ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Recent studies have demonstrated that treatment with &agr;&bgr;–T-cell receptor (TCR) monoclonal antibody and cyclosporine A (CsA) can extend survival in composite tissue allografts (CTA). The purpose of this study was to induce tolerance in fully major histocompatibility complex (MHC)-mismatched rat limb allografts under 7 days of a combined &agr;&bgr;-TCR–CsA protocol.Methods.The authors performed 30 hind-limb allotransplantations across the MHC barrier between Brown Norway donors (BN; RT1n) and Lewis recipients (LEW; RT1l). Isograft and allograft controls received no treatment. The experimental groups received monotherapy of &agr;&bgr;-TCR and CsA or a combination of &agr;&bgr;-TCR and CsA for 7 days only. Donor-specific tolerance and immunocompetence were determined by standard skin grafting in vivo and mixed lymphocyte reaction (MLR) in vitro. The efficacy of immunosuppressive therapy and the level of donor-specific chimerism were determined by flow cytometry.Results.Long-term survival (>350 days) was achieved in allograft recipients (n=6) under the 7-day protocol of combined &agr;&bgr;-TCR–CsA. Donor-specific tolerance and immunocompetence of long-term chimeras were confirmed by acceptance of skin grafts from the donors and rejection of the third-party alloantigens (A×C Irish). At day 120, MLR demonstrated unresponsiveness to the host and donor antigens but strong reactivity against third-party alloantigens. Flow cytometry confirmed the high efficacy of immunosuppressive treatment and the development of donor-specific chimerism (7.6% of CD4+-RT1n+cells, 1.3% of CD8+-RT1n+cells, and 16.5% of CD45RA+-RT1n+cells) in the periphery of tolerated recipients.Conclusions.Combined therapy of &agr;&bgr;-TCR–CsA for 7 days resulted in tolerance induction in fully MHC-mismatched rat hind-limb allografts. Tolerance was directly associated with stable, donor-specific chimerism.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The rate of success in clinical transplantation of islets of Langerhans has dramatically improved with perspectives of wide-scale applicability for patients with type 1 diabetes. One drawback is the need for lifelong immunosuppression, which is associated with significant side effects. Immunomodulatory strategies devoid of side effects and with tolerogenic potential, such as co-stimulatory blockade, would be a great improvement if successful. In this study, the authors have explored the effect of simultaneous blockade of CD40/CD154 and intercellular adhesion molecule (ICAM)/lymphocyte function-associated antigen (LFA)-1 interactions.Methods.Spontaneously diabetic nonobese diabetic (NOD) mice underwent transplantation with allogeneic (C57BL/6) islets and were treated with anti-CD154 monoclonal antibody (mAb) (500 &mgr;g, three doses), anti–LFA-1 mAb (100 &mgr;g, three doses), or a combination of both in the early peritransplant period. In another set of experiments, LFA-1 engagement was impaired by transplanting islets isolated from ICAM-1–knockout (KO) mice.Results.Untreated animals rejected their grafts within 10 days. LFA-1 blockade alone did not result in improved islet graft survival, whereas CD154 blockade alone increased graft survival to 18 days. Simultaneous blockade of both pathways led to significantly improved islet graft survival to 30 days (ICAM-1–KO islets plus anti-CD154), 35 days (anti–LFA-1 plus anti-CD154), and 44 days (ICAM-1–KO islets plus anti–LFA-1 plus anti-CD154).Conclusions.These data suggest that a synergistic effect for prolonged graft survival can be obtained by simultaneously targeting CD154 and LFA-1 in the challenging model of islet allotransplantation in NOD mice. The observation of similar results with anti–LFA-1 mAb and with ICAM-1–KO grafts suggests a key role of direct antigen presentation for the activation of LFA-1–driven signaling.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.In the pig-to-baboon model, acute vascular rejection remains the main hurdle for successful long-term xenograft survival. The production of galactosyl knockout pigs could solve concomitantly the problem of hyperacute and acute vascular rejection. This work studies in vitro the cell-mediated cytotoxicity of natural killer (NK) and T cells after priming of baboon peripheral blood lymphocytes (PBLs) with pig antigens to evaluate whether cytotoxicity is galactosyl-dependent.Material and Methods.PBLs from naive and primed baboons were used as effectors on primary porcine aortic endothelial cells (PAECs) to assess cytotoxicity. Untreated or galactosidase-digested PAECs were used to evidence the role of galactosyl residues on cell-mediated cytotoxicity. Two rat-anti baboon monoclonal antibodies were tested to inhibit either T+NK cells (LO-CD2b) or NK cells alone (LO-CD94).Results.When using PBLs from naive animals, spontaneous lysis occurred and was inhibited by both LOCD-2b and LO-CD94. In comparison, lysis of PAECs was significantly higher when baboon PBLs were first primed in vivo with pig xenoantigens. In this case, cytotoxicity was completely inhibited by LO-CD2b but only partially by LO-CD94. Reduction of galactosyl residues by galactosidase digestion showed that PAEC lysis almost completely disappeared with naive baboon PBLs but not with primed baboon PBLs, thereby indicating that anti-pig T-cell response is not dependent on galactosyl residues.Conclusion.Galactosyl knockout pigs could solve hyperacute rejection and also prevent the activation of NK cells even after xenogeneic priming. T cells will then be the next hurdle for the success of xenografting.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Up to 30% of all livers retrieved for organ transplantation exhibit steatotic transformations. Chronic organ-donor shortage has led to the acceptance of these organs for transplantation, although a higher risk of graft nonfunction is associated with the preservation of steatotic livers.Methods.A dietary steatosis was induced in Wistar rats by fasting them for 2 days and feeding them with a fat-free diet. Fatty livers (n=14) were retrieved and flushed with 60 mL of histidine, tryptophane, alpha-ketoglutarate (HTK) solution. In half of the experiments, L-carnitine (5 mM) was added to the HTK. Functional integrity of the livers was evaluated by isolated reperfusion with KHB in a recirculating system at 37°C for 45 minutes.Results.Addition of L-carnitine to the HTK promoted a significant reduction of the enzyme leakage from the livers upon reperfusion. Release of alanine-aminotransferase was reduced to one third (127±22 vs. 423±61 U/L), and the loss of glutamate dehydrogenase in the perfusate could be reduced significantly (42±7 vs. 542±134 U/L) when compared with livers stored without additional medication. Morphologic corroboration of these data was obtained by electron microscopy. Although normal appearance of liver mitochondria was preserved at the end of the cold ischemic storage, reperfusion of cold-stored fatty livers entailed massive alterations and frequent destruction of hepatic mitochondria. However, these morphologic impairments were remarkably mitigated in the carnitine-treated group.Conclusions.L-carnitine represents a feasible metabolic adjunct for a safe and more successful preservation of ischemia–reperfusion-sensitive steatotic livers.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Registry data can provide valuable information about possible treatment effects; however, pretreatment differences in patient characteristics may influence treatment assignment. Careful analysis must therefore be undertaken when evaluating treatment differences in the context of nonrandomized studies so that the impact of treatment selection bias is minimized.Methods.A multivariable risk factor analysis of adult patients registered in the US Renal Data System who received a primary renal allograft during 1995 to 1998 was undertaken to compare 3-year graft survival using tacrolimus or Neoral with mycophenolate mofetil (MMF) and steroids.Results.In total, 9,449 patients were included (cadaveric donor n=6,011; living donor n=3,438). Patients (2,130) received tacrolimus, and 7,319 received Neoral. At 3 years posttransplant, the proportion of cadaveric donor recipients experiencing all causes of graft loss was 10.0% for tacrolimus and 10.6% for Neoral; for living donor recipients these figures were 6.5% and 6.7%, respectively (unadjusted Kaplan-Meier analysis). The incidence of graft failure excluding death was also similar between the two groups. With Cox proportional hazards modeling, the adjusted relative hazard of 3-year graft failure for cadaveric donor patients taking tacrolimus versus Neoral was 1.02 (95% confidence interval [CI] 0.8–1.3), and for living-donor recipients it was 1.15 (95% CI 0.8–1.8).Conclusions.These results indicate excellent 3-year graft survival for both cadaveric and living-donor renal-transplant patients receiving either Neoral or tacrolimus with MMF and steroids, with no significant differences between treatment groups. On the basis of these results, relative cost-effectiveness may become increasingly important in selection of tacrolimus or Neoral as primary immunosuppressant for renal-transplant patients.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Although prothrombotic disorders (PTD) are known to increase the risk of graft failure in kidney transplantation only, there are no data on PTD in simultaneous pancreas and kidney transplantation (SPK).Methods.Forty-seven SPK performed between September 2000 and July 2002 underwent routine screening for PTD. Data were retrospectively analyzed in view of complications (relaparotomy, graft thrombosis, pancreatitis, rejection) and graft function (HbA1c, serum creatinine) 3 months posttransplantation.Results.Twenty-five of forty-seven (53.2%) patients had 30 PTDs. Homozygous mutations of the MTHFR gene (C677T) were found in six, factor-V Leiden mutation (homo- or heterozygous G1691A) in seven, and prothrombin mutation (20210A) in one patient (group 1). Group 2 consists of deficiencies of protein C (n=1), of protein S (n=12), of antithrombin (n=1), and antiphospholipid syndromes (n=2). Overall, PTD had no influence on graft thrombosis (P=0.36) or rejection (P=0.56). In patients with homozygous mutations, relaparotomies were more often necessary than in patients without mutations (42.9% vs. 11.8%,P=0.046). In group 1, there was a trend toward a higher incidence of graft pancreatitis than in patients without mutations (38.5% vs. 14.7%,P=0.075). Three months posttransplantation, HbA1c was 6.0% in patients with and 5.5% in patients without PTD (P=0.023). With regard to serum creatinine, no significant differences were observed.Conclusion.PTD are frequent in type-1 diabetics receiving SPK and may have a role in relaparotomies, graft pancreatitis, and pancreas graft function.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.We describe the Emilia-Romagna screening protocol for all multiorgan donors within this region of Italy and report on the first 2 years of implementation.Setting.Setting is a 24-hour multidisciplinary call service covering the 16 intensive care units in Emilia-Romagna (3,969,000 inhabitants) and a centralised pathology center, directed by a transplant coordination center.Study Population and Period.All 271 effective donor candidates presenting in Emilia-Romagna in 2001–2002.Protocol.Anamnesis, external examination, and thorough laboratory and instrumental screening is followed by sampling of internal effusions and evaluation of all internal organs. All suspect findings are then investigated by extemporary pathologic evaluation. To fit national legal requirements, candidates are classified as standard risk (no transmissible risk); nonstandard risk (low-risk of transmission, eligibility restricted to certified clinical emergencies pending informed consent); and unacceptable risk (unconditional exclusion because of high-risk pathologies).Results.The protocol was successfully implemented for all 271 candidates. In addition to 14 independent exclusions, clinical suspicion of cancer was raised for 61 donors presenting with 82 lesions or effusions. Along with one case of lymph-node tuberculosis (unacceptable risk), histocytologic screening revealed eight cases of malignancy (5 prostate, 1 papillary-thyroid, 1 follicular-thyroid, and 1 renal cell, all nonstandard risk); the remainder were benign (standard risk). Protocol implementation led to exclusion of 8 (3.0%) candidates (1 nonstandard risk transplantation was performed).Conclusions.This stringent protocol—now adopted with some modifications at a national level—provides an initial example of a feasible intervention aimed at maximising donation safety while rationalizing use of marginal donors.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The yearly increasing survival rates testify to the success of transplantation, but questions remain relating to the quality of life (QOL) associated with long-term survival.Methods.A sample of 126 liver recipients (Liver-R), 229 kidney recipients (Kidney-R), and 113 heart recipients (Heart-R) with more than 10 years posttransplant follow-up were included in the study with a response rate of 86%. Respondents were matched with healthy subjects recruited from general population (GP). The three groups of recipients and GP subjects completed a French version of the questionnaire used by the National Institute of Diabetes and Digestive and Kidney Disease, Pittsburgh, PA, and were compared for each score, with adjustments for age and sex.Results.Personal function and measures of disease by the transplant recipients were significantly worse than in the GP (P<0.0001), with the worst score in Kidney-R. No difference, either between organs or between organs and GP, was found regarding the perceived social and role function. However, for psychologic status and general health perception, Kidney-R had the least favorable performance when compared with GP (P<0.01) and also when compared with Liver-R (P<0.05). With the exception of Kidney-R, the well-being index of Liver-R and Heart-R was significantly better than the GP (P<0.001 andP<0.05, respectively).Conclusions.The QOL beyond 10 years after liver, heart, and kidney transplantation is quite similar to the GP, with Kidney-R starting out as the worst, Heart-R as intermediate, and Liver-R the best.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.We have previously shown that CD8 depletion or CD34 selection of peripheral blood stem cells (PBSC) reduced the incidence of acute graft-versus-host disease (GvHD) after nonmyeloablative stem-cell transplantation (NMSCT). In this study, we analyze the effect of CD8 depletion or CD34 selection of the graft on early T-cell reconstitution.Methods.Nonmyeloablative conditioning regimen consisted in 2 Gy total-body irradiation (TBI) alone, 2 Gy TBI and fludarabine, or cyclophosphamide and fludarabine. Patients 1 to 18 received unmanipulated PBSC, patients 19 to 29 CD8-depleted PBSC, and patients 30 to 35 CD34-selected PBSC.Results.T-cell counts, and particularly CD4+and CD4CD45RA+counts, remained low the first 6 months after nonmyeloablative stem-cell transplantation (NMSCT) in all patients. CD34 selection (P<0.0001) but not CD8 depletion of PBSC significantly decreased T-cell chimerism. Donor T-cell count was similar in unmanipulated compared with CD8-depleted PBSC recipients but was significantly lower in CD34-selected PBSC recipients (P=0.0012). T cells of recipient origin remained stable over time in unmanipulated and CD8-depleted PBSC patients but expanded in some CD34-selected PBSC recipients between day 28 and 100 after transplant. Moreover, whereas CD8 depletion only decreased CD8+counts (P<0.047), CD34 selection reduced CD3+(P<0.001), CD8+(P<0.016), CD4+(P<0.001), and CD4+CD45RA+(P<0.001) cell counts. T-cell repertoire was restricted in all patients on day 100 after hematopoietic stem-cell transplantation but was even more limited after CD34 selection (P=0.002).Conclusions.Despite of the persistence of a significant number of T cells of recipient origin, T-cell counts were low the first 6 months after NMSCT. Moreover, contrary with CD8 depletion of the graft that only affects CD8+lymphocyte counts, CD34 selection dramatically decreased both CD8 and CD4 counts.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID