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2.
Am J Transplant ; 14(11): 2491-9, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25220596

RESUMEN

We previously reported that posttransplant alloantibody production in CD8-deficient hosts is IL-4+ CD4+ T cell-dependent and IgG1 isotype-dominant. The current studies investigated the hypothesis that IL-4-producing natural killer T cells (NKT cells) contribute to maximal alloantibody production. To investigate this, alloantibody levels were examined in CD8-deficient WT, CD1d KO and Jα18 KO transplant recipients. We found that the magnitude of IgG1 alloantibody production was critically dependent on the presence of type I NKT cells, which are activated by day 1 posttransplant. Unexpectedly, type I NKT cell contribution to enhanced IgG1 alloantibody levels was interferon-γ-dependent and IL-4-independent. Cognate interactions between type I NKT and B cells alone do not stimulate alloantibody production. Instead, NKT cells appear to enhance maturation of IL-4+ CD4+ T cells. To our knowledge, this is the first report to substantiate a critical role for type I NKT cells in enhancing in vivo antibody production in response to endogenous antigenic stimuli.


Asunto(s)
Isoanticuerpos/biosíntesis , Células Asesinas Naturales/inmunología , Trasplante , Animales , Antígenos CD28/inmunología , Ensayo de Inmunoadsorción Enzimática , Interferón gamma/fisiología , Interleucina-4/fisiología , Isoanticuerpos/inmunología , Ratones , Ratones Transgénicos
3.
Am J Transplant ; 14(2): 295-304, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24472191

RESUMEN

While it is well known that CD4(+) T cells and B cells collaborate for antibody production, our group previously reported that CD8(+) T cells down-regulate alloantibody responses following transplantation. However, the exact mechanism involved in CD8(+) T cell-mediated down-regulation of alloantibody remains unclear. We also reported that alloantibody production is enhanced when either perforin or FasL is deficient in transplant recipients. Here, we report that CD8(+) T cell-deficient transplant recipient mice (high alloantibody producers) exhibit an increased number of primed B cells compared to WT transplant recipients. Furthermore, CD8(+) T cells require FasL, perforin and allospecificity to down-regulate posttransplant alloantibody production. In vivo CD8-mediated clearance of alloprimed B cells was also FasL- and perforin-dependent. In vitro data demonstrated that recipient CD8(+) T cells directly induce apoptosis of alloprimed IgG1(+) B cells in co-culture in an allospecific and MHC class I-dependent fashion. Altogether these data are consistent with the interpretation that CD8(+) T cells down-regulate posttransplant alloantibody production by FasL- and perforin-dependent direct elimination of alloprimed IgG1(+) B cells.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Proteína Ligando Fas/metabolismo , Hepatocitos/inmunología , Isoanticuerpos/inmunología , Perforina/metabolismo , Animales , Formación de Anticuerpos , Western Blotting , Células Cultivadas , Citometría de Flujo , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Isoanticuerpos/metabolismo , Trasplante de Hígado , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Trasplante Homólogo , Factor de Necrosis Tumoral alfa/metabolismo
4.
Am J Transplant ; 11(5): 1058-63, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21449943

RESUMEN

Patients who undergo Epstein-Barr virus (EBV) seromismatch (D+/R-) transplants have a higher risk for the development of post-transplant lymphoproliferative disorder (PTLD). Adult renal transplant recipients at a single institution were prospectively monitored for EBV during the first year post-transplant. Over a 2-year period, 34 patients (7.78%) were identified as being EBV D+/R-recipients. Patients who developed symptoms or had persistent viremia were pre-emptively administered rituximab. Six recipients were discharged without monitoring on the protocol. Of those six, three (50%) developed PTLD and all three lost their grafts. Twenty (60.6%) of the 34 recipients developed viremia during the first year post-transplant. Of the recipients who became viremic, six (30%) received rituximab. None of the six who received rituximab-developed PTLD. We found that recipients who were not monitored on the protocol were more likely to have PTLD and graft loss compared to those who were (p = 0.008). Post-transplant monitoring of adults who undergo EBV D+/R-kidney transplants for viremia and symptoms associated with EBV infection may prompt intervention which reduces the incidence of PTLD within the first year. Use of rituximab in preventing PTLD among patients with primary EBV infection requires further prospective study to determine its overall safety and efficacy.


