 mg sirolimus daily with levels of 3-4 ng/mL. One patient showed clinical signs of rejection at month 9 post-transplant, with slow increase in serum creatinine and histological signs of mixed cellular (endarteritis) and humoral rejection (C4d positivity in peritubular capillaries and donor-specific antibody (DSA)). In summary, the addition of tacrolimus therapy for 2 months to a steroid-free, alemtuzumab induction and sirolimus maintenance protocol limited the previously shown acute rejection development. Nevertheless, alloantibody was present in serum and/or C4d present on 1-year biopsy in half the patients. The combination of CKA and DSA monitoring or the performance of transvivo DTH correlated with immune status of the patients.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Sirolimus/uso terapéutico , Tacrolimus/uso terapéutico , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Antígenos CD/sangre , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Factores de Transcripción Forkhead/análisis , Factores de Transcripción Forkhead/inmunología , Antígenos HLA/sangre , Humanos , Hipersensibilidad Tardía/tratamiento farmacológico , Enfermedades Renales/clasificación , Enfermedades Renales/cirugía , Masculino , Monitorización Inmunológica/métodos , Población Blanca
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