摘要:

Experiments were carried out in outbred dogs and pigs to evaluate the relative immunogenicity of pancreatic islets and segmental pancreas grafts, and whether these could be ameliorated by transplanting a kidney simultaneously from the same donor animal. Various immunosuppressive regimens were also studied.Pancreatic islet allografts never normalized blood glucose in totally pancreatectomized recipients despite the use of cyclosporine (CsA) in high doses (40 mg/kg/day) and the simultaneous transplantation of a kidney from the same donor. These grafts which never “took” contrast sharply with the experience of pancreatic islet autografts prepared in the same way and incoulated into the spleen, which in all nine instances normalized blood glucose in pancreatectomized recipients.Segmental transplants were performed in swine with duct drainage into the jejunum. Totally pancreatectomized pigs died at 7.8±1.0 days. In recipients suppressed with low-dose azathioprine (Az) and prednisone (Pred) pancreas grafts alone were rejected in 12.9±10 days. Synchronous pancreas and kidney transplants treated similarly extended the mean survival of pancreatic grafts to 20±10 days—which, however, was not significant (P<0.1>0.05). Mean survival time of pancreatic grafts in recipients receiving CsA at 20 mg/kg/day and prednisone 1 mg/kg/day was 14±6.3 days. The combination of CsA 20 mg/kg/day, Az 2 mg/kg/day, and Pred 1 mg/kg/day prolonged the mean survival time to 39.8± 22 days. These results allow us to conclude that: (1) crude preparations of islet tissue invariably capable of normalizing blood surgar at day 4 when used as autografts failed to “take” despite the existence of alternative sources of antigen present in a well vascularized kidney from the same donor, and despite very high dosages of CsA; (2) triple immunosuppressive therapy had synergistic effects on pancreatic allograft survival; and (3) simultaneous transplantation of kidney and pancreas had little effect on survival times of the pancreas or the kidney.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

We have previously reported 5–30-fold increases in the expression of class I and class II major histocompatibility complex (MHC) antigens in rejecting heart and kidney allografts in the DA-to-PVG rat strain combination. We examine here the effects of immunosuppression with cyclosporine on the induction of donor class I and class II MHC antigens in heart and kidney allografts in this strain combination. Immunohistological studies and quantitative absorption analyses using monoclonal antibodies and assay systems specific for donor class I and class II MHC antigens were used throughout. Heart allografts in cyclosporine-treated rats were examined on day 3,5,7,9,11, and 14 after transplantation, and kidney allografts in cyclosporine-treated rats were examined at day 7. In addition, untreated heart and kidney isografts were studied at days 1,3,5, and 7 after grafting. Immunohistological studies on frozen sections showed that cyclosporine-treated heart and kidney allografts showed no induction of class II MHC antigens, in contrast to untreated heart and kidney allografts. Class I MHC antigen induction did occur in spite of cyclosporine-therapy, but at levels lower than those seen in untreated allografts. Moreover, the pattern and degree of class I induction in the cyclosporine-treated allografts resembled very closely those seen in isografts, and so this induction was, in all probability, a consequence of the transplantation procedure rather than of specific immune responses.We also noted, in the cyclosporine-treated heart allografts, that all donor interstitital dendritic cells had disappeared and been replaced by recipient interstitial dendritic cells by the end of the second week after grafting. In addition, there was no reduction in the class II antigen content of kidney allografts treated for 7 days with cyclosporine.The absence of class II antigen induction in allografts where rejection is effectively suppressed with cyclosporine might be of clinical value in the differential diagnosis between rejection and cyclosporine toxicity in renal transplantation, and between active and inactive cellular infiltrates in heart transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

Natural Killer cell subsets were studied in 39 long-term renal allotransplant recipients receiving conventional immunosuppression and 26 normal controls. Twocolor flow cytometry analysis was used to determine coexpression of 2 surface antigens known to allow a phenotypic and functional discrimination of NK cells—Leu-7 a marker of large granular lymphocytes, and Leu-11c directed against the FcgammaR. In 11 patients and controls, these NK cell subsets were compared with actual NK activity assessed by killing of K562 target cells. Our data clearly show that, in long-term kidney recipients, the absolute number of NK cells (Leu-11c+) is significantly decreased compared with that of the control group. Furthermore, the most cytotoxic NK cell subset (Leu-7-/Leu-11c+phenotype) is markedly diminished in the transplant population, whereas the less cytotoxic subset (Leu-7+/Leu-11c+) is unchanged. Finally, actual NK cell activity closely correlates with both relative and absolute numbers of these 2 NK cell subsets. These data provide convincing evidence that NK activity is impaired in long-term kidney recipients because of a diminished number of NK effector cells.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

The mononuclear cell infiltrate in a total of 279 human renal allograft biopsies was determined by a panel of monoclonal antibodies using an indirect immunoperoxidase technique. Two hundred and seventy-two biopsies were obtained from 83 patients randomly allocated to receive short-term cyclosporine (CsA) or conventional azathioprine and low-dose prednisolone (AP). Biopsies were obtained routinely at days 0 (control biopsies), 7, 21, 90, and 365, as well as at other times when clinically indicated. A further 7 patients on AP therapy were biopsied several years after transplantation (median: 6 years 1 month). Morphometric analysis of cryostat tissue sections using a point-counting technique has shown that the infiltration in rejecting grafts is significantly greater than in grafts with stable function. However, significant infiltration also occurs within the first week after transplantation in grafts with stable function. While this infiltrate diminishes with time, it remains significant even in grafts biopsied several years after transplantation. The infiltration with CsA treatment is significantly less than with AP therapy. The magnitude of the infiltrate therefore varies with time, graft status, and immunosuppression. In contrast the phenotypic composition of the infiltrate remains relatively constant in all biopsies after transplantation with T lymphocytes (CD3+), accounting for approximately 35% of infiltrating cells and CD8+cells more common than CD4+. Monocytes and macrophages account for most of the remainder of the infiltrate.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

We have investigated the expression of class II major histocompatibility complex (MHC) antigens in human renal allografts before, during, and after the first episode(s) of rejection, and correlated the antigen expression with the cytological pattern of inflammation as well as with the extent of steroid administration. The results confirm that the class II MHC antigens are rapidly lost from a renal transplant after successful transplantation. Downregulation of graft class II antigenicity was observed in all three immunosuppressive regimens employed, with a steroid dose ranging from 0.5±0.2 mg/kg/day to 1.8±0.3 mg/kg/day of methylprednisolone. During rejection the class II MHC antigens reappear in the graft parenchymal (vascular endothelial and tubular) cells, whereas after the successfully treated episode they again disappear from the graft. The upregulation of graft antigenicity is associated only with inflammatory patterns with a distinct blastogenic component; nonblastogenic patterns of inflammation are not associated with upregulation of class II antigens. During blastogenic inflammation, the extent of class II antigen expression was inversely proportional to the amount of steroid administered. The results support the suggestion that upregulation of class II antigen contents in a graft is due to (gamma-interferon released by) the inflammatory (T) blast cells, and suggest that a major downregulating mechanism of class II antigen expression is administration of glucocorticosteroids.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

After successful transplantation, the major histocom-patibility complex (MHC) antigens of kidney parenchymal cells are lost and no longer detectable in the graft, presumably due to administration of glucocorticosteroids. During rejection, the MHC antigens reappear in the graft parenchymal cells. The upregulation is possibly due to gamma-interferon released in situ by the allograft activated T (blast) cells. In this communication we demonstrate that cytomegalovirus (CMV) infection is invariably associated with an upregulation of the antigen display in the graft. In 12 of 14 (86%) cases with proved CMV disease, the display of class II antigens was associated with a cytological and/or clinical episode of rejection. In 223 transplant recipients without proved CMV disease transplanted during the same period, the frequency of late rejections was 17% (P<0.001). The results suggest that the display of class II antigens on the graft, mediated presumably by gamma-interferon as a consequence of CMV infection, is the reason for graft rejection in context of CMV disease.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

Adult, male Sprague-Dawely rats were given 50 mg/kg cyclosporine (CsA), cyclosporine G (nor-valine2-cy-closporine [CsG]), or drug vehicle by orogastric intubation every 24 hr for 14 days. Both drugs profoundly suppressed humoral immune responses. Similar trough whole-blood cyclosporine levels were recorded in each group at days 7 and 14. In CsA-treated animals, significant lymphopenia was evident on day 14, together with monocytosis and neutrophilia. Only the monocytosis was seen in the CsG group.CsA and CsG both caused significant impairment of renal function by day 7, although at this time the effect was less marked with CsG. In both drug-treated groups, there was evidence of further deterioration in glomerular filtration rate (GFR) by day 14. A significant rise in enzymuria was also recorded in each group. Typical cyclosporine-induced proximal straight tubular cell vacuolation was evident in four of the eight rats given CsG and in three of seven CsA-treated animals. Liver function was also significantly impaired in both CsA and CsG groups.These data show that, at the selected dose, CsG shares the nephrotoxic and hepatotoxic properties of CsA. The extent to which these effects of CsG are dose-related and the true clinical potential of this cyclosporine analogue have yet to be evaluated.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

In 83 renal transplant recipients, serum β2microglobulin (β2m) levels were significantly elevated during pretransplant uremia, rejection, cyclosorine-induced nephrotoxicity, and infections. In patients with normal serum creatinine, 74% had elevated serum β2m levels. None of the cyclosorine-treated patients had normal levels of β2m. Patients with stable renal allograft function receiving cyclosporine showed significantly higher serum β2m (P<0.001) and serum creatinine (P<0.01) levels than azathioprine treated patients. Patients with an irreversible rejection showed significantly higher serum concentrations of β2m than patients experiencing a reversible rejection (P<0.001). During cytomegalovirus (CMV) infection the serum β2m levels were elevated compared with other infections (P<0.001), while the serum creatinine was not. However, infected patients had higher serum levels of β2m and creatinine than patients with stable renal allograft function (P<0.001). Serum β2m may thereofore be useful in the early diagnosis of CMV infection. To conclude, serum β2m levels cannot distinguish between rejection, cyclosporine nephrotoxicity, or infection.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

There is much controversy as to whether the analysis of cyclosporine (CsA) should be performed by radioim-munoassay (RIA) or high-performance liquid chromatography (HPLC), and whether the specimen should be serum or whole blood. Whole-blood specimens present specific advantages, but the presence of hemoglobin (Hgb) and other endogenous compounds can produce major errors in the RIA by “quenching” the analytical signal or by interfering with the antigen-antibody binding in the assay. We have developed a simple pretreatment step to remove the Hgb and other proteins responsible for this error. Red cells in whole blood are hemolyzed with a mixture of acetonitrile and water, the protein precipitated with acetonitrile, and the supernatant assayed by RIA. In a controlled study in which CsA concentration was kept constant and the Hgb concentration varied, the errors in measurement were directly proportional (r=0.999) to the Hgb concentration. CsA values were spuriously deflated or inflated by 22.7 μg/L for each gram per 100 milliliters that the Hgb deviated from the 9.2g/100 ml Hgb in the CsA calibration standards. In a similar study in which patient samples (n=57) were assayed with and without pretreatment, the fractional error induced by Hgb was compounded in some patients by additional interferences that also appear to be removed by sample pretreatment. Without the pretreatment, CsA values could be in error by 33% when the Hgb varied 4 g/100 ml, thus providing potentially misleading results to the clinician. An I-125-labeled CsA tracer (purported not to be affected by the “quenching” interference of Hgb) produced consistantly higher results when it was substituted for the tritiated CsA tracer contained in the Sandoz kit. In summary, sample pretreatment appears to be the simplest method of effectively removing endogenous interferences and minimizing erroneous results from whole blood submitted to the Sandoz RIA for CsA analysis.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

Influenza vaccination has been strongly recommended for immunosuppressed renal transplant recipients. However, immunosuppression may lead to imparied antibody responses. We studied the antibody response to an inactivated trivalent influenza vaccine in 59 renal transplnat recipients with life-sustaining kidney function: 21 were on cyclosporine and prednisone, 38 on azathioprine and prednisone. Healthy volunteers (n=29) and patients on hemodialysis (n=28) served as controls. Despite comparable renal allograft function, cyclosporine-treated patients had a significantly lower immune response against influenza A viruses than azathioprinetreated patients, whether mean antibody levels, fourfold titer rise, or seroconversion to protective titers was analyzed. No significant differences in antibody responses were found between healthy controls and patients on azathioprine. The patients on hemodialysis showed an impaired response to vaccination. However, in contrast to the cyclosporine-treated patients, booster immunization proved valuable in this group.

ISSN:0041-1337    

出版商:OVID    

年代:1986

数据来源: OVID