Asunto(s)
Infecciones por Virus de Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Trasplante de Riñón/métodos , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Riesgo , Rituximab , Carga Viral
5.
Am J Transplant ; 11(2): 261-71, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21219568

RESUMEN

This manuscript reports the demographics, education and training, professional activities and lifestyle characteristics of 171 members of the American Society of Transplant Surgeons (ASTS). ASTS members were sent a comprehensive survey by electronic mail. There were 171 respondents who were 49 ± 8 years of age and predominantly Caucasian males. Female transplant surgeons comprised 10% of respondents. ASTS respondents underwent 15.6 ± 1.0 years of education and training (including college, medical school, residency and transplantation fellowship) and had practiced for 14.7 ± 9.2 years. Clinical practice included kidney, pancreas and liver organ transplantation, living donor surgery, organ procurement, vascular access procedures and general surgery. Transplant surgeons also devote a significant amount of time to nonsurgical patient care, research, education and administration. Transplant surgeons, both male and female, reported working approximately 70 h/week and a median of 195 operative cases per year. The anticipated retirement age for men was 64.6 ± 8.6 and for women was 62.2 ± 4.2 years. This is the largest study to date assessing professional and lifestyle characteristics of abdominal transplant surgeons.


Asunto(s)
Especialidades Quirúrgicas , Trasplantes , Centros Médicos Académicos , Adulto , Anciano , Recolección de Datos , Educación , Femenino , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Sociedades Médicas , Especialidades Quirúrgicas/educación , Estados Unidos , Carga de Trabajo
6.
Am J Transplant ; 8(6): 1113-28, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18522544

RESUMEN

Despite success of early islet allograft engraftment and survival in humans, late islet allograft loss has emerged as an important clinical problem. CD8+ T cells that are independent of CD4+ T cell help can damage allograft tissues and are resistant to conventional immunosuppressive therapies. Previous work demonstrates that islet allografts do not primarily initiate rejection by the (CD4-independent) CD8-dependent pathway. This study was performed to determine if activation of alloreactive CD4-independent, CD8+ T cells, by exogenous stimuli, can precipitate late loss of islet allografts. Recipients were induced to accept intrahepatic islet allografts (islet 'acceptors') by short-term immunotherapy with donor-specific transfusion (DST) and anti-CD154 mAb. Following the establishment of stable long-term islet allograft function for 60-90 days, recipients were challenged with donor-matched hepatocellular allografts, which are known to activate (CD4-independent) CD8+ T cells. Allogeneic islets engrafted long-term were vulnerable to damage when challenged locally with donor-matched hepatocytes. Islet allograft loss was due to allospecific immune damage, which was CD8- but not CD4-dependent. Selection of specific immunotherapy to suppress both CD4- and CD8-dependent immune pathways at the time of transplant protects islet allografts from both early and late immune damage.


Asunto(s)
Supervivencia de Injerto/inmunología , Trasplante de Islotes Pancreáticos/inmunología , Animales , Linfocitos T CD8-positivos , Células Cultivadas , Modelos Animales de Enfermedad , Hepatocitos/trasplante , Terapia de Inmunosupresión , Trasplante de Islotes Pancreáticos/métodos , Ratones
7.
Am J Transplant ; 6(10): 2268-81, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16889609

RESUMEN

The goal of this study was to determine the in vivo conditions that promote activation of the (CD4-independent) CD8+ T cell-mediated rejection pathway. We have previously noted that hepatocellular but not islet allografts readily activate this rejection pathway. In the current study, we utilized these two cell transplant models to investigate whether differences in host cell recruitment to the graft site, expression of T-cell activation markers by CD8+ graft infiltrating cells (GICs), and/or development of delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte cell-mediated effector functions could account for the differential transplant outcomes. The collective results demonstrate that recruitment of CD8+ T cells to the site of transplant, CD103 or CD69 expression on CD8+ GICs, and activation of alloreactive DTH responses are insufficient to initiate CD4-independent, CD8-dependent transplant rejection. Instead, rejection by alloreactive (CD4-independent) CD8+ T cells correlated with expression of CD25, CD154 and CD43 by CD8+ GICs, in vitro alloproliferation by recipient CD8+ T cells, and the development of in vivo allospecific cytolytic effector function. These results suggest that tissue-derived factors influence the activation and maturation of (CD4-independent) CD8+ T cells into cytolytic effectors, which correlates with transplant rejection.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Trasplante de Células , Inmunidad Celular , Activación de Linfocitos/fisiología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Modelos Animales de Enfermedad , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Hepatocitos/trasplante , Trasplante de Islotes Pancreáticos/métodos , Ratones , Ratones Transgénicos
9.
Clin Transplant ; 15(6): 410-4, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11737118

RESUMEN

Recent improvements in immunosuppression and subsequent decreases in the incidence of acute rejection have brought into question the benefit of the use peri-transplant antibody therapy (i.e. induction therapy). In the current era of immunosuppression that includes mycophenolate mofetil (MMF) and cyclosporine emulsion (Neoral, Novartis, Basle, Switzerland), we designed and have completed a prospective, randomized trial to address this question. Cadaveric and living donor renal allograft recipients were randomized to receive either OKT3/MMF/delayed Neoral/prednisone or MMF/immediate Neoral/prednisone without OKT3. The incidence of rejection episodes was the primary end point. Patients with delayed graft function were excluded. All rejection episodes were biopsy proven and all patients have been followed for a minimum of 2 yr. Fifty-four patients received OKT3 induction, of which 6 patients suffered a rejection episode (11%), while 13 patients (27%) not receiving OKT3 (p=0.04) had a rejection episode. Four patients in the no OKT3 group suffered multiple rejections, while there were only 2 with more than one episode in the OKT3 group. There was no increased incidence of infectious complications in the group receiving OKT3. Hospital costs tended to be higher in the OKT3-treated group, but were not significantly different. The low incidence of rejection in the OKT3-treated group was intriguing and validates the use of antibody therapy in the early post-operative periods even in the era of improved baseline immunosuppression.


Asunto(s)
Inmunosupresores/administración & dosificación , Trasplante de Riñón , Muromonab-CD3/administración & dosificación , Ácido Micofenólico/análogos & derivados , Adolescente , Adulto , Anciano , Ciclosporina/administración & dosificación , Quimioterapia Combinada , Femenino , Rechazo de Injerto/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Estudios Prospectivos
10.
Transplantation ; 72(4): 642-7, 2001 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-11544424

RESUMEN

BACKGROUND: The purpose of this retrospective study was to determine the benefits of daclizumab, (Zenapax, Roche Pharmaceuticals) a humanized anti-interleukin-2Ralpha (IL-2Ralpha) monoclonal antibody, for prevention of acute rejection in renal transplant recipients with delayed graft function (DGF). METHODS: Data from two multicenter randomized placebo-controlled trials were pooled. DGF was defined by urine output <30 cc/hour, decline in serum creatinine of <0.5 mg/dl, or the need for dialysis within the first 24 hours after transplantation. RESULTS: At one year posttransplantation, the incidence of biopsy-proven acute rejection in patients with DGF was reduced from 44% in the placebo group to 28% in the daclizumab group. (P=0.03) Prophylaxis with daclizumab also delayed the onset of the first biopsy-proven acute rejection episode in patients with DGF from 29+/-43 days in the placebo group to 73+/-70 days in the daclizumab group. (P=0.004) The graft survival rates in patients with DGF at 1 year posttransplantation were 78% in the placebo group and 82% in the daclizumab treated group. (P=ns) Three patients in the placebo-treated group with DGF experienced graft loss due to acute rejection, whereas no patients in the daclizumab-treated group with DGF had graft loss due to acute rejection. The 1-year patient survival rate in those with DGF in the placebo and daclizumab groups were 93% and 98%, respectively. (P=ns) CONCLUSIONS: Daclizumab effectively reduced the incidence and delayed the onset of biopsy-proven acute rejection in this high-risk subgroup of patients with DGF after renal transplantation. Graft and patient survival rates were similar between placebo- and daclizumab-treated patients with DGF.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunoglobulina G/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Riñón/fisiopatología , Enfermedad Aguda , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Biopsia , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Daclizumab , Relación Dosis-Respuesta a Droga , Rechazo de Injerto/patología , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunoglobulina G/administración & dosificación , Inmunosupresores/administración & dosificación , Riñón/patología , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Trasplante de Riñón/efectos adversos , Estudios Multicéntricos como Asunto , Cuidados Posoperatorios , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo
11.
Transplantation ; 72(5): 839-45, 2001 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-11571447

RESUMEN

BACKGROUND: Daclizumab (Zenapax, Roche Pharmaceuticals), a humanized monoclonal antibody directed against the alpha chain of the interleukin 2 receptor, has been shown to reduce the incidence of acute rejection at 6 months after renal transplantation in two phase III clinical trials. This report presents the combined 1- and 3-year outcomes of kidney transplant recipients who participated in these two phase III clinical trials. METHODS: Data from two multicenter, randomized, placebo-controlled trials were evaluated with regard to graft survival, patient survival, incidence of malignancies (including lymphoma), renal function (serum creatinine and glomerular filtration rate [GFR]), and current maintenance immunosuppressive regimen. In addition, the impact of acute rejection and acute rejection requiring treatment with antilymphocyte therapy upon 3-year graft survival was evaluated. Daclizumab was compared to placebo on a background of cyclosporine (CsA), azathioprine, and corticosteroids (triple therapy, TT) or CsA and corticosteroids (double therapy, DT). RESULTS: Treatment with daclizumab in the pooled analysis demonstrated a significant reduction in the incidence of biopsy-proven acute rejection episodes at 12 months posttransplant (43% vs. 28%, P<0.001). The 3-year graft survival was not significantly different between placebo and daclizumab-treated patients in the TT trial (83% vs. 84%) or in the DT trial (78% vs. 82%). Pooled patient survival was excellent in both placebo- (91%) and daclizumab- (93%) treated patients. The incidence of malignancies or posttransplant lymphoproliferative disorder (PTLD) in placebo- versus daclizumab-treated groups was comparable in both clinical trials. Renal function was similar between placebo- and daclizumab-treated groups in both the TT and DT trials. The occurrence of delayed graft function, acute rejection requiring antilymphocyte therapy at 6 months, and acute rejection at 12 months posttransplant were associated with decreased graft survival rates at 3 years posttransplant. CONCLUSIONS: The beneficial effect of daclizumab prophylaxis upon the incidence of acute rejection after renal transplant with TT or with DT was not associated with adverse clinical sequelae, including the development of PTLD, at 3 years posttransplant. There was no beneficial effect of daclizumab on graft survival at 3 years, but the trial was inadequately powered to detect this. Both studies showed excellent graft and patient survival at 3 years.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Rechazo de Injerto/prevención & control , Inmunoglobulina G/farmacología , Inmunosupresores/farmacología , Trasplante de Riñón/inmunología , Enfermedad Aguda , Corticoesteroides/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Azatioprina/administración & dosificación , Ciclosporina/administración & dosificación , Daclizumab , Supervivencia de Injerto , Humanos , Inmunoglobulina G/efectos adversos , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/mortalidad , Trasplante de Riñón/fisiología , Trastornos Linfoproliferativos/etiología , Neoplasias/etiología , Receptores de Interleucina-2/antagonistas & inhibidores , Tasa de Supervivencia , Factores de Tiempo
12.
Hepatology ; 32(5): 1018-28, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11050052

RESUMEN

The current study evaluated the role of CD40/CD40 ligand (CD40L) and CD28/B7 costimulation signals during alloimmune responses independently mediated by CD4(+) or CD8(+) T cells. Allogeneic hepatocytes were transplanted into CD8 or CD4 knock out (KO) mice under cover of costimulatory blockade. Rejection of FVB/N (H-2(q)) hepatocytes occurred by day 10 posttransplant in untreated CD8 or CD4 KO (H-2(b)) mice. Treatment of CD8 or CD4 KO mice with anti-CD40L monoclonal antibody (mAb; MR1) resulted in significant prolongation of hepatocyte survival indicating that CD40/CD40L interactions were critical in both CD4(+) and CD8(+) T-cell initiated hepatocyte rejection. Anti-CD40L mAb also prolonged hepatocyte survival in B-cell KO (H-2(b)) mice, indicating that the efficacy of CD40/CD40L blockade in preventing hepatocyte rejection was B-cell (and antibody) independent. In contrast, treatment with CTLA4 fusion protein (CTLA4Ig), prolonged hepatocyte survival in CD8 KO but not CD4 KO mice, showing that CD28/B7 interactions were important in CD4(+) but not CD8(+) T-cell initiated hepatocyte rejection. Under selected circumstances, such as in CD40 KO mice, both CD4(+) and CD8(+) T cells mediate hepatocyte rejection in the absence of CD40/CD40L costimulation and without a significant contribution from CD28/B7 costimulation signals. These results highlight the disparate roles of CD40/CD40L and CD28/B7 costimulation signals in CD4(+) versus CD8(+) T-cell mediated immune responses to allogeneic hepatocytes. The CD4(+) T-cell independent, CD40L-sensitive, CD28/B7-independent pathway of CD8(+) T-cell activation in response to transplantation antigens is novel.


Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Rechazo de Injerto/etiología , Hepatocitos/trasplante , Inmunoconjugados , Trasplante Homólogo , Abatacept , Animales , Anticuerpos Monoclonales/farmacología , Antígenos CD , Antígenos de Diferenciación/farmacología , Linfocitos B/fisiología , Antígenos CD40/genética , Antígenos CD40/fisiología , Ligando de CD40/genética , Ligando de CD40/inmunología , Antígeno CTLA-4 , Supervivencia de Injerto/efectos de los fármacos , Hepatocitos/fisiología , Hipersensibilidad Tardía/inmunología , Isoanticuerpos/análisis , Hígado/citología , Hígado/fisiología , Complejo Mayor de Histocompatibilidad/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados/genética , Ratones Noqueados/fisiología , Bazo/citología , Bazo/fisiología , Donantes de Tejidos
13.
Immunol Rev ; 174: 260-79, 2000 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10807522

RESUMEN

Despite the widely accepted view of the liver as an immunoprivileged tissue, purified allogeneic liver parenchymal cells delivered to the liver of a recipient mouse are highly antigenic. A functional transgenic model of hepatocyte transplantation in mice is used to explore host immune responses to allogeneic hepatocytes. Transplanted hepatocytes expressing human alpha-1-antitrypsin (hA1AT) are monitored for survival by the secretion of the transgene product hA1AT. Transplantation of transgenic hepatocytes into syngeneic or immunoincompetent severe combined immunodeficiency disease (SCID) mice results in indefinite hepatocellular allograft survival. However, transplantation of transgenic hepatocytes into allogeneic hosts results in rapid hepatocyte rejection. This rejection response is associated with prominent delayed type hypersensitivity responses to cellular alloantigen but minimal donor-reactive humoral immunity. Hepatocyte rejection is not controlled by host treatment with anti-CD4 mAb despite the ability of the same treatment regimen to produce indefinite survival of donor-matched heart allografts. Host immune responses to allogeneic hepatocytes utilize CD40L/CD40 but not CD28/B7 co-stimulation, unlike the activation of both of these systems in responses to other allografts. Furthermore, C57BL/6 mice which have been induced by anti-CD4 mAb or gallium nitrate treatment to accept heart allografts promptly reject donor-matched transgenic hepatocytes. Studies in reconstituted SCID, CD4 knockout (KO), and CD8 KO mice demonstrate that hepatocyte rejection can be initiated independently by either CD4+ T cells or CD8+ T cells, which again diverges from what has been observed for most other types of allografts. This may account for the relative resistance to immunoprotection for hepatocellular allografts with conventional immunosuppressive agents and to immunoregulatory states induced by other allografts. Three models of hepatocyte rejection are discussed.


Asunto(s)
Trasplante de Células , Hígado/citología , Trasplante Homólogo/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos , Presentación de Antígeno , Apoptosis , Antígeno B7-1/inmunología , Biomarcadores , Antígenos CD28/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos CD40/inmunología , Ligando de CD40 , Linfocitos T CD8-positivos/inmunología , Separación Celular , Supervivencia Celular , Genes Reporteros , Refuerzo Inmunológico de Injertos , Humanos , Hipersensibilidad Tardía/inmunología , Tolerancia Inmunológica , Terapia de Inmunosupresión , Hígado/inmunología , Activación de Linfocitos , Cooperación Linfocítica , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Bazo , Inmunología del Trasplante , Trasplante Heterotópico , Trasplante Homólogo/patología , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/inmunología
14.
Clin Transplant ; 14(1): 8-10, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10693628

RESUMEN

Infectious complications after renal transplantation remain a major cause of morbidity and mortality. Mucormycosis is a rare infection in renal transplant recipients; however, mortality is exceedingly high. Risk factors predisposing to this disease include prolonged neutropenia, diabetes, and patients who are immunosuppressed (Singh N, Gayowski T, Singh J, Yu LV. Invasive gastrointestinal zygomycosis in a liver transplant recipient: case report and review of zygomycosis in solid-organ transplant recipients, Clin Infect Dis 1995: 20: 617). Life-threatening infections can occur, as this fungus has the propensity to invade blood vessel endothelium, resulting in hematological dissemination. We report a case of cavitary Rhizopus lung infection, 2 months after renal transplantation, where the patient was treated successfully with Amphotericin B and surgical resection of the lesions with preservation of his allograft function. In this era of intensified immunosuppression, we may see an increased incidence of mucormycosis in transplant population. Invasive diagnostic work-up is mandatory in case of suspicion; Amphotericin B and, in selected cases, surgical resection are the mainstays of therapy.


Asunto(s)
Nefropatías Diabéticas/cirugía , Trasplante de Riñón , Enfermedades Pulmonares Fúngicas/diagnóstico , Mucormicosis/diagnóstico , Infecciones Oportunistas/diagnóstico , Rhizopus , Humanos , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Enfermedades Pulmonares Fúngicas/etiología , Masculino , Persona de Mediana Edad , Mucormicosis/tratamiento farmacológico , Mucormicosis/etiología , Infecciones Oportunistas/tratamiento farmacológico , Infecciones Oportunistas/etiología
15.
Transplantation ; 70(12): 1771-80, 2000 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-11152110

RESUMEN

INTRODUCTION: The purpose of the current study was to investigate the capacity of CD4+, CD8+, or non-T cells to independently initiate acute rejection of allogeneic hepatocytes using reconstituted SCID, CD4 or CD8 knockout (KO) recipient mice. METHODS: Allogeneic hepatocytes (FVB/N, H-2q) were transplanted into C57BL/6.SCID (H-2b), CD4 KO (H-2b), CD8 KO (H-2b), or beige/beige (H-2b) mice. SCID mice with functioning hepatocellular allografts subsequently received purified non-T cells (NTC), CD4+, or CD8+ splenocytes. Some mice were treated with anti-CD4, anti-CD8, and/or anti-nkl.1 mAb. Recipient mice were also assessed for donor-reactive delayed-type hypersensitivity (DTH) responses and donor-reactive alloantibody production. RESULTS: Median hepatocellular allograft survival time (MST) was 28 days in CD4+ reconstituted SCID mice and 14 days in CD8+ reconstituted SCID mice. SCID hosts reconstituted with NTC demonstrated indefinite hepatocellular allograft survival (>120 days). MST was 10 days in untreated beige/beige (NK cell deficient) mice. MST was 14 days in untreated, 35 days in anti-CD4 mAb treated, and 10 days in anti-nkl.1 mAb treated CD8 KO mice. MST was 10 days in untreated, 35 days in anti-CD8 mAb treated, and 7 days in anti-nk1.1 mAb treated CD4 KO mice. Donor-reactive DTH responses were not detected in reconstituted SCID mice, were minimal in CD4 KO mice, and were prominent in CD8 KO mice after rejection of allogeneic hepatocytes. Similarly, donor-reactive alloantibody, was not detected in CD4 KO hosts, but was readily detected in CD8 KO hosts. CONCLUSIONS: These studies show that both CD4+ and CD8+ T cells (but not host NTC) can independently initiate the rejection of allogeneic hepatocytes. While hepatocyte rejection by isolated CD4+ T cells is not surprising, rejection by CD8+ T cells (in the absence of CD4+ T cells) was unusual, and may explain the failure of "standard" immunosuppressive regimens to suppress acute rejection of allogeneic hepatocytes, as noted in prior studies. Furthermore, NK cells do not appear to be required for either CD4+ T cell or CD8+ T cell initiated hepatocyte rejection.


Asunto(s)
Rechazo de Injerto/etiología , Hepatocitos/trasplante , Enfermedad Aguda , Animales , Anticuerpos Monoclonales/farmacología , Antígenos CD4/genética , Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Antígenos CD8/genética , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Supervivencia de Injerto , Hepatocitos/inmunología , Humanos , Isoanticuerpos/sangre , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Factores de Tiempo , Donantes de Tejidos , Trasplante Homólogo
16.
Transplantation ; 68(10): 1491-6, 1999 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-10589945

RESUMEN

BACKGROUND: Living kidney donation has increased recently as the shortage of cadaveric organs continues. This increase has occurred in part, due to expanded donor criteria, including obese patients. This is a potential concern because obesity is associated with surgical complications, possibly death, and chronic medical problems. To address this concern, we examined the outcome of a large group of obese (ObD) and nonobese living kidney donors (NObD). METHODS: A total of 107 obese (body mass index> or =27 kg/m2) and 116 nonobese (body mass index<27 kg/m2) living kidney donors donating at a single institution between 1990 and 1996 were studied. Surgical complications, operative duration, and hospital length of stay were assessed. Preoperative blood pressure, serum creatinine, creatinine clearance, protein excretion, fasting glucose, and hemoglobin A1C were measured and first degree relatives with diabetes were identified. RESULTS: Overall complications were significantly more common in ObD, 16.8 vs. 3.4% (P=0.0012). The majority of complications in the entire cohort, 56%, were wound related and were significantly more common in ObD (P=0.016). There was no significant increase in nonwound-related infections, bleeding, or cardiopulmonary events. There were no deaths or major complications. Operative time was significantly longer in ObD 151+/-30 vs. 141+/-29 min (P<0.05) but hospital duration was no different. Predonation, blood pressure in ObD was significantly higher, (P<0.05) and they more often had a family history of diabetes, 46 vs. 30% (P<0.05) than nonobese donors. Renal function, proteinuria, fasting glucose, or hemoglobin A1C were no different. CONCLUSION: With prudent selection, the use of obese living kidney donors appears safe in the short term. They experience more minor complications, usually wound related, and slightly longer operations. Given a higher baseline blood pressure and family history of diabetes, the long-term effect on the remaining solitary kidney in ObD needs to be examined.


Asunto(s)
Complicaciones Intraoperatorias/epidemiología , Trasplante de Riñón/fisiología , Riñón , Donadores Vivos , Obesidad , Complicaciones Posoperatorias/epidemiología , Adulto , Presión Sanguínea , Estudios de Cohortes , Femenino , Humanos , Trasplante de Riñón/métodos , Tiempo de Internación , Masculino , Selección de Paciente , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
17.
Transplantation ; 68(4): 555-62, 1999 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-10480416

RESUMEN

INTRODUCTION: This is the first in a series of reports that characterizes immune responses evoked by allogeneic hepatocytes using a functional model of hepatocyte transplantation in mice. METHODS: "Donor" hepatocytes expressing the transgene human alpha-1-antitrypsin (hA1AT-FVB/N, H2q) were transplanted into C57BL/6 (H2b) or MHC II knockout (H2b) hosts treated with anti-CD4, anti-CD8, or a combination of anti-CD4 and anti-CD8 monoclonal antibodies (mAbs). Hepatocyte rejection was determined as a loss of circulating ELISA-detectable transgene product (hA1AT). In addition, some C57BL/6 mice underwent transplantation with FVB/N heterotopic cardiac allografts and were treated with anti-CD4 mAb. Cardiac allograft rejection was determined by palpation. Graft recipients were tested for donor-reactive alloantibodies and donor-reactive delayed-type hypersensitivity (DTH) responses. RESULTS: The median survival time (MST) of allogeneic hepatocytes in normal C57BL/6 mice was 10 days (no treatment), 10 days (anti-CD4 mAb), 14 days (anti-CD8 mAb), and 35 days (anti-CD4 and anti-CD8 mAbs). The MST of hepatocytes in B6 MHC class II knockout mice was 10 days (no treatment) and 21 days (anti-CD8 mAb). The MST of cardiac allografts was 11 days (no treatment) and >100 days (anti-CD4 mAb). Donor-reactive DTH responses were readily detected in both untreated and mAb-treated recipients. Donor-reactive alloantibody was barely detectable in untreated hosts. CONCLUSIONS: These studies demonstrate that allogeneic hepatocytes are highly immunogenic and stimulate strong cell-mediated immune responses by both CD4+ and CD8+ T cells, even when treated with agents that can cause acceptance of cardiac allografts. Indeed, CD4+ or CD8+ T cells seem to independently cause hepatocellular allograft rejection. Allogeneic hepatocytes evoked strong donor-reactive DTH responses but were poor stimuli for donor-reactive antibody production. This is an unusual pattern of immune reactivity in allograft recipients.


Asunto(s)
Trasplante de Hígado/inmunología , Hígado/citología , Hígado/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Suero Antilinfocítico/farmacología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Supervivencia de Injerto , Trasplante de Corazón/inmunología , Humanos , Isoanticuerpos/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Modelos Biológicos , Factores de Tiempo , Trasplante Homólogo
18.
Semin Liver Dis ; 19(2): 189-204, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10422200

RESUMEN

Transplantation of foreign tissue initiates complex inflammatory responses that are mediated by cytokines and that, in the absence of immunosuppression, usually result in acute graft rejection and graft destruction. Thus, the study of cytokines in transplantation research has been pursued with great interest. Cytokine biology has evolved from an era that focused on the identification and cataloguing of newly discovered cytokines to one that addresses (1) the complexity of cytokine interactions with other cytokines, with other biologic mediators, and with the extracellular matrix; and (2) the diversity of cytokine effects upon both lymphoid and nonlymphoid cell types. This article reviews the basic principles of transplant immunology and discusses experimental data regarding the role of prototypic cytokines in allograft rejection, in general, and liver allograft rejection, in particular.


