摘要:

OKT3, a mouse anti-human CD3 mAb, is a potent immunosuppressive agent used in clinical transplantation to prevent or treat allograft rejection. Associated with this therapy is the systemic release of several cytokines that result in a series of adverse side effects. This release of cytokines is dependent on the cross-linking mediated by OKT3 between T cells and the FcγR-bearing cells. To generate an anti-human CD3 mAb with reduced activating properties as compared with OKT3, we have transferred the complementary determining regions of OKT3 onto human IgG frameworks and then performed point mutations that reduce the affinity of the “humanized” anti-CD3 mAbs for FcγRs. Initial, in vitro, studies showed that whereas OKT3 and the parental humanized anti-CD3 mAbs activated T cells similarly, a humanized Fc variant failed to do so. Both the Fc variant and the activating anti-CD3 mAbs induced comparable modulation of the TCR and suppression of cytolytic T cell activity, in vitro. In the current study, we exploited an experimental model in which human splenocytes from cadaveric organ donors were inoculated into severe combined immunodeficient mice (hu-SPL-SCID mice) to test the activating and immunosuppressive properties of these anti-human CD3 mAbs in vivo. Unlike injection of OKT3 or of the parental humanized mAb, administration of the Fc variant did not result in T cell activation in vivo, as evidenced by the lack of induction of surface markers of activation, and of systemic human cytokines, including IL-2. Importantly, similar prolongation of human allograft survival was achieved with all anti-CD3 mAbs, indicating that the nonactivating anti-CD3 mAbs retained significant immunosuppressive properties in vivo. Thus, the use of an Fc variant in clinical transplantation should result in fewer side effects than observed with OKT3, while maintaining its clinical efficacy.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

A mouse IgG1mAb (R73) directed against the rat α/β-TCR was documented not only to prolong the survival of allografts across major RT1 plus non-RT1 antigenic disparities, but also to display a synergistic immuno-suppressive interaction with CsA. Heterotopic cardiac transplants from Buffalo (RT1b) rats survived significantly longer in Wistar-Furth (RT1u) hosts treated immediately after the operation with 0.25 mg/kg R73 i.v., with a mean survival time of 11.0\pm5.5 versus 6.8\pm1.2 days in the untreated group (PPPP2+-dependent pathways triggered after activation of TCR, the target of R73, warrants clinical investigation in order to assess the potential impact of anti-α/β-TCR mAb on CsA-based immunosuppressive regimens.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Colon transplantation has been proposed as a method to improve the function of an intestinal allograft. The present study examined the risk of colon rejection and the effect of FK506 on colon rejection in BN LEW rats with orthotopic bowel transplants. The first 4 groups included rats with untreated allografts (group 1), rats with isografts treated with 0.6 mg/kg FK506 (group 2), rats with allografts treated with 0.6 mg/kg FK506 (group 3), and rats with allografts treated with 0.4 mg/kg FK506 (group 4). In each of these groups (10–12 rats), half of the animals received a small bowel graft only (SB), while the other half received a small bowel, ascending colon, and cecum graft (SBC). The animals were followed daily until they died or were killed at 4 weeks. In group 5, an additional 18 untreated rats with SBC allografts were randomly killed on the third, fifth, seventh, and tenth postoperative days to study the sequential histopathologic and immunopathologic changes of colon rejection.There was no difference in survival, body weight, nutritional parameters, or bacterial contamination after SB and SBC transplantation. Intestinal transit was slower after SBC than SB transplantation

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Severe combined immunodeficient (SCID) mice have become a promising tool for the development of models of human immunologic process. We report the development of a reproducible technique for engrafting SCID mice with human PBL (hu-PBL-SCID). Our results show that a booster injection of anti-CD3 antibody stimulated human lymphocytes given 2 days after the initial injection of lymphocytes will improve the efficiency of chimera establishment to 86.7% (13 out of 15). There was also good correlation among detection of human Ig, human CD3+cells, and human DNA by polymerase chain reaction amplification in the circulation of hu-PBL-SCID mice.Questions remain concerning the immune function of the human lymphoid cells in the SCID mouse. In this study, we analyzed the ability of human T cells in SCID mice to reject human islet allografts transplanted under the kidney capsule. Human islet allograft function assessed by human C-peptide levels demonstrated failure of islet allografts within 21 days after transplantation in hu-PBL-SCID. In contrast, human islets grafted in unreconstituted SCID mice continued to function for greater than 60 days. Recovered human T cells from rejected islets of hu-PBL-SCID mice displayed specific cytolytic activity against HLA class I-matched islets, while the recovered cells from spleen of hu-PBL-SCID mice showed minimal specific cytotoxicity against islets. These results suggest that graft-infiltrating lymphocytes were activated by the engrafted islets within the hu-PBL-SCID, causing the eventual rejection of the human islet allograft. Thus, engraftment of the anti-CD3 antibody-primed human PBL results in a mouse-human chimera with a functionally competent human immune system that is capable of rejecting a human islet allograft.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The effect of CsA on hypoxia-reoxygenation injury was studied in perfused rat livers. CsA did not attenuate hypoxic injury, as assessed by the release of lactate dehydrogenase and mitochondrial aspartate aminotransferase. During reoxygenation, the release of lactate dehydrogenase was also not affected by CsA. However, the release of mitochondrial aspartate aminotransferase into the cytosol, which indicates mitochondrial injury, was significantly reduced by CsA.The effect of CsA on mitochondrial function during hypoxia-reoxygenation was also investigated. CsA administration increased both the respiratory control ratio and the adenine nucleotide content after reoxygenation in both isolated mitochondria and perfused livers. In addition, glucose production by perfused livers after reoxygenation was increased by CsA. We conclude that the beneficial effect of CsA on hypoxiareoxygenation injury may be partly due to protection of the mitochondria against reoxygenation injury.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

In this study, the ability of low molecular dextrans to prevent morphologically detectable acute tubular necrosis during cold storage was evaluated. Rat kidneys were flushed with a sodium phosphate buffer (pH 7.2) containing different concentrations of dextran 10 (m.w. of 10,000 or less) and stored at 0–2†C for up to 5 days (samples taken at 24-hr intervals). It was found that solutions containing 20% or more of dextran 10 provided significantly improved morphological preservation of kidney nephrons when compared with currently popular kidney cold storage preservation solutions (i.e. University of Wisconsin and Euro-Collins solutions). Adding smaller amounts (i.e., 15%) of dextran 10 to a cold storage solution already containing another effective osmotic agent (i.e., sucrose) also resulted in superior morphological preservation, indicating a beneficial additive effect of using more than one osmotic agent. Dextran 40 (m.w. 40,000) did not provide as good morphological preservation as did a similar concentration of dextran 10. It is concluded that the use of the proper kind and proper amount of low molecular weight dextrans in preservation solutions can significantly reduce the morphologically detectable acute tubular necrosis during cold storage.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The individual effects of verapamil and 2 antioxidants on perfused rat liver nucleoside triphosphate (NTP) recovery following cold storage in University of Wisconsin (UW) solution was assessed using31P nuclear magnetic resonance spectroscopy. The pharmacological agents were added to UW solution and were present only during organ storage. NTP recovery was significantly higher for the 24-hr UW + 40 μM verapamil group as compared with the 24-hr UW group. None of the other pharmacological agents caused a significant increase in NTP recovery. These findings suggest that addition of verapamil to UW organ preservation solution may result in better poststorage liver function.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Mouse mAbs directed against the α/β-TCR were tested in clinical phase II and in triple-blind, randomized phase III studies. A clinical phase II trial administered 50 mg of murine anti-human α/β-TCR mAb (BMA 031) intravenously on the day of, as well as 2 and 4 days after, cadaveric donor renal transplantation in combination with a CsA/prednisone regimen. None of 12 patients showed even moderately adverse side effects. A phase III, triple-blind randomized trial enrolled 24 patients in the BMA 031 group and 22 patients in a placebo control group. BMA 031 treatment significantly reduced the incidence of rejection events within the first 10 posttransplant days to 1 patient versus 9 episodes in the placebo group (PP=NS). After a minimum of 30 months follow-up, the actual allograft survival rate was 87% in the BMA-treated group compared with 68% in the control cohort.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Because of the almost universal recurrence of hepatitis B surface antigenemia (HBsAg) after liver transplantation, some centers have questioned whether these patients are appropriate allograft candidates. Since January 1984, 51 patients with hepatitis B (HBV) underwent OLT at our center. No therapy was given to prevent reinfection. Three patients underwent retransplantation. The indications for transplant included fulminant HBV (13 patients), chronic HBV (33 patients), and hepatocellular carcinoma (HCCA) in addition to HBV (5 patients). Incidental HCCA was found in 2 of the 33 patients thought to have only chronic HBV. Actuarial survival for the entire group was 57% at 1 year and 54% at 3 years.Of the 23 patients who died, only 4 deaths were attributable to recurrent HBV liver disease. Four patients survived less than 4 days due to primary graft nonfunction. Ten patients died in the first 3 months from sepsis. Although all patients who died beyond 30 days had recurrent HBsAg, only 4 deaths were attributable to recurrent HBV. The remaining 5 deaths were caused by portal vein thrombosis, bile leak, lymphoma, pancreatitis, and sepsis occurring at 15 months. Excluding the 4 patients who died from primary graft nonfunction, actuarial survival was 63% at 1 year and 60% at 3 years. Of the 28 survivors, 24 are HBsAg positive; however, only 5 have recurrent HBV

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Sixteen patients with acute and chronic liver disease undergoing OLT were studied regarding the role of the liver and the gut in complement activation. Also, the relation between complement activation and clinical manifestations during the liver transplantation reperfusion period was investigated. Blood samples for measurement of complement anaphylatoxin C3a (C3a), complement anaphylatoxin C5a (C5a), and terminal C5b-9 complement complex (TCC) were taken simultaneously from the central venous catheter and the radial arterial line before starting the operative procedure, 1 min before declamping, and 1–2 min, 5 min, 30 min and 6–12 hr after declamping. Simultaneous blood sampling from the radial arterial line, central venous catheter, portal vein, and hepatic vein was performed 1–2 min and 5 min after completed unclamping. Elevated plasma levels of C3a and TCC were found upon reperfusion, while C5a levels remained unchanged throughout the operation compared with the preoperative levels. The levels of C3a in the portal vein were higher compared with the levels in the simultaneously obtained samples from the radial artery. The results indicate complement cascade activation located to the gut during the reperfusion phase of OLT. Seventy-five percent of the patients studied suffered from the postreperfusion syndrome, indicated by profound hypotension upon reperfusion of the transplanted liver. There was a significant correlation between high concentration of C3a anaphylatoxin and development of profound hypotension.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID