RESUMO
Half of the recovered expanded criteria donor (ECD) kidneys are discarded in the United States. A new kidney allocation system offers kidneys at higher risk of discard, Kidney Donor Profile Index (KDPI)>85%, to a wider geographic area to promote broader sharing and expedite utilization. Dual kidney transplantation (DKT) based on the KDPI is a potential option to streamline allocation of kidneys which otherwise would have been discarded. To assess the clinical utility of the KDPI in kidneys at higher risk of discard, we analyzed the OPTN/UNOS Registry that included the deceased donor kidneys recovered between 2002 and 2012. The primary outcomes were allograft survival, patient survival and discard rate based on different KDPI categories (<80%, 80-90% and >90%). Kidneys with KDPI>90% were associated with increased odds of discard (OR=1.99, 95% CI 1.74-2.29) compared to ones with KDPI<80%. DKTs of KDPI>90% were associated with lower overall allograft failure (HR=0.74, 95% CI 0.62-0.89) and better patient survival (HR=0.79, 95% CI 0.64-0.98) compared to single ECD kidneys with KDPI>90%. Kidneys at higher risk of discard may be offered in the up-front allocation system as a DKT. Further modeling and simulation studies are required to determine a reasonable KDPI cutoff percentile.
Assuntos
Seleção do Doador , Rejeição de Enxerto/etiologia , Falência Renal Crônica/cirurgia , Transplante de Rim/estatística & dados numéricos , Obtenção de Tecidos e Órgãos/estatística & dados numéricos , Idoso , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/mortalidade , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Doadores de TecidosRESUMO
The number of kidneys obtained from deceased diabetic donors available for transplantation has increased >eightfold increase in the past 15 years. We assessed allograft outcomes associated with deceased diabetic donors and compared them with that of standard and extended criteria donors (ECD) in the UNOS data registry. We identified 1982 recipients of diabetic standard criteria donors over a 10-year period from 1995 through 2004. Both overall and death-censored survival of organs from diabetic standard criteria donors was significantly better than that of organs obtained from nondiabetic ECD while inferior to that from nondiabetic standard criteria donors. Compared with ECD donors, diabetic donors had lower serum creatinine, less cold ischemia and these kidneys were less likely to be pump-perfused. Recipients of diabetic kidneys were younger and less likely to experience delayed graft function compared with recipient of ECD kidneys. More recently, many diabetic donor kidneys have been given to diabetic recipients with early graft survival being similar to that among nondiabetic recipients. These findings demonstrate the potential to expand and to improve utilization of this resource without compromising outcomes for recipients. Improved, evidence-based evaluation and allocation of deceased diabetic donor kidneys is needed to optimize their use.
Assuntos
Diabetes Mellitus/fisiopatologia , Transplante de Rim , Sistema de Registros , Obtenção de Tecidos e Órgãos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Estados UnidosRESUMO
The HLA and Bf genotypes were determined in 10 families with one or more children with JDM. A statistically significant association was found between HLA-D-identity and the chance to present JDM within a sibship. No such association was detectable with the SD antigens. A highly significant increase in the frequency of intra-HLA recombination was also found in these families.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA , Antígenos de Histocompatibilidade , Diabetes Mellitus Tipo 1/genética , Antígenos HLA/classificação , Antígenos de Histocompatibilidade/classificação , Humanos , Linhagem , Recombinação GenéticaRESUMO
Intramuscular endocrine gland transplantation has been well described as it pertains to parathyroid autotransplantation; however, transplantation of the adrenal gland is less well characterized. While adrenal autotransplantation in the setting of Cushing's disease has been described, intramuscular adrenal allotransplantation as a cure for adrenal insufficiency to our knowledge has not been previously carried out. Current treatment for adrenal insufficiency leaves patients without diurnal variation in cortisol release and susceptible to the detrimental effects of chronic hypercortisolism. We describe here the case of a 5-year-old girl with renal failure who had adrenal insufficiency following fulminant meningococcemia that led to requirements for both stress-dose steroid and mineralocorticoid replacement. Ten months after the onset of her disease, she received a simultaneous renal and adrenal gland transplant from her mother. The adrenal gland allograft was morselized into 1 mm(3) segments and implanted into three 2 cm pockets created in her rectus abdominis muscle. Three years after surgery, her allograft remains fully functional, responding well to adrenocorticotropin hormone stimulation and the patient does not require any steroid or mineral-corticoid supplementation. We believe this case represents the first description of successful functional intramuscular adrenal allograft transplantation with long-term follow up as a cure for adrenal insufficiency.
Assuntos
Glândulas Suprarrenais/transplante , Síndrome de Cushing/terapia , Doença de Addison/tratamento farmacológico , Insuficiência Adrenal/tratamento farmacológico , Hormônio Adrenocorticotrópico/uso terapêutico , Pré-Escolar , Ritmo Circadiano , Síndrome de Cushing/tratamento farmacológico , Feminino , Humanos , Hidrocortisona/uso terapêutico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Transplante AutólogoRESUMO
The divalent cation ionophore A 23187 was used to evaluate the action of intracellular calcium on net transepithelial water movement across the isolated frog urinary bladder. Incubation with the ionophore increases the net basal water flux in a dose-dependent fashion but independent of the extracellular calcium concentration. Bladders pretreated with A 23187 and exposed thereafter to an increase in calcium concentration exhibit a water permeability that under certain conditions can be comparable to that achieved with antidiuretic hormone (ADH). Lowering the serosal calcium at the peak of the hydrosmotic responses to both ADH and A 23187 inhibited the maintenance of the net water flux. The action of a supramaximal dose of ADH is blunted in bladders pretreated with A 23187, while the hydrosmotic effects of a submaximal dose are enhanced when the ionophore is added together with the hormone. The results show that an increase in transepithelial water movement can be triggered by calcium and that serosal calcium is needed to sustain the response. This hydrosmotic response may be dependent upon the rate at which intracellular calcium concentrations change and on the absolute concentration attained. It is suggested that calcium is involved in the action of ADH on water permeability and may act as a modulator of the hydrosmotic response.
Assuntos
Cálcio/metabolismo , Bexiga Urinária/metabolismo , Água/metabolismo , Animais , Anuros , Transporte Biológico/efeitos dos fármacos , Calcimicina/farmacologia , Epitélio/metabolismo , Ranidae , Vasopressinas/farmacologiaRESUMO
Survival of allografts of islets of Langerhans in nonimmunosuppressed adult rats was prolonged by transfusions of donor blood irradiated with ultraviolet light before transplantation across a major histocompatibility barrier. This treatment is donor blood-specific and has produced greater than 160-day survival of transplanted islets without the administration of immunosuppressive agents.
Assuntos
Terapia de Imunossupressão , Transplante das Ilhotas Pancreáticas , Animais , Células Sanguíneas/imunologia , Células Sanguíneas/efeitos da radiação , Transfusão de Sangue , Sobrevivência de Enxerto , Ratos , Raios UltravioletaRESUMO
Ultraviolet irradiation of rat dendritic cells completely abrogated their allostimulatory capacity in a mixed lymphocyte reaction. Rat islets of Langerhans similarly irradiated remained hormonally functional when transplanted into syngeneic diabetic rats. Allogeneic transplantation across a major histocompatibility barrier of islets initially treated in vitro with ultraviolet irradiation resulted in prolonged allograft survival without the use of any immunosuppressive agents.
Assuntos
Transplante das Ilhotas Pancreáticas , Raios Ultravioleta , Animais , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Ilhotas Pancreáticas/efeitos da radiação , Cinética , Ratos , Ratos Endogâmicos Lew , Transplante Homólogo , Transplante IsogênicoRESUMO
It is critical to balance waitlist mortality against posttransplant mortality. Our objective was to devise a scoring system that predicts recipient survival at 3 months following liver transplantation to complement MELD-predicted waitlist mortality. Univariate and multivariate analysis on 21,673 liver transplant recipients identified independent recipient and donor risk factors for posttransplant mortality. A retrospective analysis conducted on 30,321 waitlisted candidates reevaluated the predictive ability of the Model for End-Stage Liver Disease (MELD) score. We identified 13 recipient factors, 4 donor factors and 2 operative factors (warm and cold ischemia) as significant predictors of recipient mortality following liver transplantation at 3 months. The Survival Outcomes Following Liver Transplant (SOFT) Score utilized 18 risk factors (excluding warm ischemia) to successfully predict 3-month recipient survival following liver transplantation. This analysis represents a study of waitlisted candidates and transplant recipients of liver allografts after the MELD score was implemented. Unlike MELD, the SOFT score can accurately predict 3-month survival following liver transplantation. The most significant risk factors were previous transplantation and life support pretransplant. The SOFT score can help clinicians determine in real time which candidates should be transplanted with which allografts. Combined with MELD, SOFT can better quantify survival benefit for individual transplant procedures.
Assuntos
Técnicas de Apoio para a Decisão , Determinação de Ponto Final/métodos , Transplante de Fígado/mortalidade , Modelos Teóricos , Avaliação de Resultados em Cuidados de Saúde/métodos , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Hepatopatias/diagnóstico , Hepatopatias/mortalidade , Hepatopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Listas de Espera , Isquemia QuenteRESUMO
The present studies probe the role of Ca2+ and Na+ in the stimulation-permeability coupling sequences by which antidiuretic hormone (ADH) induces a cyclic AMP (cAMP)-mediated increase in urea permeability in toad urinary bladder. The following results were obtained: (a) Removal of mucosal Na+ or Ca2+ or deletion of serosal Ca2+ did not modify ADH action. (b) Reduction of the serosal Na+ concentration to less than 50 mM inhibited the effects of both ADH and cAMP. The minimal concentration of serosal Na+ needed for the hormone to elicit its maximal effect was reduced to approximately 10 mM if serosal Ca2+ was concomitantly deleted. (c) The Na+ ionophore monensin produced an inhibition of ADH and cAMP actions that was dependent on the presence of Na+ and Ca2+ in the serosa. (d) The Ca2+ ionophore A23187 produced a serosal Ca2+-dependent inhibition of ADH effect and did not modify cAMP action. (e) Carbachol, which increases Ca2+ uptake to the same extent that A23187 does, had no effect on ADH action. (f) Quinidine, which releases Ca2+ from intracellular stores, produced a large inhibition of the action of ADH but not that of cAMP; the inhibition was greatly reduced if serosal Ca2+ was deleted. (g) Dinitrophenol and iodoacetate, which also release Ca2+ from intracellular pools, had no effect on ADH action. (h) The Ca2+ channel blocker diltiazem had no effect on ADH action and did not modify the inhibitions produced by deletion of serosal Na+ or monensin. (i) The cyclooxygenase inhibitor indomethacin partially removed the inhibition produced by deletion of serosal Na+ and almost completely impeded the inhibitions produced by either monensin or A23187. It is concluded: (a) Extracellular Ca2+, Na+ transport rates, and serosal Na+, in concentrations between 10 and 110 mM, have no participation in modulating the increase in urea permeability produced by ADH. (b) Increases in cytosolic Ca2+ activity, which are capable of inhibiting the effect of ADH on urea permeability at pre- and/or post-cAMP steps, seem to be highly compartmentalized. (c) Endogenous prostaglandins might play a role in the inhibitions produced by absence of serosal Na+, monensin, or A23187.
Assuntos
Arginina Vasopressina/fisiologia , Cálcio/fisiologia , Permeabilidade da Membrana Celular , Sódio/fisiologia , Ureia/metabolismo , Bexiga Urinária/metabolismo , Animais , Arginina Vasopressina/antagonistas & inibidores , Arginina Vasopressina/metabolismo , Bufo marinus , Calcimicina/farmacologia , Cálcio/metabolismo , Carbacol/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Diltiazem/farmacologia , Dinitrofenóis/farmacologia , Feminino , Indometacina/farmacologia , Iodoacetatos/farmacologia , Ácido Iodoacético , Monensin/farmacologia , Quinidina/farmacologia , Sódio/metabolismo , Bexiga Urinária/citologiaRESUMO
The role of the indirect allorecognition pathway in acute allograft rejection has been documented both in organ recipients and in experimental models. However, it is unknown whether self-restricted recognition of donor alloantigens also contributes to chronic allograft rejection. The aim of this study was to determine the relationship between allopeptide reactivity, epitope spreading, and chronic rejection. Using synthetic peptides corresponding to the hypervariable region of 32 HLA-DR alleles, we have followed the specificity of self-restricted T cell alloresponses to the donor in a population of 34 heart allograft recipients. T cells from sequential samples of blood collected from the patients up to 36 mo after transplantation were studied in limiting dilution analysis for allopeptide reactivity. The incidence of coronary artery vasculopathy (CAV) was significantly higher in patients who displayed persistent alloreactivity late after transplantation than in patients who showed no alloreactivity after the first 6 mo after transplantation. Both intra- and intermolecular spreading of epitopes was observed with an increased frequency in patients developing CAV in less than 2 yr, compared with patients without CAV; this suggests that diversification of the immune response against the graft contributes to chronic rejection. These data provide a strategy for identifying patients at risk of developing CAV and a rationale for therapeutic intervention aimed to prevent the progression of the rejection process.
Assuntos
Doença das Coronárias/etiologia , Epitopos , Rejeição de Enxerto , Antígenos HLA-DR/imunologia , Transplante de Coração/imunologia , Adulto , Idoso , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
BACKGROUND: The aim of this study was to evaluate the effectiveness of the Edmonton Donor Scoring System for use in our much less active islet center. Because the ability to recognize an appropriate donor may help to achieve consistent and predictable success of pancreatic islet isolation, it should lead to increased effectiveness and lower cost. MATERIAL AND METHODS: Charts of 36 consecutive pancreas donors were reviewed to assess the donor points (DP). DP ranged from 0 to 100 based on donor age, body mass index, cause of death, social and medical history, hospital stay, vasopressor dosages, laboratory tests, cold ischemia time and procurement team, as well as pancreas size, consistency, fat content, damage, and quality of procurement and packing. RESULTS: Successful isolation was achieved in 39% of donors (14 of 36), a value similar to that achieved in Edmonton (40%). We used the optimal cutoff value (DP = 79) proposed by the Edmonton group. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 66%, 75%, 57%, 82% and 72%, respectively. Successful islet isolation from poor or marginal donors (DP < 49.5 and 50 to 59.5) was 0% and 28.6% respectively; it was 63% and 100% in optimal donors (DP = 80 to 89.5 and 90 to 100). We concluded that islet isolation success correlated with the previously proposed donor scoring system. CONCLUSIONS: The Donor Scoring System can be successfully implemented regardless of the level of activity of an experienced isolation center. This system permits identification of a suitable donor prior to organ processing. It may guide a center's donor selection strategy based on its goals and its budget.
Assuntos
Ilhotas Pancreáticas/citologia , Adulto , Cadáver , Separação Celular/métodos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Doadores de TecidosRESUMO
INTRODUCTION: Our center has recently observed foreign carbohydrate-appearing particles (FP) on transplant postreperfusion biopsy specimens: (PRBx). METHODS: To further characterize FPs, we reviewed all renal transplant RBx (30-45 minutes) performed between September 1, 2004 and December 3, 2005. Donor, preservation, and outcome variables were collected among patients with FP. RESULTS: A total of 135 PRBx were performed (45 deceased donors [DD] and 90 live donors [LD]). Fifteen PRBx demonstrated FP. All 15 cases were DD kidneys that underwent machine perfusion (MP) on the Waters RM3 (Waters Medical Systems, Rochester, Minn, United States) with Belzer MP solution (Trans Med, Elk River, Minn, United States). Donor age was 39.8 +/- 15.7 years. Terminal creatinine level was 1.45 +/- 0.8 mg/dL. Two of 15 were flushed in situ with HTK solution (no starch). Cold ischemia time was 28.8 +/- 9.1 hours with 14.3 +/- 5.1 hours of MP. In 13 of 15 patients, perfusion parameters were excellent (flow > 100 mL; resistance < .35). CHARACTERISTICS OF FP: Particles were 10-30 mu and globular in shape. FP were not visible on hematoxylin and eosin stain, but stained strongly periodic acid-Schiff-(PAS) positive and were refractile under polarized light. FP were seen segmentally within glomerular capillaries in all cases and in peritubular capillaries in 3. In 11 of the 15 cases with FP, focal glomerular fibrin thrombi or intracapillary neutrophil margination was seen. Ten of 15 patients with FP had a biopsy within the first week with no identifiable FP. OUTCOMES: Recipient age was 45.3 +/- 11.6 years. Eight patients (53.3%) had delayed graft function. Biopsy-proven rejection occurred in 3 patients (20%). Three-month creatinine level was 1.59 +/- 0.35 mg/dL. One graft was lost to early thrombosis in a patient with a hypercoagulable state and 1 patient died of sepsis at 2 months. All remaining 13 patients are alive with excellent graft function at a median follow-up of 6.7 months (range, 3-17 months). CONCLUSIONS: Microscopic intrarenal particles may be seen on DD kidney PRBx after MP. These FPs likely originate from surgical gloves. FPs are too small to be captured by standard filters but clear spontaneously and do not have deleterious effects on renal function or outcomes.
Assuntos
Transplante de Rim/patologia , Preservação de Órgãos/métodos , Adulto , Biópsia , Cadáver , Carboidratos/análise , Creatinina/sangue , Seguimentos , Corpos Estranhos/patologia , Humanos , Glomérulos Renais/citologia , Glomérulos Renais/ultraestrutura , Transplante de Rim/fisiologia , Doadores Vivos , Pessoa de Meia-Idade , Fatores de Tempo , Doadores de Tecidos , Resultado do TratamentoRESUMO
Culture of islets isolated from the pancreas of neonatal rats successfully preserved function for 6 days, as indicated by release of insulin into the culture medium and reversal of experimental diabetes bu cultured islet isografts. Release of insulin into the culture medium correlated with lowering of fasting blood glucose in the diabetic recipient. Intravenous glucose tolerance was normal in recipients of immediate and 24-h cultured islets but abnormal in recipients of 6-day cultured islets. Culture of the islets isolated from human pancreases (cadaveric) resulted in islet purification but at the expense of loss of islets, with only 1--5% surviving 1 wk of culture. During 8--10 days in culture, insulin release declined, and histological examination revealed only a few viable islets. Islets isolated from surgical specimens survived the culture conditions as demonstrated by viable cell clumps and insulin secretion. After an 85% pancreatectomy in the patient with chronic pancreatitis, islets were isolated, cultured for 7 days, and then autografted into muscle pockets and the subcutaneous space of the forearm. There was no evidence of function.
Assuntos
Transplante das Ilhotas Pancreáticas , Animais , Glicemia/metabolismo , Sobrevivência Celular , Células Cultivadas , Sobrevivência de Enxerto , Humanos , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Ratos , Ratos Endogâmicos Lew , Transplante IsogênicoRESUMO
Fasting blood glucose (FBG), serum immunoreactive insulin (IRI), plasma immunoreactive glucagon (IRG), body weight, and caloric intake were measured in long-term islet-isografted rats eight to 10 months following intraperitoneal islet transplantation in in age-matched, sham-operated, concurrently followed normal and diabetic controls. Islet recipients had normal body weights, but they were significantly polyphagic, hyperinsulinemic, and hyperglucagonemic when compared with normals. Fasting blood glucose levels were reduced by 10 per cent. Several factors may be related to the occurrence of these abnormalities in long-term islet-isografted rats, including (1) the mass of islets transplanted, (2) the age of donor tissue, (3) the heterotopic location of islet grafts, and (4) the lack of normal innervation of transplanted islet cells.
Assuntos
Diabetes Mellitus/sangue , Glucagon/sangue , Hiperinsulinismo/etiologia , Transplante das Ilhotas Pancreáticas , Fatores Etários , Animais , Regulação do Apetite , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus/induzido quimicamente , Jejum , Ilhotas Pancreáticas/inervação , Ratos , Ratos Endogâmicos Lew , Estreptozocina , Transplante IsogênicoRESUMO
Pancreatic islet transplantation remains a promising approach to the treatment of type 1 diabetes. Unfortunately, graft failure continues to occur because of immunologic rejection, despite the use of potent immunosuppressive agents. It is therefore reasoned that induction of peripheral tolerance by the use of self-dendritic cells (DCs) as a vehicle to deliver specific target antigens to self-T-cells without ex vivo manipulation of the recipient is an attractive strategy in the treatment of type 1 diabetes. The finding that intrathymic inoculation of an immunodominant WF major histocompatibility complex (MHC) Class I (RT1.A(u)) peptide five (P5) or P5-pulsed host myeloid DCs induces acquired thymic tolerance raises the possibility that adoptive transfer of allopeptide-primed host myeloid or lymphoid DCs might induce transplant tolerance. To address this hypothesis, we studied the effects of intravenous transfer of in vitro P5-pulsed syngeneic myeloid DCs or in vivo P5-primed syngeneic lymphoid (thymic) DCs on islet survival in the WF-to-ACI rat combination. In vivo primed thymic DCs isolated from ACI rats given intrathymic inoculation of P5 for 2 days were capable of in vitro restimulation of in vivo P5-primed T-cells (memory cells). In the first series of studies, we showed that intravenous-like intrathymic-inoculation of in vitro P5-pulsed host myeloid DCs induced donor-specific permanent acceptance of islets in recipients transiently immunosuppressed with antilymphocyte serum (ALS). We next examined whether thymic DCs isolated from animals that had been previously intrathymically inoculated with P5 could induce T-cell tolerance. The results showed that intravenous adoptive transfer of in vivo P5-primed thymic DCs led to donor-specific permanent acceptance of islets in recipients transiently immunosuppressed with ALS. This finding suggested that the thymic DCs take up and present P5 to developing T-cells to induce T-cell tolerance, thus providing evidence of a direct link between indirect allorecognition and acquired thymic tolerance. The second series of studies examined the mechanisms involved in this model by exploring whether in vivo generation of peptide-specific alloreactive peripheral T-cells by intravenous inoculation of P5-pulsed self-DCs was responsible for the induction of T-cell tolerance. Intrathymic inoculation of splenic T-cells obtained from syngeneic ACI rats primed with intravenous injection of P5-pulsed DCs with a high in vitro proliferative response to P5 in the context of self-MHC induced donor-specific permanent acceptance of islets from WF donors. In addition, the clinically relevant model of intravenous injection of P5-activated T-cells combined with transient ALS immunosuppression similarly induced transplant tolerance, which was then abrogated by thymectomy of the recipient before intravenous injection of the activated T-cells. These data raise the possibility that circulation of peptide-activated T-cells to the host thymus plays a role in the induction and possibly the maintenance of T-cell tolerance in this model. Our findings suggest that intravenous administration of genetically engineered host DCs expressing alloMHC peptides might have therapeutic potential in clinical islet transplantation for the treatment of autoimmune diabetes.
Assuntos
Transferência Adotiva , Células Dendríticas/imunologia , Tolerância Imunológica , Transplante das Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/imunologia , Linfócitos T/fisiologia , Timo/imunologia , Animais , Biomarcadores , Células da Medula Óssea/imunologia , Separação Celular , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Modelos Animais de Doenças , Citometria de Fluxo , Teste de Cultura Mista de Linfócitos , Ratos , TimectomiaRESUMO
AIMS: CD8+CD28- human T-suppressor cells (Ts), which can be generated in vitro, act directly on APC rendering them tolerogenic to unprimed and primed CD4+ T cells. The aim of this study was to investigate the possibility that CD8+ T cells mediate the induction of tolerance in a heart transplantation model in rodents. MATERIALS AND METHODS: Blood from Lewis rats was UV-B-irradiated and transfused into ACI recipients on days -21, -14, and -7 before heart allograft transplantation on day 0. CD4(+) and CD8(+) T cells were positively selected from ACI rats, which had tolerated Lewis heart allografts for more than 100 days and were adoptively transferred to naive ACI rats pretreated (day -1) with gamma irradiation. These ACI rats underwent transplantation with Lewis hearts 24 hours after adoptive transfer of putative T-suppressor cells. RESULTS: Adoptive transfer of CD8(+) T cells from tolerant ACI to naive ACI rats significantly prolonged Lewis heart mean allograft survival time (MST +/- SD) to 69 +/- 13 days as compared with 15 +/- 1 and 14 +/- 1 days in animals adoptively transferred with CD4+ T cells or untreated controls, respectively (P < .001). Similarly, adoptive transfer of CD8(+) T cells from secondary ACI recipients to naive syngeneic animals also significantly prolonged survival of heart allografts to MST +/- SD of 72 +/- 4 for CD8(+) and 15 +/- 4 days for CD4(+) T cells (P < .001). CONCLUSIONS: These data demonstrate that allogeneic tolerance induced in ACI recipients by treatment with UV-B-irradiated blood from Lewis donors is mediated by CD8+ T-suppressor cells.
Assuntos
Transfusão de Sangue , Sobrevivência de Enxerto/efeitos da radiação , Transplante de Coração/imunologia , Transfusão de Linfócitos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos da radiação , Tolerância ao Transplante/imunologia , Raios Ultravioleta , Transferência Adotiva , Animais , Ratos , Ratos Endogâmicos ACI , Ratos Endogâmicos Lew , Fatores de Tempo , Transplante Homólogo/imunologiaRESUMO
BACKGROUND: We sought to determine whether the two-layer method (TLM) offers advantages over UW storage solution for locally procured pancreata with cold ischemia time of <8 hours for successful islet isolation. METHODS: From October 2003 through February 2005, 22 human pancreata were procured locally from cadaveric donors and preserved using UW solution (n = 11) or TLM (n = 11). RESULTS: Donor characteristics were similar in the two groups, with no statistical difference. Cold ischemia time was 4.5 +/- 0.6 (2.5 to 8) hours in the UW and 5.1 +/- 0.5 (3 to 8) hours in TLM group (P > .05). Organs preserved with TLM were exposed to PFC for 4 +/- 0.5 (2 to 7.5) hours. After TLM preservation, 8 of 11 (72%) pancreata yielded >300,000 IEQ pancreatic islets, which met all criteria for clinical transplantation; after UW cold storage, only 3 of 11 isolations were equally successful (27%) (P < .05). Mean IEQ was higher in the TLM than in the UW group: 349,000 +/- 37,000 vs 277,800 +/- 34,000; IEQ/g was also higher at 5100 +/- 760 vs 3000 +/- 570, respectively (P < .05). Islet quality, characterized by purity, viability, and insulin SI, did not differ statistically in the two groups: 67 +/- 4 vs 74 +/- 4%, 87 +/- 2 vs 83 +/- 4%, and 4 +/- 0.7 vs 4.8 +/- 1, respectively (P > .05). CONCLUSIONS: The Two Layer Method for locally procured human pancreata with cold ischemia time lower than 8 hours offers significant advantage over UW cold storage increasing the pancreatic islet isolation yield and the isolation success rate.
Assuntos
Ilhotas Pancreáticas/citologia , Preservação de Órgãos/métodos , Pâncreas , Coleta de Tecidos e Órgãos/métodos , Adenosina , Adolescente , Adulto , Alopurinol , Glutationa , Humanos , Insulina , Pessoa de Meia-Idade , Soluções para Preservação de Órgãos , RafinoseRESUMO
AIM: The aim of this study was to evaluate the effectiveness of streptavidin immunomodulation in the high-responder WF-to-Lewis combination. METHODS/RESULTS: We examined the effects of streptavidin on the proliferative response of T cells in coculture studies. Two to 200 microg/mL streptavidin significantly (P < .001) suppressed the proliferation of Lewis T cells to WF by 76%-83% compared with untreated responders. Next, we studied the survival of WF cardiac allografts in Lewis recipients pretreated with streptavidin. A 5-day course of peritransplantation recipient treatment with streptavidin doses of 8, 12, 20, 40, and 60 mg/kg combined with single dose of 0.5 mL antilymphocyte serum (ALS) significantly (P < .001) prolonged cardiac allograft survival from MST of 7 +/- 0.5 and 8 +/- 0.5 days in naive and ALS-treated controls to 15 +/- 1, 20 +/- 3, 16 +/- 3, 17 +/- 3, and 23 +/- 2 days, respectively. In contrast, posttransplantation administration of 80 mg/kg streptavidin resulted in animal death, suggesting toxicity of this dose. Additionally, 10 mg/kg or 20 mg/kg streptavidin administration for 10 consecutive days resulted in significant graft prolongation (MST of 18 +/- 1 and 21 +/- 1 days, respectively; P < .001). CONCLUSION: Although peritransplantation streptavidin treatment is effective in prolonging rat cardiac allografts in the high-responder WF-to-Lewis combination, it does not induce permanent graft survival as observed in the low-responder combination of Lewis-to-ACI. Our finding of in vitro immunomodulatory effect of streptavidin on T-cell proliferation suggests that its in vivo effect is partly due to prevention of T-cell activation following antigen exposure.
Assuntos
Sobrevivência de Enxerto/imunologia , Transplante de Coração/imunologia , Estreptavidina/uso terapêutico , Linfócitos T/imunologia , Animais , Soro Antilinfocitário/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Transfusão de Linfócitos , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos WF , Baço/imunologia , Baço/efeitos da radiação , Linfócitos T/efeitos dos fármacos , Transplante Homólogo/imunologiaRESUMO
A patient with classic clinical and biochemical features of tumor-induced osteomalacia (hypophosphatemia, phosphaturia, and undetectable serum concentrations of 1,25-dihydroxyvitamin D [1,25(OH)2D]) was studied before and after resection of a benign extraskeletal chondroma from the plantar surface of the foot. Presurgical laboratory evaluation was notable for normal serum concentrations of calcium, intact parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), and osteocalcin, increased serum alkaline phosphate activity, and frankly elevated urinary cyclic adenosine monophosphate (cAMP) and pyridinium cross-link excretion. Quantitative histomorphometry showed severe osteomalacia and deep erosions of the cancellous surface by active osteoclasts. After resection, serum 1,25(OH)2D normalized within 24 h, while renal tubular phosphorus reabsorption and serum phosphorus did not normalized until days 2 and 3, respectively; serum Ca declined slightly, and serum intact PTH, osteocalcin, and urinary pyridinium cross-link excretion increased dramatically. Urinary cAMP excretion declined immediately after resection and then began to increase concomitant with the increase in serum intact PTH. A second bone biopsy taken 3 months after resection demonstrated complete resolution of the osteomalacia, increased mineral apposition rate (1.09 mu/day), resorption surface (9.2%), mineralizing surface (71%), and bone formation rate (0.83 mm3/mm2/day), and marked decrease in cancellous bone volume (13.1%) and trabecular connectivity compared with first biopsy. Tumor extracts did not affect phosphate transport in renal epithelial cell lines or 1 alpha-hydroxylase activity in a myelomonocytic cell line. The patient's course suggests that the normal 1,25(OH)2D and phosphorus metabolism is due to a tumor product that may be acting via stimulation of adenylate activity. Increased bone resorption prior to surgical resection suggests that the tumor may also produce an osteoclast activator. The rise in resorption surface and pyridinium cross-link excretion, increase in serum osteocalcin and bone mineralization, normalization of osteoid width, and fall in cancellous bone volume after resection are consistent with healing of osteomalacia by rapid remodeling.
Assuntos
Condroma/complicações , Doenças do Pé/complicações , Osteomalacia/etiologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Adulto , Densidade Óssea , Remodelação Óssea , Calcitriol/sangue , Condroma/enzimologia , Doenças do Pé/enzimologia , Humanos , Hipofosfatemia/etiologia , Masculino , Osteomalacia/enzimologiaRESUMO
OBJECTIVE: To assess the efficacy of lamotrigine, a novel antiepileptic drug that inhibits glutamate release, to retard disease progression in Huntington disease (HD). BACKGROUND: Excitatory amino acids may cause selective neuronal death in HD, and lamotrigine may inhibit glutamate release in vivo. METHODS: A double-blinded, placebo-controlled study was conducted of 64 patients with motor signs of less than 5 years' duration who were randomly assigned to either placebo or lamotrigine and assessed at 0 (baseline), 12, 24, and 30 months. The primary response variable was total functional capacity (TFC) score. Secondary response variables included the quantified neurological examination and a set of cognitive and motor tests. Repeated fluorodeoxyglucose measurements of regional cerebral metabolism using PET also were included. RESULTS: Fifty-five patients (28 on lamotrigine, 27 on placebo) completed the study. Neither the primary response variable nor any of the secondary response variables differed significantly between the treatment groups. Both the lamotrigine and the placebo group deteriorated significantly on the TFC, in the lamotrigine group by 1.89 and the placebo group by 2.11 points. No effect of CAG size on the rate of deterioration could be detected. CONCLUSIONS: There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.