ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.The new herpesvirus, human herpesvirus-6 (HHV-6), is able to cause clinical illness after transplantation; however, the pathogenic potential and the clinical features of HHV-6 have not been defined in liver transplant recipients.Methods.We report the first cases of invasive and symptomatic infection due to HHV-6 in liver transplant recipients.Results.HHV-6 infection occurred in four liver transplant recipients at a median of 50 days after transplant (range 17-90 days). Severe cytopenia was observed in all patients; leukopenia (with median leukocyte count of 1400/mm3) was the most commonly effected bone marrow lineage. One of the four patients had interstitial pneumonitis due to HHV-6. No other virus (e.g., cytomegalovirus) or another pathogen was detected in the lungs, blood, or bone marrow in any of the above patients.Conclusions.Our data suggest that HHV-6 can be a pathogen in liver transplant recipients; idiopathic bone marrow suppression is its predominant clinical sequelae. Recognition of HHV-6 infection is clinically pertinent because HHV-6 is potentially treatable with the currently available antiviral agents.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Impaired salivary function with resultant severe dryness of the mouth, or xerostomia, may occur in association with a variety of systemic disorders or therapies. No adequate treatment exists for this debilitating condition, which impedes normal oral function, in particular alimentation and phonation. This study explores the feasibility of salivary gland auto-transplantation, using a canine model. A salivary gland with its duct and surrounding blood vessels still attached was excised and reimplanted in the dog's thigh by anastomosing the graft's blood vessels to the femoral artery and vein. The duct was sutured to an artificial orifice cut in the thigh's skin, from which the saliva was collected. Salivary secretion was induced by a single intravenous bolus of pilocarpine (5 mg). Preoperative (normal) salivation was measured by collecting saliva from the gland in situ. Periodic functional studies showed normal saliva production during the first month after grafting, after which the salivary flow was reduced by 35% over the next 2 months. This reduction was interpreted as a sign of disuse atrophy resulting from the lack of autonomic innervation. To overcome this impediment, oral pilocarpine (5 mg/day) was administered to the recipient dog, after which normal levels of saliva were excreted through the graft during the 3-month follow-up period. The quality of the graft saliva was assessed by its protein and electrolyte levels, which showed close to normal values.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.In testing new anti-CD3 agents for transplantation tolerance induction, an anti-CD3 monoclonal antibody was used as a carrier for the cytotoxic drug idarubicin (IDA).Methods.Anti-CD3 (KT3) was covalently coupled with IDA, producing the IDA-KT3 immunoconjugate, which was tested for specificity by fluorometry and for inhibition of proliferation of CD3+E3 cells ([3H]thymidine uptake). KT3 and IDA-KT3 were used to treat CBA recipients of BALB/c vascularized cardiac allografts. Mice with hearts surviving >100 days were challenged with donor and third-party (C57BL/6) skin.Results.Conjugation to IDA did not reduce binding of KT3 to E3 cells, although the toxicity of IDA was reduced by conjugation. In BALB/c to CBA cardiac allografts (rejected in 12-17 days), both KT3 and IDA-KT3 (0.25-0.5 mg/20 g mouse i.p. at the time of transplantation) induced tolerance. Hearts survived >100 days and skin graft challenge showed indefinite survival of donor grafts but not third-party grafts. KT3 was less toxic, as measured by tumor necrosis factor-α release and blood glucose levels, than equivalent dosages of 145-2C11. At lower dosages (0.1 mg/20 g mouse), KT3-treated animals rejected BALB/c allografts in 15 to 19 days, but IDA-KT3 induced long survival (>100 days) and donor-specific tolerance in 5 of 6 mice.Conclusions.Coupling IDA to anti-CD3 reduced the in vivo toxicity of IDA and improved the immunosuppressive performance of KT3, reducing the side effects seen with other anti-CD3 agents. IDA-KT3 is a new, effective, nontoxic tolerogen in this donor-recipient combination.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Aortic allotransplantation in mice has been well established as a model of choice to study the evolvement of chronic rejection, the etiopathology of which is believed to be that of immune origin. This has prompted the postulation that prior induction of donor-specific tolerance would attenuate or abrogate the underlying events that culminate in posttransplant arteriosclerosis. To study the effects of donor-specific tolerance on chronic rejection, we performed orthotopic liver transplantation without immunosuppression in mice 30 days before aortic allotransplantation across C57Bl/10J (H2b)→C3H (H2k) strain combinations (group III). Aortic allografting in syngeneic (group I; C3H→C3H) and allogeneic (group II, C57Bl/10J→C3H) animals served as controls. No morphological changes were evidenced in the transplanted aortas in group I animals. Contrarily, aortic allografts in group II animals underwent a self-limiting acute cellular rejection, which resolved completely and was succeeded by day 30 after transplantation by histopathological changes pathognomonic of chronic rejection. There was evidence for diffuse myointimal thickening, progressive concentric luminal narrowing, and patchy destruction of internal elastic membranes resulting in massive vascular obliteration by day 120 after transplantation. It was of interest that no arteriosclerotic changes were observed for the duration of follow-up (up to 120 days after transplantation) in transplanted aortas (liver donor-type) harvested from animals in group III. However, vasculopathy was prominent in third-party aortic grafts transplanted into tolerant recipients. Taken together, these data suggest that prior induction of tolerance abrogates the development of chronic rejection; this protection seems to be donor specific.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.If complement (C) activation is prevented or the host is C depleted, discordant vascularized xenografts undergo delayed xenograft rejection (DXR), characterized by graft infiltration by macrophages (MØ) and natural killer (NK) cells, endothelial cell activation, and widespread fibrin deposition. Given a lack of effect of T cell-directed therapies on development of DXR, we evaluated two novel agents, 15-deoxyspergualin (DSG) and leflunomide (LEF), with reported anti-B-cell and/or anti-MØ actions.Methods.DSG and LEF were administered to C-depleted, splenectomized rat recipients of guinea pig cardiac xenografts, and their effects on graft survival and production of anti-guinea pig antibodies were determined. Serial intragraft events were studied by immunohistology using monoclonal antibodies to rat leukocytes, cytokines, and novel proteins, including rat MØ lectin, which in other systems is important to MØ binding, activation, and target cell killing.Results.Median graft survival was 62 hr in cobra venom factor (CVF)-treated controls versus 108 hr (DSG), 129 hr (LEF), and 120 hr (DSG and LEF; all groupsP<0.01 vs. CVF alone). LEF and DSG each decreased (immunoglobulin M [IgM]) or abrogated (IgG) posttransplant production of anti-guinea pig antibodies. Immunohistologic studies showed that each agent also inhibited graft infiltration by NK and T cells, and expression of various cytokines, including the chemokine monocyte chemoattractant protein-1 (MCP-1), but did not affect the tempo or extent of MØ infiltration. Consistent with this, the rapid induction of MØ lectin postxenografting, and induction of MØ lectin by rat MØ exposed to guinea pig cells in vitro, were unaffected by therapy with DSG and/or LEF.Conclusions.LEF or DSG along with CVF can result in the longest prolongation of xenograft survival yet reported in this model, in conjunction with a dampening of host mononuclear cell responses, including suppression of B cell activation. However, the persistent influx of MØ in this model, despite lack of C-, Fc receptor- or apparent chemokine-dependent mechanisms, suggests the presence of additional mechanisms for cell recruitment and activation. It was of importance that, in this regard, although MØ depletion is technically difficult and can lead to undesired effects, the demonstration of rapid MØ lectin induction postxenografting indicates opportunities for blockade of MØ recruitment and functions during DXR by use of anti-MØ lectin monoclonal antibodies or administration of competing sugars.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.In this study we have analyzed the local immunosuppression with budesonide, a topically selective glucocorticosteroid, in rats after orthotopic liver transplantation. Because of its high first-pass hepatic clearance budesonide can be given orally, achieving high intrahepatic and low systemic concentrations.Methods.Using an acute rejection model from Dark Agouti (DA) to Lewis rats, the histomorphological degree of rejection was assessed on histological sections at the ninth postoperative day.Results.Livers of the DA to Lewis study group without immunosuppression revealed severe allograft rejection with vast cellular infiltrates, massive endothelialitis, and hepatocyte necrosis. In the three budesonide study groups (250 μg, 500 μg, and 1 mg/kg/day) a moderate to mild liver allograft rejection was seen. Rejection was most prominent in the 250 μg group, whereas the 1 g group showed almost no signs of rejection, similar to the Lewis to Lewis control group. Aspartate and alanine transaminase (sGOT, sGPT) as well as alkaline phosphatase serum levels correlated with the degree of rejection, achieving highest levels in the DA to Lewis group without immunosuppression. Animals treated with 1 g of budesonide had serum levels similar to Lewis to Lewis control animals.Conclusions.These results implicate a beneficial effect of local immunosuppression with budesonide in rats based on the histomorphological degree of liver allograft rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.We demonstrated previously that a nonmyeloablative preparative regimen can induce mixed chimerism and allograft tolerance in cynomolgus monkeys.Methods.The current studies were designed to clarify the importance and toxicity of various elements of the allotolerance conditioning regimen by: fractionating or reducing the whole-body irradiation (WBI) dosage; adding deoxyspergualine; or deleting donor bone marrow, cyclosporine, irradiation, or splenectomy.Results.Monkeys treated without donor bone marrow, cyclosporine, or irradiation did not develop chimerism or long-term allograft survival. One of three monkeys treated without splenectomy developed chimerism but died of a surgical complication. The other two did not develop chimerism and rejected by day 117. Six of six monkeys treated with 300 cGy of fractionated WBI developed chimerism. Five of these recipients had long-term graft survival. Only two of four monkeys treated with 250 cGy developed chimerism, so a 2-week course of deoxyspergualine was added. This led to chimerism in two monkeys, but one died of ureteral stenosis and the other died of allograft rejection. An unanticipated high incidence of ureteral complications felt to be secondary to rejection episodes and ischemic injury was observed in the long-term surviving animals.Conclusions.All parameters of the original preparative regimen seem to be essential for consistent success. The degree of lymphocyte depletion was proportional to the WBI dose. Long-term graft survival was observed only in recipients achieving lymphocyte chimerism of >1.5%. In this model, lymphocyte depletion seems to be the best predictor of chimerism, and significant lymphocyte chimerism seems to be important in achieving tolerance.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Invasive aspergillosis occurred in 26 liver transplant recipients since 1990 at five liver transplant centers. The median time to onset was 17 days after transplantation. Twenty-seven percent of the patients had undergone retransplantation. Invasive aspergillosis occurred significantly earlier after transplantation in smokers than in nonsmokers (P=0.017). Patients with late-onset aspergillosis (occurring after posttransplant day 90) were more likely to have had prior cytomegalovirus infection than those with early-onset aspergillosis (occurring within 90 days of transplantation) (67% vs. 10%, respectively,P=0.013). Only 8% of the patients had received additional corticosteroids or OKT3, which suggests that augmented immunosuppression may not be a relevant risk factor for invasive aspergillosis in the 1990s due to less frequent use of these agents. The median serum bilirubin level of the patients was 21.8 mg/dl, 85% of the patients had renal insufficiency, and 54% were on dialysis before the onset of invasive aspergillosis, which suggest that overall severity of illness, including poorly functioning hepatic allograft and renal failure may be the major determinants of disease occurrence. Overall mortality was 92% (24/26). No difference in mortality could be shown for the patients who received amphotericin B versus liposomal amphotericin B preparations (100% vs. 89%); however, the mean time to death after the initiation of therapy was 20 days in patients who received amphotericin B and 43 days in those who received liposomal amphotericin B preparations.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Despite recent advances in diagnosis and treatment, cytomegalovirus (CMV) infection continues to be a common cause of morbidity in liver transplant (LT) recipients. Because CMV infection suppresses cell-mediated immunity, which seems to be important in neutralizing hepatitis C virus (HCV) infection, we assessed the impact of CMV infection on histopathological HCV recurrence after LT.Methods.The study group was comprised of 43 consecutive LT recipients with at least 6 months of histologic follow-up. Group 1 consisted of the 8 patients who developed CMV viremia after LT; group 2 comprised the 35 patients without CMV viremia. There was no significant difference with regard to age, initial immunosuppression, incidence of rejection, distribution of HCV genotypes, or mean follow-up between the groups. Semiquantitative histopathologic assessment of allograft hepatitis was performed using the Knodell's score.Results.The mean total Knodell score of the final allograft biopsy was significantly greater in group 1 patients (P=0.016), with most of the difference due to periportal/bridging necrosis (P=0.009) and lobular activity subitem (P=0.01) scores. Half of the CMV viremic patients eventually developed allograft cirrhosis as compared with 11% of the CMV-negative patients (P=0.027). Accordingly, the cirrhosis-free actuarial survival by Kaplan-Meier estimates was significantly diminished in the CMV viremic patients. Glycoprotein B genotype analysis of CMV isolates revealed no significant differences between patients who did and those who did not develop allograft cirrhosis.Conclusions.After LT for chronic HCV, patients who develop CMV viremia incur a significantly greater risk of severe HCV recurrence.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID