Identification of regulatory elements of human alpha 6 integrin subunit gene

BACKGROUND: A study was performed by 17 different U.S. liver transplantation centers to determine the safety and efficacy of conversion from cyclosporine to tacrolimus for chronic allograft rejection. METHODS: Ninety-one patients were converted to tacrolimus a mean of 319 days after liver transplantation. The indication for conversion was ongoing chronic rejection confirmed by biochemical and histologic criteria. Patients were followed for a mean of 251 days until the end of the study. RESULTS: Sixty-four patients (70.3%) were alive with their initial hepatic allograft at the conclusion of the study period and were defined as the responder group. Twenty-seven patients (29.7%) failed to respond to treatment, and 20 of them required a second liver graft. The actuarial graft survival for the total patient group was 69.9% and 48.5% at 1 and 2 years, respectively. The actuarial patient survival at 1 and 2 years was 84.4% and 81.2%, respectively. Two significant positive prognostic factors were identified. Patients with a total bilirubin of < or = 10 mg/dl at the time of conversion had a significantly better graft and patient survival than patients converted with a total bilirubin > 10 mg/dl (P=0.00002 and P=0.00125, respectively). The time between liver transplantation and conversion also affected graft and patient survival. Patients converted to tacrolimus < or = 90 days after transplantation had a 1-year actuarial graft and patient survival of 51.9% and 65.9%, respectively, compared with 73.2% and 87.7% for those converted > 90 days after transplantation. The mean total bilirubin level for the responder group was 7.1 mg/dl at the time of conversion and decreased significantly to a mean of 3.4 mg/dl at the end of the study (P=0.0018). Thirteen patients (14.3%) died during the study. Sepsis was the major contributing cause of death in most of these patients. CONCLUSIONS: Our results suggest that conversion to tacrolimus for chronic rejection after orthotopic liver transplantation represents an effective therapeutic option. Conversion to tacrolimus before development of elevated total bilirubin levels showed a significant impact on long-term outcome.     

Do cold agglutinins have any impact on the outcome of liver transplantation?

Cold agglutinins, IgM red blood cell autoantibodies, cause cold agglutinin disease with hemolysis and microvascular occlusion. Cold preservation of kidneys during renal transplantation in the presence of cold agglutinins can cause graft malfunction. However, the impact of cold agglutinins on the outcome of liver transplantation is unknown. We measured the pretransplant presence and titer of cold agglutinins in 327 primary liver allograft recipients and analyzed their relationship to outcome after transplant. Thirty-three percent of pretransplant patients had cold agglutinins. Cold agglutinins were more common in patients with viral-related liver diseases (49%) compared with those with nonviral-related liver disease (32%). There was no difference between recipients with and without cold agglutinins in usage of blood products, postoperative day 2 aminotransferase levels, acute rejection at day 7, the development of hepatic artery thrombosis, nonanastomotic biliary strictures, or 4-month allograft survival. In conclusion, cold agglutinins are common in liver transplant patients before surgery, especially those with viral-related liver diseases. However, the presence of cold agglutinins does not impact on outcome after liver transplantation.     

The lack of long-term detrimental effects on liver allografts caused by donor-specific anti-HLA antibodies

Recent reports indicate a higher incidence of both acute and chronic liver allograft rejection when, at the time of transplantation, the recipients serum contains donor-specific anti-HLA antibodies. From 9/89 to 5/91, 133 liver allografts were performed at our institution. Thirteen liver recipients had donor-specific IgG anti-HLA antibodies (complement-fixing) at the time of transplantation. In eleven patients, antibodies reacted to donor class I antigens while in 1 patient the donor-specific antibody had class II reactivity. Twelve patients have been followed for a minimum of 12 months (median 18 months, range 28-12 months). No hyperacute rejection was seen in any of the cases and four patients had acute rejections. Thus far only one of the twelve patients has biopsy evidence suggestive of chronic liver injury. The remaining have normal liver enzymes and bilirubin. Three of these twelve patients died (one from a myocardial infarction and the others from sepsis) accounting for a one-year graft survival of 75%. There was no significant statistical difference in the one-year graft survival in those recipients without donor-specific antibodies (i.e., 80.5%). In eight of the twelve patients, pretransplant preformed antibody level (PRA) was > 50%. In six of the thirteen patients donor-specific antibody was present at dilutions greater than 1:64. As previously reported, the donor-specific antibody disappeared from the serum posttransplant within hours and did not reappear. In vitro studies demonstrated no factor in portal or hepatic artery blood that could inhibit rabbit complement mediated lysis of anti-HLA antibodies. We conclude that it is not a contraindication to do liver transplants in the presence of donor-specific anti-HLA antibodies.     

Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation

Infection and rejection remain the greatest threats to the survival of pulmonary allograft recipients. Furthermore, a relationship may exist between these events, because the occurrence of one may predispose to the other. By using multivariate analysis for repeated events, we analyzed the risk factors for bacterial, fungal, and viral infection, grade II or greater acute rejection, and death among 239 lung transplant recipients who received 250 allografts between January 1988 and September 1993. A total of 90 deaths, 491 episodes of acute rejection, and 542 infectious episodes occurred during a follow-up of 6 to 71 months. The hazard or risk patterns of death, infection, and rejection each followed an extremely high risk during the first 100 days after transplantation, a second modest risk period at 800 to 1200 days, and a lower constant risk. Infection and graft failure manifested by diffuse alveolar damage were the major causes of early death (< 100 days), whereas infection and chronic rejection were primary causes of later death after pulmonary transplantation. By multivariate analysis, cytomegalovirus mismatching risk for primary infection was the most significant risk factor for death, rejection, and infection. Absence of cytomegalovirus prophylaxis was also a risk factor for early and late death and late infection. Survival of recipients who received cytomegalovirus prophylaxis was significantly improved. Immunosuppression based on cyclosporine versus FK 506 was a risk factor for late death and late infection. Graft failure manifested by diffuse alveolar damage/adult respiratory distress syndrome was a significant risk for death late after transplantation. These data suggest the following: (1) The hazard for death, infection, and rejection after pulmonary transplantation appears biphasic; (2) lower survival is associated with ischemia-reperfusion lung injury represented by diffuse alveolar damage/adult respiratory distress syndrome; (3) cytomegalovirus mismatch, absence of cytomegalovirus prophylaxis, and development of cytomegalovirus disease are significant threats for death, rejection, and infection after pulmonary transplantation; (4) prevention of cytomegalovirus disease should improve survival by decreasing the prevalence of infection and rejection.     

Hepatitis B infection and liver transplantation

Patients with chronic hepatitis B virus (HBV) infection have historically incurred high rates of allograft reinfection from extrahepatic reservoirs of HBV, with worse long term outcome compared with that of transplant recipients without HBV infection. As a result, chronic HBV infection has been considered a contrandication for transplantation. Prophylaxis against HBV recurrence, in the form of passive immunization with high dose hepatitis B hyperimmunoglobulin and the antiviral agent lamivudine, has recently been demonstrated to decrease the risk of reinfection. With appropriate prophylaxis, liver transplantation can be a viable proposition for patients with HBV infection. Past experience and current status of HBV infection and transplantation are reviewed, with emphasis on the issues surrounding prophylaxis.     

Epidemiology of factor V Leiden: clinical implications

A pronounced similarity exists between liver allograft rejection and graft-versus-host disease (GVHD) in the damage and eventual destruction of small intrahepatic bile ducts. Although an immunologic reaction has an important role, precisely identifying the target antigens or reason for persistence of the immune response has been difficult. An important difference between GVHD and liver rejection is the development of obliterative arteriopathy only in rejection. The three main histopathologic features of acute rejection are a predominantly mononuclear but mixed portal inflammation, subendothelial inflammation of portal or terminal hepatic veins (or both), and bile duct inflammation and damage. In acute rejection, a controversial issue is determining when therapeutic intervention is needed. The recommended approach is to base treatment on a combination of histopathologic changes and liver injury or dysfunction. Chronic rejection, which usually does not occur before 2 months after transplantation, is characterized by two main histopathologic features: (1) damage and loss of small bile ducts and (2) obliterative arteriopathy. Acute GVHD begins within the first month after transplantation and most commonly involves the skin, gastrointestinal tract, and liver, whereas chronic GVHD usually develops more than 80 to 100 days after liver transplantation and affects 30 to 50% of long-term survivors. Recognition of the early, cellular stages of chronic GVHD is important in preventing irreversible damage.     

Long-term follow-up of anatomic heart transplantation. Apropos of 60 patients with a mean follow-up of 36 months

The aim of this study was to collect different problems seen in long-term evolution of patients who had anatomical cardiac transplantation and to compare with those seen in patients with standard transplantation. During the mean follow-up of 36 months, we analysed different data of 60 patients mean aged 51, who underwent anatomical cardiac transplantation. Six patients (10%) died within the 30 days after surgery. No patient needed the use of permanent pacemaker. Echocardiographic examination found normal atrial shape. One month after surgery, echocardiography described 16 tricuspid regurgitations (22.66%) and 8 mitral regurgitations (13.33%), 1 year later, there was respectively 13.33 and 6.66% tricuspid and mitral regurgitation. We had 8 late deaths: 1 sudden death, 2 chronic rejections, 1 pancreatitis and 4 cancers. The survival analysis pointed out 84% at 1 year, 80 at 2 years, 78 at 3 years and 73 at 5 years. Six months after surgery, 80% of patients were treated for high blood pressure; 85% had serum creatinine level equal or superior to 13 mg/L, with mean serum ciclosporin at 130 ng/mL. At the 3rd month, 6 endomyocardial biopsies were equal or superior to grade 2 rejection (International Society for Heart Transplantation). Between the 3rd and 12th month, 3 endomyocardial biopsies were equal or superior to grade 2 rejection, and the same between the 12th and 24th month. The infections rate was 0.8 episode per patient. Long term follow-up of anatomical cardiac transplantation faces the same problems as in standard cardiac transplantation. It is better to perform anatomical cardiac transplantation because of its early postsurgical advantages. Long term care is the same as in standard cardiac transplantation.     

Low level of interleukin 10 synthesis during liver allograft rejection

Interleukin 10 (IL-10) is a macrophage and T-cell-derived cytokine with potent immunosuppressive properties. To assess its role in liver allograft rejection, we evaluated the plasma level and in situ production of IL-10 after liver transplantation and designed in vitro studies to asses the effects of IL-10 on the allogeneic response. Normal controls and liver transplant recipients with acute rejection, chronic rejection, other complications (recurrent hepatitis C, biliary complications), or no complications were evaluated. The plasma IL-10 level was measured by an immunoenzymatic technique. IL-10 expression in the liver was detected on frozen liver biopsies by in situ hybridization and immunohistochemistry. Plasma IL-10 levels were not elevated during acute or chronic rejection, when compared with liver recipients with uncomplicated transplants. IL-10 mRNA and protein expressions in the liver graft were restricted to rare scattered sinusoidal cells of transplant recipients with acute or chronic rejection, as well as in those with no complications. In mixed lymphocyte cultures performed with peripheral blood mononuclear cells (PBMC) from normal subjects, IL-10 decreased the cell proliferation in a dose-dependent manner, and this immunosuppression was synergistic with that of cyclosporine or FK506. These findings indicate that IL-10 production is low during allograft rejection. Thus, IL-10 therapy in association with cyclosporine or FK506 might be proposed after liver transplantation.     

Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tarolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group

BACKGROUND: This paper reports the histopathologic results of 2-year protocol biopsies from patients who were enrolled in the U.S. FK506 kidney transplant study . METHODS: Recipients of cadaveric kidney transplants were randomized to tacrolimus or cyclosporine therapy. Patients active in the trial at 2 years after transplantation were approached for a protocol biopsy. Biopsies were scored by the Banff classification in a blinded fashion by one pathologist. RESULTS: A total of 144 patients (41.3% of those active at 2 years) had a 2-year protocol biopsy performed; 79 patients were treated with tacrolimus and 65 patients were treated with cyclosporine. Evidence of acute rejection was found in seven (8.9%) of the 2-year biopsies in tacrolimus-treated patients and six (9.2%) cyclosporine-treated patients. Chronic allograft nephropathy was found in 49 (62.0%) tacrolimus biopsies and 47 (72.3%) cyclosporine biopsies (P=0.155). There were no apparent histopathologic differences between the tacrolimus and cyclosporine biopsies. The occurrence of chronic allograft nephropathy was significantly higher in patients who received a graft from an older donor (P<0.01), who experienced presumed cyclosporine or tacrolimus nephrotoxicity (P<0.001), who developed a cytomegalovirus infection (P=0.038), or who experienced acute rejection in the first year after transplantation (P=0.045). A multivariate analysis showed that nephrotoxicity and acute rejection were the most significant predictors for chronic allograft nephropathy. CONCLUSIONS: The occurrence of histologic acute rejection was rare at 2 years, confirming the absence of subclinical acute rejection in these late biopsies. A majority of the biopsies showed features consistent with chronic allograft nephropathy that was associated with acute rejection (particularly in cyclosporine-treated patients), nephrotoxicity, and cytomegalovirus infection in the first year. This suggests that nonimmunologic factors, such as drug-induced toxicity, may play an important role in chronic allograft nephropathy.     

Posttransplantation chronic hepatitis in fulminant hepatic failure

Non-A, non-B or seronegative hepatitis is the leading indication for liver transplantation in patients with fulminant hepatic failure (FHF). We examined protocol annual review liver allograft biopsy specimens in consecutive adult patients transplanted for FHF in an attempt to determine the extent of the histological changes. One hundred eleven biopsy specimens from 41 patients transplanted for fulminant seronegative hepatitis and 34 from a comparison group of 16 patients transplanted for other causes of FHF (11 paracetamol overdose, 2 idiosyncratic drug reaction, 3 Wilson's disease) were available. Specimens were analyzed using standard proforma without knowledge of the original diagnosis. Chronic hepatitis was present in 29 patients (71%) transplanted for fulminant seronegative hepatitis (23 mild, 3 moderate, and 3 severe) compared with 5 patients (31%, all mild) transplanted for other causes of FHF. Twenty-five patients (61%) grafted for seronegative FHF had fibrosis (13 mild, 9 moderate, and 3 severe) in contrast to 4 fibrosis (25%) (all mild) in the comparison group. Excluding early allograft failure because of primary graft nonfunction or vascular complications, six patients with seronegative FHF required retransplantation (2 = chronic rejection; 1 = severe hepatitis with panacinar necrosis, resembling original liver; and 3 = chronic hepatitis with precirrhotic fibrosis and prominent cholestasis of unknown cause). One patient in the comparison group had a second graft (chronic rejection). Posttransplantation chronic hepatitis is more frequent and severe in patients transplanted for seronegative hepatitis. Graft survival may be adversely influenced by the development of chronic hepatitis, which may represent persistent or recurrent disease.     

Study of the beta -delayed neutron decay of 18N

The shortage of suitable liver donors for children has motivated the use of ABO-incompatible (ABO-I) grafts for transplantation in urgent situations. However, survival after ABO-I liver grafts has been reported at about 30% as compared with 80% in cases of ABO-identical or -compatible liver grafts. This difference has been attributed to antibody-mediated, hyperacute or chronic liver rejection, due to preformed ABO antibodies (alloantibodies). In this study, we report our results with ABO-I livers in children without alloantibodies at the time of transplantation. From January 1988 to June 1993, 143 OLT were performed in 122 children. Eight children received 8 ABO-I liver grafts. Of these, 7 patients were included in the study. All 7 were alloantibody free before OLT. Five children were spontaneously alloantibody free, while in 2 children, the plasma alloantibodies were eliminated before and after transplantation using intravenous infusion of specific blood group antigens of the donor blood group (soluble antigens). Immunosuppression consisted of a triple-drug treatment combining CsA, AZA, and steroids. The follow-up period was between 10 and 48 months. One child died from a surgical complication. Six children survived, but 1 died 10 months later from intestinal obstruction. There were no graft losses and no episodes of hyperacute or chronic rejection. The graft and patient survival rate was 71%. There was a 28% incidence of rejection, but all were mild (requiring steroid boluses only). Our results suggest that the absence of ABO alloantibodies at the time of and after transplantation can protect ABO-I liver grafts against antibody-mediated rejection, whether hyperacute or chronic, and that soluble antigens are effective in eliminating alloantibodies in children.     

Efficacy of lamivudine in controlling hepatitis B virus recurrence after liver transplantation

BACKGROUND: Indication of liver transplantation for patients infected with hepatitis B virus (HBV) remains controversial because of the high incidence of posttransplant HBV recurrence and aggressive involvement of the allograft. In this article, we provide evidence that the introduction of lamivudine may favorably alter the prognosis of these patients. METHODS: Lamivudine was used in 40 HBV-infected adult patients suffering from chronic end-stage liver disease who underwent liver transplantation. The drug was used in the following settings: failure of prolonged passive immunoprophylaxis, elective conversion from immunoprophylaxis, de novo posttransplant HBV infection, and primary treatment with lamivudine which started before and continued after transplantation. Twenty patients (50%) had viral replication at the time lamivudine was started. Posttransplant and antiviral treatment follow-ups were 8-64 months (median follow-up: 27.5 months) and 9-39 months (median follow-up: 19 months), respectively. RESULTS: The patient and graft survival rates were 97.5% (39/40). Thirty-three patients (82.5%) have remained free of viral recurrence. In the seven re-infected patients, the manifestations of HBV involvement of the allograft have been mild. There have been no side effects related to lamivudine, and the treatment is substantially less costly than with other anti-HBV agents. CONCLUSIONS: Compared with historic series utilizing other modalities of treatment, the use of lamivudine has, so far, yielded superior results. This drug may be an important acquisition for antiviral prophylaxis in HBV-infected liver recipients. Because of the risk of viral mutations, however, efforts should proceed to achieve more efficacious methods for prevention and control of HBV recurrence.     

Steroid withdrawal from long-term immunosuppression in liver allograft recipients

Corticosteroids were withdrawn from the immunosuppressive regimen of 168/197 (85%) of liver transplant patients who survived for more than three months. In 14, steroids were restarted for reasons other than rejection. The remaining 154 patients were evaluated for the occurrence of rejection and graft loss. Risk factors for the development of rejection after steroid withdrawal were assessed. There were 13 episodes of rejection in 12 (7.8%) grafts; 7 (4.5%) experienced acute cellular rejection, and 6 (3.9%) developed chronic ductopenic rejection. All cases of acute rejection resolved with high-dose steroids. Graft and patient loss due to chronic rejection was 3 (1.9%) and 2 (1.3%), respectively. Chronic rejection resolved in 1 patient, 1 was successfully retransplanted, and in the other 2 the principal cause of death was recurrent tumor. None of the risk factors examined (primary indication for transplant, severity of previous acute rejection, use of OKT3, retransplantation, ABO blood group donor/recipient match, CMV infection, and CsA mono versus CsA and AZA double therapy) were associated with the development of chronic rejection poststeroid withdrawal. The prevalence of side effects, after steroid withdrawal, was low; 66% of patients never required antihypertensive medication; 14% experienced a significant septic episode, and only 4 died with sepsis as the major factor. There were no fungal sepsis and no new cases of diabetes. Withdrawal of corticosteroids after 3 months can be successfully achieved in the majority of liver allograft recipients and is associated with a low rate of rejection, graft loss, and complications attributable to immunosuppressive medication.     

Ethnic variations in patient and graft survival after liver transplantation. Identification of a new risk factor for chronic allograft rejection

The ethnic origin of renal graft recipients is recognized as an important determinant of graft survival. In liver transplantation, the effect of racial origin has been studied in black American recipients and has suggested a trend toward inferior graft survival in this group. In this study, we have analyzed outcome of transplantation in a large multiethnic liver transplant program. Non-Caucasoid recipients had an inferior patient survival compared with Caucasoids and, in particular, European Caucasoids at 1, 3, and 5 years after transplantation (46.7% vs. 60.2% at 3 years, P = 0.05). Non-European recipients had an inferior graft survival compared with European recipients at 1, 2, and 3 years after transplantation (e.g., north Europeans 53.5%, south Europeans 48.5%, Middle Eastern 40%, and non-Caucasoids 27% at 3 years, P < 0.01). Different frequencies of chronic allograft rejection in the ethnic groups contributed to the rates of graft survival, with the non-European recipients developing chronic rejection at over twice the rate of European recipients (12.6% vs. 5.9%, respectively, P = 0.002). The findings in this study support the evidence from renal transplant programs that the ethnic origin of recipients is an important determinant of outcome after transplantation, with increasing frequency of chronic rejection in recipients nonindigenous to the donor population contributing to the variations in patient and graft survival rates.     

Postoperative complications after Mainz pouch construction--with emphasis on measures to deal with narrowing of the duct aperture

Cutaneous sinus tracts in the face and neck region are often dental in origin. The purpose of this study was to characterize the clinical features and treatment of 37 consecutive cases of odontogenic cutaneous sinus tracts, collected and reviewed in a 15-year period. More than half of the patients (21 cases, 57%) were referred from medical doctors, particularly plastic surgeons and dermatologists. The sinus tracts were associated with caries (26 cases), incomplete endodontic treatment (7), crown fracture (2), vertical root fracture (1) and impacted mandibular third molar (1). They occurred most often in adolescents and adults (30 cases, 81%). The most common causative teeth were mandibular teeth (34 teeth, 85%). The chin, submental, and cheek areas were the most common sites of sinus tracts (30 cases, 81%). The majority of causative teeth (32 teeth, 80%) were treated endodontically. All fistulas healed uneventfully after proper dental treatment, without cosmetic surgery. In 63% (20 cases) of the recorded cases, complete resolution occurred within 8 weeks. Half of the patients had had fistulas for more than 6 months before receiving dental treatment, demonstrating that delays in proper diagnosis and treatment were common. As most patients suffered from unnecessary medication or surgery due to the delay of dental treatment, early dental consultation and treatment is important. Conventional endodontic treatment should be the treatment of choice if the tooth is salvageable. The increasing incidence of incomplete endodontic treatment in association with the occurrence of sinus tracts indicates that standardized endodontic therapy should be emphasized for prevention.     

The effect of hexetidine spray on dental plaque following periodontal surgery

The aim of the present study was to determine the effects of a 0.2% hexetidine spray, used as a supplement to regular oral hygiene measures, on dental plaque and gingival condition following periodontal surgery. This study was carried out on 38 patients who required 2 episodes of periodontal surgery. Examinations regarding dental plaque were performed at 0, 7, 14, 21 and 28 days, while the condition of the gingiva were examined at 0 and 28 days. Dental plaque was assessed by the Turesky modification of Quigley-Hein index; the gingival condition was evaluated using the gingival index of L?e-Silness and the papilla bleeding index. In a double-blind cross-over study of 28 days duration, significant reduction in plaque accumulation and an improvement in wound healing were demonstrated for the test spray compared to the placebo.     

Transcriptional regulation of aquaporin-2 water channel gene by cAMP

In patients awaiting heart transplantation, end-stage disease of a second organ may occasionally require consideration of simultaneous multiorgan transplantation. Outcome statistics in multiorgan transplant recipients are needed to define optimal utilization of scarce donor resources. Incidence of cardiac allograft rejection, actuarial recipient survival, and cardiac allograft rejection-free survival were evaluated in 82 recipients of 84 simultaneous heart and kidney transplants. Twenty-three of the 82 dual-organ recipients have died with 1, 6, 12, and 24-month actuarial survival rates of 92%, 79%, 76%, and 67%, respectively. The actuarial survival rates in the heart-kidney recipients were similar to those observed in 14,340 isolated heart recipients (United Network for Organ Sharing Scientific Registry) during the same period (92%, 86%, 83%, and 79%, respectively; P=0.20). Clinical data on all episodes of treated rejection in either organ and on immunosuppressive regimens were available on 56 patients; 48% of these patients have had no rejection in either organ, 27% experienced heart rejection alone, 14% experienced kidney rejection alone, and 11% had both heart and kidney allograft rejection. Heart allograft rejection was less common in heart-kidney recipients, as compared with isolated heart transplant recipients; 0, 1, and > or = 2 treated cardiac allograft rejection episodes occurred in 63%, 20%, and 18% of heart-kidney recipients compared with 46%, 27%, and 28% of 911 isolated heart recipients reported by Transplant Cardiologists' Research Database (P=0.02). The rejection-free survival rates at 1, 3, and 6 months were 88%, 74%, and 71% in the double-organ recipients, as compared with 66%, 44%, and 39%, respectively, in the single-organ recipients. Compared with isolated heart transplantation, combined heart-kidney transplantation does not adversely affect intermediate survival and results in a lower incidence of treated cardiac allograft rejection. The findings suggest that combined heart-kidney transplantation may be an acceptable option in a small subset of potential heart transplant recipients with severe renal dysfunction.     

Expression of interleukin-6 in association with rat lung reimplantation and allograft rejection

Organ transplantation has become a therapeutic option for the replacement of malfunctioning tissues and organs. Since the advent of the first combined heart-lung transplant in 1981, there has been a rapid growth in the popularity of lung transplantation for a number of end-stage pulmonary disorders. Interestingly, these lung transplant patients experience more complications of acute and chronic allograft rejection compared with recipients of other solid organs. These episodes of rejection are related to a complex series of events that depend on the interaction of many cells and soluble mediators leading to cellular and tissue injury. The histopathology of lung allograft rejection has been actively studied and is associated with the sequestration of activated mononuclear phagocytes, T and B lymphocytes. These cells secrete a number of soluble mediators, that is, cytokines, that participate in the evolution of the immune response via autocrine, paracrine, or endocrine mechanisms. The interaction of cytokines with their targets leads to cellular activation, proliferation, and differentiation. In this study, we postulated that interleukin-6 (IL-6) may have a central role in the pathogenesis of acute lung allograft rejection. To test this hypothesis, we employed an unmodified RT1-incompatible rat lung allograft model and assessed the time course and major tissue compartment(s) of IL-6 production during the evolution of lung allograft rejection. The expression and production of IL-6 during the pathogenesis of lung allograft rejection was measured at the whole-animal, organ, cellular, and molecular levels. The expression of IL-6 was found to be bimodal in character, initially related to the reimplantation response and finally to the maximal allograft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Apoptosis as a mechanism of tissue injury in liver allograft rejection

Recent studies suggest that apoptosis is an important mechanism of cell death in the rejection of liver allografts and that infiltrating host lymphocytes mediate this process. The first section of this chapter addresses the cells and molecules that initiate the immune response following transplantation of a liver allograft. The recognition of donor alloantigens by infiltrating host lymphocytes stimulates a cascade of immune events which culminate in development of the effector cells that mediate tissue damage. Studies which demonstrate that apoptosis of hepatocytes and bile duct cells accompany allograft rejection are detailed in the second section of this chapter. The final section discusses the potential pathways which lead to apoptosis in liver allograft rejection. The contributions of the granule-exocytosis pathway, the Fas-mediated pathway, and cytokines to the induction of apoptosis in liver allografts are discussed. In addition, the concept that alloreactive graft infiltrating cells are deleted by apoptosis is presented. A further understanding of the mechanisms involved in apoptosis will lead to unique approaches toward the goal of achieving allograft tolerance.     

Delayed function reduces renal allograft survival independent of acute rejection

BACKGROUND: Mechanisms by which delayed allograft function reduces renal allograft survival are poorly understood. This study evaluated the relationship of delayed allograft function to acute rejection and long-term survival of cadaveric allografts. METHODS: 338 recipients of cadaveric allografts were followed until death, resumption of dialysis, retransplantation, loss to follow-up, or the study's end, which ever came first. Delayed allograft function was defined by dialysis during the first week following transplantation. Multivariate Cox proportional hazards survival analysis was used to assess the relationship of delayed allograft function to rejection and allograft survival. RESULTS: Delayed allograft function, recipient age, preformed reactive antibody levels, prior kidney transplantation, recipient race, rejection during the first 30 days and rejection subsequent to 30 days following transplantation were predictive of allograft survival in multivariate survival models. Delayed allograft function was associated with shorter allograft survival after adjustment for acute rejection and other covariates (relative rate of failure [RR]+1.72 [95% CI, 1.07, 2.76]). The adjusted RR of allograft failure associated with any rejection during the first 30 days was 1.99 (1.23, 3.21), and for rejection subsequent to the first 30 days was 3.53 (2.9 08, 6.00). The impact of delayed allograft function did not change substantially (RR=1.84 [1.15, 2.95]) in models not controlling for acute rejection. These results were stable among several subgroups of patients and using alternative definitions of allograft survival and delayed allograft function. CONCLUSIONS: This study demonstrates that delayed allograft function and acute allograft rejection have important independent and deleterious effects on cadaveric allograft survival. These results suggest that the effect of delayed allograft function is mediated, in part, through mechanisms not involving acute clinical rejection.