Asunto(s)
Citocinas/fisiología , Inmunología del Trasplante , Animales , Rechazo de Injerto/inmunología , Humanos , Inmunosupresores , Trasplante de Hígado/inmunología , Subgrupos de Linfocitos T/inmunología , Trasplante Homólogo
19.
Transplantation ; 67(5): 690-6, 1999 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-10096523

RESUMEN

BACKGROUND: After transplantation renal allografts frequently develop interstitial fibrosis and tubular atrophy, and these pathologic changes are the hallmarks of chronic allograft nephropathy (CN). However, the diagnosis of CN has no specific pathogenic implications. In this study we sought to determined whether a subclassification of CN according to vascular pathology correlates with posttransplant events, particularly acute rejection, and graft survival. METHODS: A total of 419 patients with moderate to severe CN were subdivided into: (1) transplant arteriopathy (TA, n=233, 56%); (2) arteriolar hyalinosis (AH, n=89, 21%); and (3) no characteristic vascular pathology (IFb, n=97, 23%). RESULTS: Patients with AH differed significantly from patients with TA or IFb in the following parameters: (1) AH was diagnosed later after transplantation (P=0.001); (2) fewer patients with AH had acute rejection (AR) before the diagnosis of CN (P<0.0001). For example, 44% of AH and 75% of TA had AR before CN; (3) patients with AH also had fewer AR episodes than the other two groups (P<0.0001); finally, (4) graft survival was better in patients with AH than in patients with TA (P=0.01 by chi2, P=0.001 by Cox). In contrast, there were no significant differences between patients with TA and IFb. By multivariate analysis the survival of grafts with CN correlated with: (1) serum creatinine at diagnosis (P<0.0001), (2) recipient's weight (P=0.004); (3) presence of FGS or level of proteinuria (P=0.03); and (4) the occurrence of AR after the diagnosis of CN (P<0.0001). Regarding the latter, AR were more common (P=0.007) and more numerous (P=0.005) in patients with TA or IFb than in AH. CONCLUSIONS: CN can be classified according to vascular pathology in the majority of cases, and this classification correlates with graft survival. Although some forms of CN are closely associated with the occurrence of AR others are not. This study also uncovered several variables that correlate with the survival of grafts with CN.


Asunto(s)
Rechazo de Injerto/patología , Fallo Renal Crónico/patología , Trasplante de Riñón/patología , Riñón/patología , Adulto , Femenino , Supervivencia de Injerto , Humanos , Masculino , Pronóstico , Trasplante Homólogo
20.
Transplantation ; 67(2): 262-6, 1999 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-10075591

RESUMEN

BACKGROUND: We had the impression that, although our renal transplant recipients with polycystic kidney disease (PKD) had excellent long-term renal graft function, they had an increased incidence of postoperative gastrointestinal (GI) complications. METHODS: Over a 10-year period (1987 through 1996), 1467 renal transplants were performed in 1417 patients; 145 of these transplants involved PKD recipients. In the PKD group, 18 patients (12.4%) developed a posttransplant complication necessitating GI surgery (PKD-GI), an incidence twice that in the non-PKD recipients (73 patients or 6.2%, non-PKD-GI). RESULTS: PKD and non-PKD recipients displayed no significant difference in mortality. The PKD patients had better long-term renal graft survival than the non-PKD patients (P=0.08). There was no difference in mortality (P>0.6) or renal graft survival (P>0.6) between the PKD-GI and PKD-non-GI groups. The PKD-GI group had no increased mortality over the non-PKD-GI patients (P>0.6), despite a higher incidence of GI surgical complications in the PKD group versus the non-PKD group (overall: 12.4 vs. 6.2%, P<0.01; within 90 days of transplant: 7.6 vs. 3.3%, P<0.02) and a greater propensity for small and large bowel complications (overall: 9.0 vs. 2.6%; P< 0.001; less than 90 days: 6.9 vs. 2.0%, P<0.002). The PKD-GI recipients tended toward less long-term graft loss than their non-PKD-GI counterparts (11.1 vs. 27.4%; P=.22). The PKD-GI recipients suffered no acute rejection episodes within 90 days after their GI operation versus 11 of 73 non-PKD-GI recipients (O vs. 15.1%; P=0.075). CONCLUSIONS: PKD recipients of renal grafts should be watched closely early after transplant because of their increased risk of GI complications. These complications resulted in no increase in mortality or graft loss compared to non-PKD recipients with GI complications despite the PKD group's higher incidence of bowel perforation and increased age at time of transplant.


Asunto(s)
Enfermedades Gastrointestinales/epidemiología , Supervivencia de Injerto , Trasplante de Riñón/fisiología , Enfermedades Renales Poliquísticas/cirugía , Complicaciones Posoperatorias/epidemiología , Adulto , Arizona/epidemiología , Colecistitis/epidemiología , Colecistitis/etiología , Enfermedades del Colon/epidemiología , Enfermedades del Colon/etiología , Estudios de Seguimiento , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/mortalidad , Humanos , Incidencia , Enfermedades Intestinales/epidemiología , Enfermedades Intestinales/etiología , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/mortalidad , Persona de Mediana Edad , Ohio/epidemiología , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo
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