RESUMO
The selectin antagonist known as recombinant P-selectin glycoprotein ligand IgG (rPSGL-Ig) blocks leukocyte adhesion and protects against transplantation ischemia reperfusion injury (IRI) in animal models. This randomized (1:1) single-center double-blind 47-patient phase 2 study with 6-month follow-up assessed rPSGL-Ig's safety and impact on early graft function at 1 mg/kg systemic dose with pretransplant allograft ex vivo treatment in deceased-donor liver transplant recipients. Safety was assessed in all patients, whereas efficacy was assessed in a prospectively defined per-protocol patient set (PP) by peak serum transaminase (TA) and bilirubin values, and normalization thereof. In PP patients, the incidence of poor early graft function (defined as peak TA >2500 U/L or bilirubin >10 mg/dL), average peak liver enzymes and bilirubin, normalization thereof and duration of primary and total hospitalization trended consistently lower in the rPSGL-Ig group compared to placebo. In patients with donor risk index above study-average, normalization of aspartate aminotransferase was significantly improved in the rPSGL-Ig group (p < 0.03). rPSGL-Ig treatment blunted postreperfusion induction versus placebo of IRI biomarker IP-10 (p < 0.1) and augmented cytoprotective IL-10 (p < 0.05). This is the first clinical trial of an adhesion molecule antagonist to demonstrate a beneficial effect on liver transplantation IRI and supported by therapeutic modulation of two hepatic IRI biomarkers.
Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Fígado , Glicoproteínas de Membrana/farmacologia , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Interleucina-10/metabolismo , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
BACKGROUND: Recently, peptides derived from the heavy chain of HLA-B2702 have been shown to modulate immune responses. In this study, we examined the use of these peptides for immunosuppression in a pig to mouse islet xenograft model. METHODS: Purified porcine islets were transplanted in autoimmune (non-obese diabetic) and non-autoimmune (streptozotocin-injected CBA or C57/Bl6) diabetic mice. Various dosing regimens of HLA-derived peptides with and without antilymphocyte therapy were administered to recipient mice. Graft rejection was determined by daily serum glucose determinations, and, at selected time points, grafts were removed to demonstrate function and provide immunohistochemical examination. RESULTS: HLA-derived peptides were demonstrated to prolong graft survival in both pretransplant and posttransplant treatment regimens. This effect was increased with concomitant antilymphocyte therapy. CONCLUSIONS: Further elucidation of the mechanism of action of these immunomodulatory peptides may help in the development of novel immunosuppressive protocols.
Assuntos
Transplante das Ilhotas Pancreáticas/imunologia , Transplante Heterólogo , Adjuvantes Imunológicos/uso terapêutico , Animais , Soro Antilinfocitário/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/fisiologia , Antígenos de Histocompatibilidade/uso terapêutico , Imunossupressores/uso terapêutico , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos NOD , Suínos , Regulação para CimaRESUMO
BACKGROUND: Treatment of fetal pancreas (FP) isografts with insulin-like growth factor-I greatly improves the rate of conversion to euglycemia in diabetic rats. Complete knowledge of other factors that may facilitate the engraftment and function of FP in vivo is still embryonic. Augmenter of liver regeneration (ALR) is a newly described polypeptide growth factor found in weanling rat livers. ALR has trophic effects on regenerating liver. We studied the effects of in situ administration of this agent on FP isografts in rats. METHODS: Streptozotocin-diabetic Lewis rats (blood glucose > 300 mg/dl) received 16 FP isografts transplanted intramuscularly. ALR was delivered from day 1 through day 14, in doses of 40 or 400 ng/kg/d. Animals were followed for 3 months with serial weights and blood glucose monitoring. These animals were compared with those treated with vehicle alone. RESULTS: Of the group treated with ALR at 40 ng/kg/day for 14 days, 89% (eight of nine) were euglycemic (P=0.0003). Of the group treated with ALR at 400 ng/kg/day for 14 days, 88% (seven of eight) were euglycemic (P=0.0007). Of the group treated with vehicle alone, none of the six were euglycemic. Euglycemia is defined here as glucose < 200 mg/dl for 3 days. Pathology of the intramuscular transplant site showed patches of islet tissue embedded in fat. These patches demonstrated insulin immunoreactivity. CONCLUSIONS: Diabetes was reversed in a significantly greater proportion of FP + ALR-treated recipients than those animals treated with vehicle alone. Local delivery of growth factors may be used as an adjunct to FP transplantation to improve the rate of success. This in situ model may be useful to further evaluate other soluble factors.
Assuntos
Substâncias de Crescimento/farmacologia , Transplante das Ilhotas Pancreáticas , Regeneração Hepática , Pâncreas/embriologia , Proteínas , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/terapia , Fator de Crescimento Insulin-Like I/farmacologia , Pâncreas/patologia , Ratos , Ratos Endogâmicos LewRESUMO
We report a case of adenovirus infection of the renal allograft in a combined kidney/pancreas transplant recipient. The clinical presentation was renal allograft failure, which eventually reversed. The pancreatic graft function remained stable. A renal biopsy showed massive tubular necrosis associated with a prominent granulomatous reaction. The process had a striking regional distribution within the kidney with the injury and inflammation limited to the outer medulla. Adenovirus type 11 was isolated from renal tissue by culture, and adenovirus was demonstrated by immunofluorescence and electron microscopy in the kidney biopsy. Immunosuppression may result in unusual patterns of response to infectious agents. This case demonstrated tropism of the adenovirus to only selected tubules within the kidney, with sparing of other organ function including, specifically, the pancreas allograft. The differential diagnosis of a granulomatous reaction in the transplant kidney must be expanded to include viral infection, in particular, adenovirus.
Assuntos
Infecções por Adenovirus Humanos/complicações , Transplante de Rim , Transplante de Pâncreas , Complicações Pós-Operatórias/virologia , Infecções por Adenovirus Humanos/patologia , Adulto , Diabetes Mellitus Tipo 1/cirurgia , Retinopatia Diabética/complicações , Diagnóstico Diferencial , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Rim/patologia , Rim/virologia , Nefropatias/diagnóstico , Transplante de Rim/patologia , Túbulos Renais/ultraestrutura , Microscopia Eletrônica , Pâncreas/patologia , Pâncreas/virologia , Transplante de Pâncreas/patologiaRESUMO
BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.
Assuntos
Soro Antilinfocitário/uso terapêutico , Rejeição de Enxerto/terapia , Imunossupressores/uso terapêutico , Transplante de Rim , Doença Aguda , Adolescente , Adulto , Idoso , Animais , Soro Antilinfocitário/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , CoelhosAssuntos
Intestino Delgado/transplante , Transplante Homólogo/imunologia , Transplante Homólogo/métodos , Anastomose Cirúrgica , Animais , Aorta Abdominal/cirurgia , Ciclosporina/uso terapêutico , Furões , Sobrevivência de Enxerto/imunologia , Doença Enxerto-Hospedeiro , Humanos , Imunossupressores/uso terapêutico , Recém-Nascido , Masculino , Artéria Mesentérica Superior/cirurgia , Veia Porta/cirurgia , Transplante Heterotópico , Transplante Homólogo/patologiaAssuntos
Diabetes Mellitus Experimental/cirurgia , Sobrevivência de Enxerto , Antígenos de Histocompatibilidade Classe I/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Peptídeos/uso terapêutico , Transplante Heterólogo/imunologia , Animais , Glicemia/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/sangue , Camundongos , Camundongos Endogâmicos CBA , Ensaio de Cápsula Sub-Renal , Suínos , Fatores de Tempo , Transplante Heterólogo/fisiologiaAssuntos
Sobrevivência de Enxerto/imunologia , Intestino Delgado/transplante , Teste de Cultura Mista de Linfócitos , Complexo Principal de Histocompatibilidade , Peptídeos/uso terapêutico , Transplante Homólogo/imunologia , Animais , Ciclosporina/uso terapêutico , Terapia de Imunossupressão/métodos , Isoantígenos/imunologia , Transfusão de Linfócitos , Ratos , Ratos Endogâmicos ACI , Ratos Endogâmicos Lew , Ratos Sprague-DawleyAssuntos
Doenças do Colo/prevenção & controle , Ciclosporinas/uso terapêutico , Perfuração Intestinal/prevenção & controle , Transplante de Rim/efeitos adversos , Doenças do Colo/etiologia , Bases de Dados Bibliográficas , Sobrevivência de Enxerto , Humanos , Terapia de Imunossupressão , Perfuração Intestinal/etiologia , Transplante de Rim/imunologia , Estudos RetrospectivosAssuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Transplante de Rim/efeitos adversos , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Transplante de Pâncreas/efeitos adversos , Adulto , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/cirurgia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/cirurgia , Feminino , Rejeição de Enxerto/etiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , MasculinoAssuntos
Anemia/induzido quimicamente , Antígenos CD55/genética , Ciclofosfamida/efeitos adversos , Sobrevivência de Enxerto/fisiologia , Transplante de Coração/imunologia , Transplante de Rim/imunologia , Complicações Pós-Operatórias/sangue , Animais , Animais Geneticamente Modificados , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos CD55/imunologia , Hemoglobinas/metabolismo , Humanos , Imunossupressores/efeitos adversos , Macaca fascicularis , Masculino , Suínos , Fatores de Tempo , Transplante HeterólogoAssuntos
Intestino Delgado/transplante , Protoporfirinas/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Transplante Isogênico/fisiologia , Animais , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Preservação de Órgãos , Pré-Medicação , Ratos , Ratos Endogâmicos Lew , Doadores de Tecidos , Transplante Isogênico/patologiaRESUMO
Many factors interact to determine genetic structure within populations including adult density, the mating system, colonization history, natural selection, and the mechanism and spatial patterns of gene dispersal. We examined spatial genetic structure within colonizing populations of Quercus rubra seedlings and Pinus strobus juveniles and adults in an aspen-white pine forest in northern Michigan, USA. A 20-year spatially explicit demographic study of the forest enables us to interpret the results in light of recent colonization of the site for both species. We assayed 217 Q. rubra seedlings and 171 P. strobus individuals at 11 polymorphic loci using nine allozyme systems. Plant genotypes and locations were used in an analysis of spatial genetic structure. Q. rubra and P. strobus showed similar observed levels of heterozygosity, but Q. rubra seedlings have less heterozygosity than expected. Q. rubra seedlings show spatial genetic clumping of individuals on a scale to 25 m and levels of genetic relatedness expected from the clumped dispersion of half-siblings. In contrast, P. strobus has low levels of genetic relatedness at the smallest distance class and positive spatial genetic structure at scales < 10 m within the plot. The low density of adult Q. rubra outside the study plot and limited, spatially clumped rodent dispersal of acorns is likely responsible for the observed pattern of spatial genetic structure and the observed heterozygote deficit (i.e. a Wahlund effect). We attribute weaker patterns observed in P. strobus to the longer dispersal distance of seeds and the historical overlap of seed shadows from adults outside of the plot coupled with the overlap of seed shadows from younger, more recently established reproductive adults. The study demonstrates the utility of long-term demographic data in interpreting mechanisms responsible for generating contemporary patterns of genetic structure within populations.
Assuntos
Pinus/enzimologia , Pinus/genética , Quercus/enzimologia , Quercus/genética , Variação Genética , Pinus/fisiologia , Folhas de Planta/enzimologia , Quercus/fisiologia , Reprodução , Plântula/enzimologiaRESUMO
Portal venous (PV) injection of alloantigen can result in tolerance. We have previously reported that this effect is abrogated by pretreatment with gadolinium (Gd), an element known to inhibit Kupffer cell phagocytosis. To further elucidate the role of Kupffer cells (KC) in PV tolerance, the present study examined the ability of KC to present alloantigen in vitro to syngeneic responder lymphocytes after in vivo PV administration of alloantigen with or without pretreatment with Gd. Wistar Furth (WF) rats were pretreated 24 hr prior to KC harvest with a PV injection of 1 x 10(7) allogeneic Lewis (LEW) rat lymphocytes (KC-L) or saline (KC-N). Another group received Gd intravenously 24 h prior to the PV injection of LEW cells (KC-L + Gd). KC were isolated from the WF rats using collagenase digestion and Percoll (90% pure by morphologic criteria and by monoclonal antibodies KU-1 and ED-2). Responder WF lymphocytes were cocultured with media alone, or with KC as prepared above, for 72 hr. KC-L demonstrated significant stimulation of the WF responders (P = 0.02 vs KC-N). Gd abrogated this stimulation (P = 0.04, KC-L vs KC-L + Gd) but not by nonspecific inhibition of the cocultures (KC-N vs KC-L + Gd, P > 0.05, no difference). This study demonstrates that KC can effectively present PV alloantigen for the activation of naive syngeneic T lymphocytes, thereby further supporting the hypothesis that KC play an integral role in the induction of PV tolerance by presentation of antigen to responder T cells.
Assuntos
Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Gadolínio/farmacologia , Isoantígenos/imunologia , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/imunologia , Animais , Células Cultivadas , Injeções Intravenosas , Teste de Cultura Mista de Linfócitos , Transfusão de Linfócitos , Masculino , Veia Porta , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos WF , Baço/citologiaRESUMO
The rat has been used as a model to study the significance of graft and host interactions in small bowel transplantation (SBTX). A mouse model of SBTX would allow investigators to apply the knowledge of the well-defined genetics in the mouse to this field of study. Therefore, we have developed a mouse model of heterotopic SBTX using syngeneic C57BL6/J mice. Animals were anesthetized with a combination of ketamine and xylazine. Donor animals underwent midline laparotomy, with isolation of a segment of bowel as an isograft for transplantation to a recipient animal. The bowel was flushed in situ prior to removal of the graft with a Carrel patch of aorta and portal vein. The recipient animal underwent midline laparotomy and preparation of its infrarenal aorta and inferior vena cava for end-to-side anastomosis of the graft with 10-0 nylon. After vascular reperfusion of the graft the ends of the isografted bowel were brought out as stomata. Successful grafts were later assessed for viability by laparotomy or histological examination at the time of sacrifice. Areas of technical difficulty in this model and issues that might improve the experimental results are discussed. This model should allow investigators to apply the well-defined genetics of the mouse to probe the challenging field of intestinal transplantation.
Assuntos
Intestino Delgado/transplante , Anastomose Cirúrgica/métodos , Animais , Aorta/cirurgia , Modelos Animais de Doenças , Sobrevivência de Enxerto , Obstrução Intestinal/etiologia , Intestino Delgado/irrigação sanguínea , Artérias Mesentéricas/cirurgia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Necrose , Veia Porta/cirurgia , Complicações Pós-Operatórias , Taxa de Sobrevida , Trombose/etiologia , Transplante IsogênicoRESUMO
Renal multicystic dysplasia is commonly regarded as a sporadic anomaly, although several studies of renal agenesis have shown the occasional occurrence of multicystic dysplasia in relatives of propositi with bilateral agenesis. We report the occurrence of unilateral multicystic dysplasia in an infant whose mother and maternal aunt had unilateral renal agenesis. The aunt's daughter, a first cousin of the proposita, had unilateral megaureter and hydronephrosis secondary to obstruction at the ureteropelvic junction. These observations suggest that nonsyndromal multicystic renal dysplasia can occur as part of the spectrum of hereditary renal adysplasia, with what appears to be autosomal dominant inheritance, and that the primary abnormality may reside in the ureter, with secondary renal maldevelopment.