RESUMO
Although transplantation immunology as a distinctive field began with the development of experimental models that showed the feasibility of bone marrow transplantation, organ engraftment was accomplished first in humans, and was thought for many years to occur by drastically different mechanisms. Here, we present our view of the concepts of allograft acceptance and acquired tolerance from a historical perspective, and attempt to amalgamate them into simple and unifying rules that might guide improvements in clinical therapy.
Assuntos
Imunologia de Transplantes , Animais , Transplante de Medula Óssea/história , Quimera , Deleção Clonal , Rejeição de Enxerto/história , História do Século XIX , História do Século XX , Humanos , Tolerância Imunológica , Modelos ImunológicosRESUMO
Until the present time, the first experimental liver transplant which led to the development of human liver transplantation is attributed to C. Stuart Welch who performed a heterotopic transplant in the canine species in 1955. In 1956, Jack Cannon is credited with the first animal orthotopic liver transplant although the species was not disclosed. This report is intended to set the historical record straight by acknowledging that Vittorio Staudacher in 1952 was the first to perform a liver transplant in a large animal model.
Assuntos
Transplante de Fígado/história , Animais , Cães , História do Século XXRESUMO
Prostaglandins have been evaluated for their ability to reduce IRI after liver transplantation; however, poor stability, side effects and the inability to show a significant difference in primary endpoint have limited their clinical application. Treprostinil, a prostacyclin (PGI(2) ) analog, has a higher potency and longer elimination half-life than other commercially available PGI(2) analogs. We examined the efficacy of treprostinil to prevent IRI during OLT. OLT was performed in syngeneic Lewis rats after 18 h of cold preservation (4°C) in the UW solution. IRI significantly increased serum ALT and AST levels, neutrophil infiltration, hepatic necrosis and mRNA levels of proinflammatory cytokines post-OLT, while treatment with treprostinil decreased all the parameters. Cold storage of liver grafts significantly reduced ATP levels and treprostinil restored energy levels in liver grafts early postreperfusion. In addition, treprostinil preserved the sinusoidal endothelial cell lining and reduced platelet deposition early post-transplantation compared to placebo. Hepatic tissue blood flow was significantly compromised in the placebo group, whereas treprostinil maintained blood-flow similar to normal levels. Treprostinil protected the liver graft against IRI during OLT. Treprostinil has the potential to serve as a therapeutic option to protect the liver graft against I/R injury in patients undergoing OLT.
Assuntos
Epoprostenol/análogos & derivados , Transplante de Fígado/fisiologia , Traumatismo por Reperfusão/prevenção & controle , Trifosfato de Adenosina/metabolismo , Animais , Isquemia Fria , Epoprostenol/uso terapêutico , Interferon gama/biossíntese , Circulação Hepática/efeitos dos fármacos , Transplante de Fígado/efeitos adversos , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Within 1 wk of liquid culture in granulocyte/macrophage colony-stimulating factor (GM-CSF), normal B10 BR (H-2k I-E+) mouse liver nonparenchymal cells (NPC) formed loosely adherent myeloid cell clusters that have been shown to contain dendritic cell (DC) progenitors in similar studies of mouse blood or bone marrow. Mononuclear cell progeny released from these clusters at and beyond 4 d exhibited distinct dendritic morphology and were actively phagocytic. After 6-10 d of culture, these cells strongly expressed CD45, CD11b, heat stable antigen, and CD44. However, the intensity of expression of the DC-restricted markers NLDC 145, 33D1, and N418, and the macrophage marker F4/80, intercellular adhesion molecule 1, and Fc gamma RII was low to moderate, whereas the cells were negative for CD3, CD45RA, and NK1.1. Splenocytes prepared in the same way also had a similar range and intensity of expression of these immunophenotypic markers. Unlike the splenic DC, however, most of the GM-CSF-propagated putative liver DC harvested at 6-10 d expressed only a low level of major histocompatibility complex (MHC) class II (I-Ek), and they failed to induce primary allogeneic responses in naive T cells, even when propagated additionally in GM-CSF and tumor necrosis alpha and/or interferon gamma-supplemented medium. However, when 7-d cultured GM-CSF-stimulated liver cells were maintained additionally for three or more days on type-1 collagen-coated plates in the continued presence of GM-CSF, they exhibited characteristics of mature DC: MHC class II expression was markedly upregulated, mixed leukocyte reaction stimulatory activity was increased, and phagocytic function was decreased. Similar observations were made when Ia+ cells were depleted from the GM-CSF-propagated cells before exposure to collagen. Further evidence that the GM-CSF-stimulated class IIdim or class II-depleted hepatic NPC were immature DC was obtained by injecting them into allogeneic B10 (H-2b I-E-) recipients. They "homed" to T cell-dependent areas of lymph nodes and spleen where they strongly expressed donor MHC class II antigen 1-5 d later. These observations provide insight into the regulation of DC maturation, and are congruent with the possibility that the migration of immature DC from normal liver and perhaps other organ allografts may help explain their inherent tolerogenicity.
Assuntos
Colágeno/farmacologia , Células Dendríticas/citologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fígado/citologia , Fagocitose , Células-Tronco/citologia , Animais , Anticorpos Monoclonais , Antígenos de Superfície/análise , Células da Medula Óssea , Adesão Celular , Agregação Celular , Divisão Celular , Separação Celular , Células Cultivadas , Técnicas de Cultura/métodos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/ultraestrutura , Antígenos de Histocompatibilidade Classe II/análise , Imunofenotipagem , Cinética , Fígado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Microscopia Eletrônica , Proteínas Recombinantes/farmacologia , Ovinos , Células-Tronco/efeitos dos fármacos , Células-Tronco/ultraestruturaRESUMO
Allografts of the liver, which has a comparatively heavy leukocyte content compared with other vascularized organs, are accepted permanently across major histocompatibility complex barriers in many murine strain combinations without immunosuppressive therapy. It has been postulated that this inherent tolerogenicity of the liver may be a consequence of the migration and perpetuation within host lymphoid tissues of potentially tolerogenic donor-derived ("chimeric") leukocytes, in particular, the precursors of chimeric dendritic cells (DC). In this study, we have used granulocyte/macrophage colony-stimulating factor to induce the propagation of progenitors that give rise to DC (CD45+, CD11c+, 33D1+, nonlymphoid dendritic cell 145+, major histocompatibility complex class II+, B7-1+) in liquid cultures of murine bone marrow cells. Using this technique, together with immunocytochemical and molecular methods, we show that, in addition to cells expressing female host (C3H) phenotype (H-2Kk+; I-E+; Y chromosome-), a minor population of male donor (B10)-derived cells (H-2Kb+; I-A+; Y chromosome+) can also be grown in 10-d DC cultures from the bone marrow of liver allograft recipients 14 d after transplant. Highly purified nonlymphoid dendritic cell 145+ DC sorted from these bone marrow-derived cell cultures were shown to comprise approximately 1-10% cells of donor origin (Y chromosome+) by polymerase chain reaction analysis. In addition, sorted DC stimulated naive, recipient strain T lymphocytes in primary mixed leukocyte cultures. Evidence was also obtained for the growth of donor-derived cells from the spleen but not the thymus. In contrast, donor cells could not be propagated from the bone marrow or other lymphoid tissues of nonimmunosuppressed C3H mice rejecting cardiac allografts from the same donor strain (B10). These findings provide a basis for the establishment and perpetuation of cell chimerism after organ transplantation.
Assuntos
Células da Medula Óssea , Células Dendríticas/citologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Transplante de Fígado/imunologia , Animais , Sequência de Bases , Primers do DNA/química , Feminino , Citometria de Fluxo , Rejeição de Enxerto , Transplante de Coração/imunologia , Fígado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Timo/citologia , Cromossomo YRESUMO
Genetic types of plasminogen were determined from a donor and a recipient before and after hepatic homotransplantation. Examination of the plasminogen types demonstrated that the liver is the principal site of synthesis of human plasminogen.
Assuntos
Fígado/metabolismo , Plasminogênio/biossíntese , Feminino , Humanos , Transplante de Fígado , Masculino , Plasminogênio/genética , Polimorfismo Genético , Transplante HomólogoRESUMO
The current study aims to investigate species-related differences in the in-vitro hepatic metabolism of tacroliums using liver microsomes obtained from rat, hamster, guinea pig, rabbit, pig, dog, baboon and humans. Tacrolimus metabolism was characterized using high-performance liquid chromatography- ultraviolet light (HPLC-UV) and two soft ionization mass spectrometric techniques; matrix-assisted lasers desorption/ionization (MALDI) and time-of-flight-secondary ion mass spectrometry (TOF-SIMS). The extent of tacrolimus metabolism, when normalized to the cytochrome P-450 content, was in the order: rat < hamster < rabbit < pig < guinea pig < dog < human < baboon. Tacrolimus metabolism exhibited significant qualitative and quantitative differences between the animal species tested. Desmethyl- (MI-MIII), didesmethyl- (MIV-MVI), monohydroxy- (MVII), dihydroxy- (MVIII), epoxide- (MIX), dihydrodiol- (MX), monodesmethyl and monohydroxy- (MXI-MXIII), and didesmethyl and monohydroxy- (MXIV-MXVI) tacroliums metabolites were identified in the species tested. MI-MX were identified in all the species tested; MXI-MXVI were identified in all species except rat, rabbit and guinea pig; and MXIV-MXVI were identified only in baboon. The current investigation was unable to detect any phase II metabolites due to the limitations of the test system used. The analytical methods were not able to differentiate optical and positional isomers of metabolites due to the nature of the analytical tools used, therefore groups of metabolites were identified based on their molecular weights and available information. From the current in-vitro metabolism studies, the pattern of tacroliums metabolism in baboons closely resembled that in humans and thus it is ideal for studying tacroliums metabolism-related work of clinical relevance.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Imunossupressores/metabolismo , Microssomos Hepáticos/enzimologia , Tacrolimo/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Cricetinae , Cães , Cobaias , Humanos , Imunossupressores/química , Cinética , Papio , Coelhos , Ratos , Especificidade da Espécie , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Tacrolimo/químicaRESUMO
Conventional allogeneic bone marrow transplantation after myeloablation can prevent experimental autoimmunity and has been proposed as treatment for humans. However, trace populations of donor hematolymphoid cells persisting in solid organ allograft recipients have been associated in some circumstances with therapeutic effects similar to replacement of the entire bone marrow. We therefore examined whether inducing hematolymphoid microchimerism without myeloablation could confer the ability to resist mercuric chloride (HgCl2)-induced autoimmunity. Brown-Norway (BN) rats were pretreated with a syngeneic or allogeneic bone marrow infusion under transient FK506 immunosuppression before receiving HgCl2. They were compared with BN rats receiving either no pretreatment (naive) or FK506 alone. Administration of HgCl2 to naive BN rats induced marked autoantibody production, systemic vasculitis and lymphocytic infiltration of the kidneys, liver and skin in all of the animals and a 47% mortality. In contrast, BN rats pretreated with HgCl2-resistant allogeneic Lewis bone marrow and transient FK506 showed less clinical disease and were completely protected from mortality. More specifically, IgG anti-laminin autoantibody production was decreased by 40% (P < 0.05), and there was less histopathological tissue injury (P < 0.005), less in vitro autoreactivity (P < 0.05), less of an increase in class II MHC expression on B cells (P < 0.01), and 22% less weight loss (P < 0.01), compared with controls. Protection from the experimental autoimmunity was associated with signs of low grade activation of the BN immune system, which included: increased numbers of circulating B and activated T cells before administration of HgCl2, and less autoreactivity and spontaneous proliferation in vitro after HgCl2.
Assuntos
Doenças Autoimunes/prevenção & controle , Autoimunidade/imunologia , Transplante de Medula Óssea/métodos , Quimeras de Transplante/imunologia , Animais , Autoanticorpos/biossíntese , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/química , Movimento Celular/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/análise , Imunossupressores/farmacologia , Laminina/imunologia , Antígenos do Grupo Sanguíneo de Lewis , Ativação Linfocitária , Linfócitos/imunologia , Masculino , Cloreto de Mercúrio/farmacologia , Ratos , Tacrolimo/farmacologia , Vasculite/induzido quimicamente , Redução de PesoRESUMO
Patients with familial hypercholesterolemia have elevated levels of plasma low density lipoproteins (LDL), increased hepatic synthesis of apolipoprotein B-containing lipoproteins, defective binding of low density lipoproteins to fibroblasts, and premature atherosclerosis. The role of a hepatic low density lipoprotein receptor in normal man and its importance in the pathogenesis of familial hypercholesterolemia have not been previously determined. In the present study, direct comparison was made of the binding of LDL to hepatic membranes from normal and receptor-negative homozygous familial hypercholesterolemic subjects. The effects of calcium, EDTA, and temperature on the binding of lipoproteins to the hepatic membranes were also evaluated. At 4 degrees C, no significant difference in specific binding of LDL to hepatic membranes from normal and familial hypercholesterolemic subjects was observed. At 37 degrees C, both total and specific binding of LDL were significantly reduced in patients with familial hypercholesterolemia. Hepatic membrane binding of LDL from the two patients homozygous for receptor-negative familial hypercholesterolemia was 53 and 59% of normal. The activity of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase was normal; however, the total hepatic cholesterol and cholesteryl ester content was significantly increased from 53 to 129%. These results indicate that patients with familial hypercholesterolemia have a defect in the interaction of hepatic membranes with low density lipoproteins. This defect may lead to accelerated atherosclerosis by decreasing the cellular catabolism of LDL and enhancing the production of LDL, which is characteristic of patients homozygous for familial hypercholesterolemia.
Assuntos
Colesterol/metabolismo , Hiperlipoproteinemia Tipo II/metabolismo , Lipoproteínas LDL/metabolismo , Fígado/metabolismo , Receptores de Superfície Celular/metabolismo , Adulto , Membrana Celular/metabolismo , Criança , Ésteres do Colesterol/metabolismo , Feminino , Fibroblastos/enzimologia , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Masculino , Receptores de LDL , TemperaturaRESUMO
The daily transport of human plasma apolipoproteins A-I and A-II, triglyceride, and total cholesterol from the thoracic duct lymph into plasma was measured in two subjects before and three subjects after renal transplantation. Lymph triglyceride transport was approximately 83% of the daily ingested fat loads, whereas lymph cholesterol transport was consistently greater than the amount of daily ingested cholesterol. Lymph apolipoprotein transport significantly (P < 0.05) exceeded the predicted apolipoprotein synthesis rate by an average of 659+/-578 mg/d for apolipoprotein A-I and 109+/-59 mg/d for apolipoprotein A-II among the five subjects. It is estimated that 22-77% (apolipoprotein A-I) and 28-82% (apolipoprotein A-II) of daily total body apolipoprotein synthesis takes place in the intestine. Lymph high density lipoprotein particles are mostly high density lipoprotein(2b) and high density lipoprotein(2a) and have a greater overall relative triglyceride content and a smaller relative cholesteryl ester content when compared with homologous plasma high density lipoproteins. The major quantity of both lymph apolipoprotein A-I (81+/-8%) and apolipoprotein A-II (90+/-11%) was found within high density lipoproteins with almost all of the remainder found in chylomicrons and very low density lipoproteins. The combined results are consistent with a major contribution of the intestine to total body synthesis of apolipoprotein A-I and apolipoprotein A-II. An important role of lymph in returning filtered apolipoprotein to plasma in association with high density lipoproteins is proposed. Accompanying the return of filtered apolipoprotein to the plasma is a probable transformation, both in size and composition, of at least some of the lymph high density lipoprotein(2b) and high density lipoprotein(2a) particles into high density lipoprotein(3).
Assuntos
Apolipoproteínas/metabolismo , Linfa/metabolismo , Transporte Biológico , Colesterol/sangue , Colesterol/metabolismo , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismo , Peso Molecular , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
Chronic allograft nephropathy (CAN) is a major indication for initiation of sirolimus (SRL) in renal transplantation (TX) to prevent deterioration of renal function. We evaluated whether the CAN score at time of sirolimus rescue (SRL-R) predicts renal allograft function. CAN score is the sum of the following 4 categories: glomerulopathy (cg, 0-3), interstitial fibrosis (ci, 0-3), tubular atrophy (ct, 0-3), and vasculopathy (cv, 0-3). This is a retrospective cohort study of renal transplant recipients from July 2001 to March 2004. Immunosuppression consisted of preconditioning with rabbit anti-thymocyte globulin or alemtuzumab and maintenance with tacrolimus (TAC) monotherapy with spaced weaning, if applicable, SRL-R was achieved by conversion from TAC, or by addition to reduced doses of TAC. Ninety patients received SRL. Thirty-three of these patients met the inclusion criteria of the following: (1) receipt of SRL for >6 months, and (2) follow-up of > or =6 months. There were 16 patients in the low-CAN (0-4) group and 17 patients in the high-CAN (>4) group. Cockcroft-Gault (C-G) glomerular filtration rate (GFR) was calculated at SRL-R and at 1, 3, 6, and 12 months. The DeltaGFR was significantly better in the low-CAN group at 1, 3, and 6 months. A trend toward an improved DeltaGFR was present at 12 months in the low-CAN group (P = .16). CAN scoring at the time of SRL-R predicts recovery of renal allograft function (as measured using DeltaGFR), and should be used in preference to biochemical markers (Cr and C-G GFR), which may not be reliable predictors.
Assuntos
Transplante de Rim/imunologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/patologia , Sirolimo/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Soro Antilinfocitário , Doença Crônica , Feminino , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/mortalidade , Transplante de Rim/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo/imunologia , Transplante Homólogo/patologiaAssuntos
Antígenos Virais , Rejeição de Enxerto/imunologia , Tolerância Imunológica , Vírus da Coriomeningite Linfocítica/imunologia , Transplante de Pele/imunologia , Linfócitos T Citotóxicos/imunologia , Proteínas Virais , Animais , Glicoproteínas/genética , Glicoproteínas/imunologia , Vírus da Coriomeningite Linfocítica/genética , Camundongos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologiaRESUMO
Injection of a substantially purified hepatomitogen into recipient rats that had 40% of their liver removed resulted in a significant stimulation of hepatic DNA synthesis as determined by the labeling index and the mitotic index. Normal or sham-operated rats did not respond to the injection of the mitogen. The extraction and partial purification of this hepatomitogen have previously been reported (A. Francavilla et al., Cancer Res., 47:5600-5605, 1987). Addition of the factor to an epithelial-like liver-derived cell line in culture (clone 9) or to a hepatoma cell line (HTC-SR) resulted in a dose-dependent stimulation of DNA synthesis. Hepatocytes in primary culture, on the other hand, were not stimulated by the addition of the factor. However, when the mitogen was added to hepatocytes in primary culture, together with conditioned medium, obtained from the responsive cell lines, a significant stimulation of DNA synthesis could be demonstrated in hepatocytes in culture. The stimulation was dose dependent with respect to the mitogen, was abolished by 10 mM hydroxyurea, and was independent of epidermal growth factor. The conditioned medium could be replaced by a protein factor extracted from the two cell lines as previously reported (P. Ove et al., J. Cell. Physiol., 131: 165-174, 1987). It appears that a cofactor is provided by the conditioned medium or by the cell extract, enabling the hepatomitogen to act on hepatocytes in primary culture.
Assuntos
DNA/biossíntese , Fígado/metabolismo , Mitógenos/farmacologia , Animais , Células Cultivadas , Meios de Cultura , Fator de Crescimento Epidérmico/farmacologia , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
Primary hepatocyte cultures have been prepared from normal adult rat liver and from rat liver at 4, 8, 12, 24, and 48 h following partial hepatectomy (removal of 70% of the liver). Cells were maintained in minimal essential medium alone or supplemented with hormones. Comparing DNA synthesis in normal adult rat hepatocytes with DNA synthesis in hepatocytes isolated from regenerating livers, we found with minimal essential medium alone little DNA synthesis in normal adult rat hepatocytes and in hepatocytes isolated 4, 8, or 12 h after 70% hepatectomy. In hepatocytes isolated 24 h after partial hepatectomy, however, the incorporation of [3H]thymidine was 3 times the rate of normal hepatocytes. The addition of insulin to minimal essential medium had minimal effect on DNA synthesis in all hepatocytes. Addition of epidermal growth factor alone or in combination with insulin resulted in a dramatic increase in DNA synthesis in hepatocytes from regenerating rat liver. Increased incorporation was detectable as early as 4 h after partial hepatectomy and reached a maximum at 24 h after the operation. Results obtained with [3H]thymidine incorporation were confirmed by autoradiography and by direct DNA determinations in hepatocyte cultures. Epidermal growth factor binding to the hepatocytes was determined and agreed with previously reported binding studies. Binding of epidermal growth factor in hepatocytes isolated at 4 h after partial hepatectomy was the same as in normal hepatocytes but was undetectable in hepatocytes isolated from rats at 12 and 24 h after partial hepatectomy.
Assuntos
Fator de Crescimento Epidérmico/metabolismo , Regeneração Hepática , Fígado/citologia , Animais , Ciclo Celular , Células Cultivadas , Meios de Cultura , DNA/biossíntese , Células Epiteliais , Receptores ErbB , Fígado/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Receptores de Superfície Celular/metabolismo , Fatores de TempoRESUMO
A factor has been isolated from weanling rat liver which stimulates in vivo hepatic DNA synthesis in a dose dependent manner when injected into 40% hepatectomized rats. The factor has been partially purified by successive steps, involving ethanol precipitation, ultrafiltration through an Amicon PM 30 membrane, and finally fast protein liquid chromatography, resulting in a 38,000-fold increase in specific activity over that in the original cytosol. The factor contains a few bands in the molecular weight range of 14,000-50,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Active fractions from fast protein liquid chromatography (F150), when injected into 40% hepatectomized rats, increased hepatic DNA synthesis 3-fold over the background stimulation due to the hepatectomy. The response was dose dependent over a range from 1.76 micrograms to 6.8 micrograms per 200-g (body weight) rat. Mitotic and labeling indexes confirmed that F150 stimulates both replicative DNA synthesis and cell proliferation. The factor is heat and neuraminidase resistant, trypsin sensitive, organ specific, but not species specific.
Assuntos
DNA/biossíntese , Substâncias de Crescimento/isolamento & purificação , Fígado/efeitos dos fármacos , Animais , Citosol/análise , Cães , Substâncias de Crescimento/análise , Substâncias de Crescimento/farmacologia , Fígado/metabolismo , Regeneração Hepática/efeitos dos fármacos , Masculino , Camundongos , Peso Molecular , Especificidade de Órgãos , Ratos , Ratos Endogâmicos F344 , Especificidade da EspécieRESUMO
At the 14th International Small Bowel Transplant Symposium, (ISBTS2015) held in Buenos Aires, a session to recognize the pioneers that have dedicated their lives to make our current field possible was organized. Dr Thomas Starzl received the first Living Legend Award. A video interview was obtained at his office, edited, and later presented during the scientific meeting. More than 600 people saw Dr Starzl's interview, which captivated the audience for 40 minutes, before smiles, tears and the final applause erupted at the conclusion. We would like to share this video with all of you to inspire the current generations and the generations to come. The manuscript has the main parts of the interview, which can also be accessed at http://isbts2015.tts.org/starzl.mp4.
Assuntos
Distinções e Prêmios , Intestinos/transplante , Transplante de Órgãos/história , História do Século XX , História do Século XXI , Humanos , Transplante de Fígado/históriaRESUMO
The profoundly elevated concentrations of low-density lipoproteins (LDL) present in homozygous familial hypercholesterolemia lead to symptomatic cardiovascular disease and death by early adulthood. Studies conducted in nonhepatic tissues demonstrated defective cellular recognition and metabolism of LDL in these patients. Since mammalian liver removes at least half of the LDL in the circulation, the metabolism of LDL by cultured hepatocytes isolated from familial hypercholesterolemic homozygotes was compared to hepatocytes from normal individuals. Fibroblast studies demonstrated that the familial hypercholesterolemic subjects studied were LDL receptor-negative (less than 1% normal receptor activity) and LDL receptor-defective (18% normal receptor activity). Cholesterol-depleted hepatocytes from normal subjects bound and internalized 125I-labeled LDL (Bmax = 2.2 micrograms LDL/mg cell protein). Preincubation of normal hepatocytes with 200 micrograms/ml LDL reduced binding and internalization by approx. 40%. In contrast, 125I-labeled LDL binding and internalization by receptor-negative familial hypercholesterolemic hepatocytes was unaffected by cholesterol loading and considerably lower than normal. This residual LDL uptake could not be ascribed to fluid phase endocytosis as determined by [14C]sucrose uptake. The residual LDL binding by familial hypercholesterolemia hepatocytes led to a small increase in hepatocyte cholesterol content which was relatively ineffective in reducing hepatocyte 3-hydroxy-3-methylglutaryl-CoA reductase activity. Receptor-defective familial hypercholesterolemia hepatocytes retained some degree of regulatable 125I-labeled LDL uptake, but LDL uptake did not lead to normal hepatocyte cholesterol content or 3-hydroxy-3-methylglutaryl-CoA reductase activity. These combined results indicate that the LDL receptor abnormality present in familial hypercholesterolemia fibroblasts reflects deranged hepatocyte LDL recognition and metabolism. In addition, a low-affinity, nonsaturable uptake process for LDL is present in human liver which does not efficiently modulate hepatocyte cholesterol content or synthesis.
Assuntos
Hiperlipoproteinemia Tipo II/metabolismo , Lipoproteínas LDL/metabolismo , Fígado/metabolismo , Albuminas/biossíntese , Criança , Pré-Escolar , Feminino , Homozigoto , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Hiperlipoproteinemia Tipo II/genética , Lipídeos/sangue , Lipoproteínas/sangue , Membranas/metabolismo , Receptores de LDL/metabolismoRESUMO
One line of thought in organ transplantation feels that immunosuppressive drugs can lead to tolerance induction by allowing a previously unrecognized common mechanism of cell migration and microchimerism to occur, persist, and in some cases, become drug independent. It has been recognized that there is a spectrum of susceptibility of different organs to cellular rejection and that the variable ability of these organs to induce donor-specific nonreactivity reflects their comparative content of migratory leukocytes. Here, Thomas Starzl and colleagues discuss how many of the enigmas of transplantation immunology can be explained by this chimerism.
Assuntos
Quimera/imunologia , Imunossupressores/uso terapêutico , Linfócitos/imunologia , Transplante de Órgãos , Doadores de Tecidos , Animais , Movimento Celular , Rejeição de Enxerto/prevenção & controle , Humanos , Tolerância ImunológicaRESUMO
From days 30-120 after birth, 59 BB rats were treated with water (n = 20) or FK 506 in intragastric doses of 1 mg.kg-1.day-1 (n = 19) or 2 mg.kg-1.day-1 (n = 20). Diabetes developed in 75, 15, and 0% of the 3 groups, respectively. Animals protected from diabetes by FK 506 had normal intraperitoneal glucose tolerance tests, virtual absence histopathologically of autoimmune insulitis, and normal pancreatic insulin content. Forty-five to 75 days after stopping FK 506, approximately 75% of the rats that were diabetes free at 120 days remained so.