无皮质激素的免疫抑制方案对肝移植后近期急性排斥反应发生率的影响

目的 探讨无皮质激素的免疫抑制方案对原位肝移植术后近期急性排斥反应发生率的影响.方法 采用随机数字表法将186例肝移植受者分为两组.无皮质激素组(研究组)术后均采用他克莫司(Tac)[或环孢素A(CsA)]+吗替麦考酚酯(MMF)的免疫抑制方案,未使用皮质激素;有皮质激素组(对照组)术后均采用Tac(或CsA)+MMF+皮质激素的三联免疫抑制方案.观察术后6个月内两组间急性排斥反应发生率的差异.急性排斥反应的诊断参照Banff标准.结果 两组受者间性别、年龄、原发病、Child-Pugh评分、终末期肝病模型(MELD)评分、手术时间、术中出血量、输注红细胞悬液及供肝热、冷缺血时间等基本资料的比较,差异均无统计学意义(P＞0.05).观察期内,研究组和对照组接受移植肝穿刺活检各9例次,诊断为急性排斥反应者分别为5和4例,发生率分别为5.3％ (5/94)和4.4％(4/92),两组间比较,差异有统计学意义(P＜0.05).结论 肝移植术后采用无皮质激素的免疫抑制方案不会增加近期(半年内)急性排斥反应的发生率.     

Activated circulating dendritic cells after hematopoietic stem cell transplantation predict acute graft-versus-host disease

BACKGROUND: Dendritic cells (DC) are central to the development of acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (alloHSCT). We hypothesized that DC activation status determines the severity of GVHD and that activated DC may be detected in the circulation prior to clinical presentation of GVHD. METHODS: Following transplant, blood samples were obtained twice weekly from alloHSCT patients. Myeloid (CD11c+) and plasmacytoid (CD123hi) DC were enumerated by flow cytometry, and activated myeloid DC were identified using the CMRF-44 monoclonal antibody. RESULTS: Of 40 alloHSCT patients, 26 developed acute GVHD. Severity of GVHD was associated with low total blood DC counts (P=0.007) and with low myeloid and plasmacytoid DC numbers (P=0.015 and 0.003). The CMRF-44 antigen was expressed on blood CD11c+ DC in all cases prior to GVHD onset, whereas of the 14 patients without GVHD, seven had no CMRF-44+ CD11c DC. Patients with CMRF-44+ CD11c+ DC in more than 20% of samples were more likely to subsequently develop acute GVHD (P=0.001, odds ratio=37.1), while patients who developed grade 2-4 GVHD had prior higher percentages of CMRF-44+ CD11c+ DC compared to grade 0-1 GVHD patients (P=0.001). CMRF-44 expression on >7.9% CD11c+ DC predicted for subsequent development of GVHD with a sensitivity of 87.5% and specificity of 79.2%. CONCLUSIONS: Activation status, as assessed by CMRF-44 antigen expression, of blood CD11c+ DC is highly associated with acute GVHD and these cells may be targets for therapeutic intervention.     

Low circulating regulatory T-cell levels after acute rejection in liver transplantation.

Immune regulatory CD4+CD25+ T cells play a crucial role in inducing and maintaining allograft tolerance in experimental models of transplantation (Tx). In humans, the effect of Tx and immunosuppression on the function and homeostasis of CD4+CD25+ regulatory T cells (Tregs) is not well characterized. In this study, the frequency of Tregs in liver transplant recipients was determined based on flow cytometric analysis of CD4, CD25, CD45RO, and cytotoxic T lymphocyte antigen (CTLA)-4 markers, and the suppressor activity of Tregs was assessed in a mixed-leukocyte reaction. A link between Tregs, acute rejection, and immune-suppressive treatment was investigated. Liver transplant recipients had significantly higher Treg levels in peripheral blood pre-Tx than healthy controls. After Tx, a significant drop in the Treg fraction was observed. This reduction of circulating Tregs was transient and was associated with immunosuppression. In recipients who did not develop rejection, a relative recovery of Treg levels was seen within the first year after Tx. Recipients who experienced an episode of steroid-treated acute rejection, however, had sustained low Treg levels. The suppressive activities of CD4+CD25+ Tregs from rejectors, nonrejectors, and healthy controls on proliferation and interferon (IFN)-gamma production were indistinguishable. In conclusion, the percentage of CD4+CD25+CD45RO+CTLA-4+ quadruple-positive Tregs in peripheral blood decreases significantly after liver Tx. Treatment with methylprednisolone during Tx and for acute rejection is associated with low circulating Tregs. Despite these quantitative differences between rejectors and nonrejectors, the suppressive quality of CD4+CD25+ Tregs is identical in both groups.     

Surveillance of alloantibodies after transplantation identifies the risk of chronic rejection

The monitoring of the levels of alloantibodies following transplantation might facilitate early diagnosis of chronic rejection (CR), the leading cause of renal allograft failure. Here, we used serial alloantibody surveillance to monitor patients with preoperative positive flow cytometric crossmatch (FCXM). Sixty-nine of 308 renal transplant patients in our center had preoperative positive FCXM. Blood was collected quarterly during the first postoperative year and tested by FCXM and single antigen bead luminometry, more sensitive techniques than complement-dependent cytotoxic crossmatching. Distinct post-transplant profiles emerged and were associated with different clinical outcomes. Two-thirds of patients showed complete elimination of FCXM and solid-phase assay reactions within 1 year, had few adverse events, and a 95% 3-year graft survival. In contrast, the remaining third failed to eliminate flow FCXM or solid-phase reactions directed against HLA class I or II antibodies. The inferior graft survival (67%) with loss in this latter group was primarily due to CR. Thus, systematic assessment of longitudinal changes in alloantibody levels, either by FCXM or solid-phase assay, can help identify patients at greater risk of developing CR.     

Outcomes of acute rejection after interferon therapy in liver transplant recipients.

Interferon alfa has been increasingly used against recurrent hepatitis C (HCV) disease in post-liver transplant (LT) recipients. A serious potential adverse effect is acute rejection. We reviewed our experience using interferon-based therapy (interferon or pegylated interferon with or without ribavirin) for treating recurrent HCV in LT recipients. Forty-four LT recipients were treated with interferon for recurrent HCV. Five of the 44 patients developed acute rejection during interferon-based therapy. These 5 patients started treatment of 42.4 +/- 33.89 months (mean +/- SD) after LT. Mean (+/- SD) histological activity index and fibrosis scores before initiating antiviral therapy were 8.8 (+/- 1.92) and 2.6 (+/- 0.55), respectively. Patients were treated for 3.3 +/- 2.28 months (mean +/- SD) prior to rejection. At the time of rejection, HCV load was not detectable in 4 of the 5 recipients. All 5 patients had tolerated interferon therapy, and none had stopped therapy because of adverse effects. The rejection was successfully treated in 3 patients. In 2 of those 3 patients, cirrhosis eventually developed. In the 2 patients who did not respond to rejection treatment, immediate graft failure occurred, leading to re-LT in 1 patient and death from sepsis in the other. In conclusion, the results indicate that further studies are needed to assess the safety of interferon in LT recipients. Interferon-based therapy may lead to acute rejection and subsequent graft loss and should therefore be used with caution. Treated recipients may also develop progressive cirrhosis despite achieving a sustained virological response.     

Sequential big endothelin plasma levels in heart transplant recipients during bridging therapy and after successful heart transplantation.

BACKGROUND: The purpose of this study was to investigate the impact of successful heart transplantation in patients with refractory heart failure receiving bridging therapy on sequential plasma levels of big endothelin, norepinephrine, atrial natriuretic peptide and aldosterone. METHODS: Fourteen patients (2 women, 12 men) accepted for heart transplantation were studied. All had severe chronic heart failure refractory to optimized oral therapy with angiotensin-converting enzyme inhibitors and furosemide, were in New York Heart Association functional Class IV, and had a left ventricular ejection fraction of <15%, Right heart catheterization was performed in all patients (cardiac index 1.9 +/- 0.1 liters/min. m(2), pulmonary capillary wedge pressure 30 +/- 2 mmHg, systemic vascular resistance index 2,827 +/- 253 dyn. s/cm(5). m(2)). As bridging therapy, patients received either prostaglandin E(1), prostaglandin E(1) and dobutamine or dobutamine alone as a continuous infusion. Neurohumoral variables were measured prior to bridging therapy and 3.5 months before and 7 and 10 months after successful heart transplantation. RESULTS: Big endothelin, norepinephrine and atrial natriuretic peptide plasma levels decreased from 7.4 +/- 2.9 fmol/ml, 1112 +/- 686 pg/ml and 366 +/- 312 pg/ml to 6.0 +/- 4.5 fmol/ml, 720 +/- 503 pg/ml and 198 +/- 160 pg/ml, respectively, after bridging therapy, and further to 2.1 +/- 0.9 fmol/ml (p < 0.00001 vs baseline), 527 +/- 31 pg/ml (p < 0.02 vs baseline) and 115 +/- 70 pg/ml (p < 0.03 vs baseline), respectively, after cardiac transplantation. Aldosterone plasma levels decreased from 242 +/- 220 pg/ml to 183 +/- 142 pg/ml during bridging therapy and increased after heart transplantation to 252 +/- 189 pg/ml. Plasma creatinine levels increased from 1.2 +/- 0.4 mg/dl at baseline to 1.4 +/- 0.2 mg/dl after transplantation (NS). CONCLUSIONS: The study suggests that excessive overproduction of big endothelin, atrial natriuretic peptide and norepinephrine is predominantly related to pump failure and, after cardiac transplantation, a moderate spillover of big endothelin persists. Its specific origin, however, remains to be elucidated. Furthermore, our data suggest a protective effect of prostaglandin E(1) on kidney function after heart transplantation.     

Cyclophosphamide rescue therapy for chronic rejection after lung transplantation.

BACKGROUND: Obliterative bronchiolitis remains the leading cause of late mortality after heart-lung and lung transplantation. Although several treatment options have been advocated, none has proven to be very successful. Cyclophosphamide is effective in the treatment of idiopathic pulmonary fibrosis, and chronic rejection after lung transplantation is also a fibroproliferative process. We therefore conducted an open, uncontrolled study to look at the effect of cyclophosphamide rescue therapy in the treatment of chronic rejection in lung transplant recipients. METHODS: Between October 1996 and March 1998 cyclophosphamide was prescribed to 7 patients with chronic and persistent rejection who failed to respond to conventional therapy (pulse steroids or antilymphocyte products or both). RESULTS: Cyclophosphamide therapy was initiated on postoperative day 478+/-366. At that time 2 patients were in bronchiolitis obliterans syndrome stage 0, 3 patients in stage 1, and 2 patients in stage 2. Their best postoperative forced expiratory volume in one second (FEV1) was 2.19+/-0.75 L. Three months before the start of cyclophosphamide the FEV1 had declined to 1.90+/-0.83 L, with a further decline to 1.63+/-0.64 L at the time of initiating cyclophosphamide. In 6 of the 7 patients the FEV1 stabilized or increased after cyclophosphamide had been started (mean FEV1 3 and 6 months after cyclophosphamide of 1.77+/-0.58 L and 1.79+/-0.48 L, respectively). One patient died 18 months after the introduction of cyclophosphamide due to progressive obliterative bronchiolitis. In one patient cyclophosphamide had to be stopped because of persistent leucopenia. CONCLUSIONS: Cyclophosphamide might be a promising therapeutic alternative for the treatment of chronic persistent rejection after lung transplantation.     

Hepatic transplantation into sensitized recipients. Demonstration of hyperacute rejection

Hepatic transplantation into humorally presensitized patients has occasionally been performed without reported accelerated rejection. To study survival of orthotopic hepatic transplants in sensitized recipients a series of studies in rats were performed. Lewis rats sensitized by three successive skin grafts from fully allogeneic ACI strain donors then underwent orthotopic hepatic transplantation from ACI donors. Nine of ten recipients died within 4 hr with bleeding from the liver surface. By comparison, nine unsensitized recipients survived a mean of 10.7 +/- 0.5 days before succumbing with cellular rejection. Death of the sensitized recipients was not due to coagulopathy or technical failure. Histological studies of hyperacutely rejected livers demonstrated marked hemorrhage, edema, congestion, and necrosis within the hepatic parenchyma. There was a relative lack of cellular infiltrate compared with livers rejected by unsensitized recipients. Immunofluorescent staining showed IgG bound to perivascular tissues and sinusoids, and complement bound to perivascular tissue. Serum from presensitized, but not control, recipients showed a high titer of donor-specific, complement-dependent cytotoxic activity. It is concluded that hyperacute rejection of hepatic transplants can occur in sensitized rats and is mediated by a humoral mechanism. The immunohistopathology of this process is described.     

Role of routine endomyocardial biopsy to monitor late rejection after heart transplantation.

Endomycardial biopsy remains the standard used to monitor rejection after heart transplantation. There is, however, no consensus as to how often surveillance endomyocardial biopsy should be carried out after heart transplantation. We have analyzed 131 patients undergoing orthotopic heart transplantation during the first 4 years of the transplant program at St. Vincent's Hospital. The majority of endomyocardial biopsies that showed acute rejection occurred in the first 3 months after transplantation; after 9 months only 2.5% of endomyocardial biopsies performed showed rejection. Of those patients with rejection, 47% had symptoms. Seven patients experienced late rejection and all made a good recovery with normal cardiac function. We conclude that the incidence of acute rejection decreases significantly more than 3 months after-transplantation; after 9 months only 2.5% of endomyocardial biopsies will show rejection. Of these, 47% will be associated with symptoms. On the basis of experience, we believe that in our own unit, endomyocardial biopsy more than 9 months after transplantation seems unwarranted unless clinically indicated.     

Plasmapheresis and cyclophosphamide in the treatment of humoral rejection after heart transplantation.

BACKGROUND: Clinical reports on humoral rejection after heart transplantation showed that these episodes were often more severe than those mediated through T lymphocytes and that the patient's prognosis was significantly worsened. METHODS: To evaluate the impact of plasmapheresis on the course of humoral rejection with hemodynamic compromise (HRHC) episodes, we retrospectively investigated the records of 1,108 heart transplant patients. All patients received triple-drug immunosuppression (cyclosporine a, azathioprine, prednisone) and cytolytic antibodies for induction. Between April 1986 and December 1990, HRHC episodes were treated with cortisone boli and cytolytic antibodies for at least 3 days (Group A). Between January 1991 and April 1999, HRHC episodes were treated with cortisone boli, cytolytic antibodies, and plasmapheresis for at least 3 days (Group B). All patients who survived their first HRHC episode received cyclophosphamide instead of azathioprine as maintenance immunosuppression. RESULTS: Altogether we observed 29 HRHC episodes. In 11 cases, no therapy could be administered or the therapy regimen did not correspond to either Protocol A or B. In the remaining 18 HRHC episodes, 7 episodes in 7 patients were treated without plasmapheresis (Group A), but only 2 patients survived, whereas in 11 HRHC episodes in 6 patients, therapy included plasmapheresis (Group B) and all patients survived (p = 0.002). Four of 6 patients who received cyclophosphamide after their first HRHC episode experienced at least 1 further HRHC episode. CONCLUSIONS: Plasmapheresis seems to improve outcomes in HRHC. However, cyclophosphamide as a maintenance immunosuppressive drug failed to prevent further humoral rejection episodes.     

Reevaluation of steroid tapering after steroid pulse therapy for heart rejection.

A retrospective analysis was conducted to determine the efficacy and complications resulting from steroid pulse therapy, with or without a steroid taper, in 93 episodes of heart transplant rejection that occurred in 72 patients (58 men, 14 women; mean age, 47.6 years). Each rejection episode was classified according to severity (Texas Heart Institute endomyocardial biopsy scale) and the treatment. Group 1 included 25 episodes of grade 7, 8, 9, or 10 rejection (International Society for Heart Transplantation [ISHT] grade IIIB or IV) that were treated with high-dose methylprednisolone (2.5 to 3.0 gm) and a steroid taper of 1.75 gm over 30 days. Group 2 included 16 episodes of rejection, with the severity of rejection and methylprednisolone pulse therapy being similar to that in group 1, but without a steroid taper. The results of treatment in group 1 were compared with those in group 2. Group 3 included 12 episodes of grade 5, 6, or 7 rejection (ISHT grade IIIA or IIIB) that were treated with moderate-dose methylprednisolone (1.0 to 2.0 gm) and a steroid taper, as described. Group 4 included 40 episodes of rejection, with the severity of rejection and methylprednisolone therapy being similar to that of group 3, but without a steroid taper. The results of treatment in group 3 were compared with those in group 4. No statistically significant differences were found among the groups regarding subsequent episodes of rejection or infection within 3 months of treatment. No statistically significant difference was noted among the groups in the number of rejection episodes requiring additional therapy to control the rejection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of plasmapheresis for acute humoral rejection after heart transplantation

OBJECTIVE: The objective of this study was to report our experience of treating acute humoral rejection with plasmapheresis in heart transplant (HT) recipients. PATIENTS AND METHODS: From May 1996 to December 2005, 238 HTs were performed using therapy with cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisolone as well as induction treatment with rabbit anti-human thymocyte globulin. Endomyocardial biopsy for rejection surveillance was performed weekly for the first month, monthly for 3 months, yearly after the first year, and whenever rejection was suspected. Immunofluorescence studies with IgG, IgM, C3, C4, C1q, and HLA-DR were performed routinely on the first month biopsy. After a 2-year trial, immunofluorescence studies were not performed routinely, because no significant findings were observed; thus they were performed only when clinical deterioration, unstable hemodynamic status, or suspicion of rejection occurred on routine echocardiographic examinations. Plasmapheresis with fresh frozen plasma exchanging twice the blood volume of the patients was performed for 5 days. Rescue immunosuppression with methylprednisolone (1 g/d) was delivered for 3 days and the immunosuppressants changed, but no intravenous immunoglobulin was prescribed. RESULTS: Twelve patients suffered biopsy-proven acute humoral rejection at 3 days to 32 months after HT (mean, 9.4 months). Immunofluorescence studies showed positive HLA-DR in 7 patients; IgG in 4 patients; IgM in 1 patient; C3 in 4 patients; C4 in 1 patient; and C1q in 1 patient. One patient who was 3 months after HT showed only C1q positive but was treated with extracorporeal membrane oxygenation and intra-aortic balloon pumping support and died 1-month after plasmapheresis. Another patient who deteriorated on the 3rd postoperative day and died 3 days after plasmapheresis was considered to have vascular rejection by interstitial edema, vacuolated endothelial cells and no pathognomonic clinical features, although there was no positive immunofluorescence result. All other subjects were discharged from the hospital, although 3 required mechanical support during plasmapheresis. Hypotension with hypocalcemia was frequently noted during plasmapheresis. The 1-year survival rate was 75% +/- 11%, and 5-year survival rate, 51% +/- 15%. CONCLUSION: Plasmapheresis with concurrent rescue immunosuppression was an effective treatment for acute humoral rejection in HT even with unstable hemodynamics.