ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

CD4+T cells are obvious targets for immunotherapy since they appear to be pivotal in rejection responses. Current interest in clinical transplantation is focused on the potential use of nondepleting anti-CD4 antibodies largely because depletion of CD4+T cells may lead to prolonged periods of nonspecific immunosuppression. We have examined the efficacy of two nondepleting antibodies, KT6 and YTS 177.9, in a mouse cardiac allograft model. KT6 causes abrupt and prolonged occupation of CD4 molecules in vivo, while YTS 177.9 results in rapid and almost complete modulation of CD4 from the cell surface. In identical perioperative two-dose protocols, equivalent doses of KT6 were more effective than YTS 177.9 (MST 58 days and 24 days, respectively). When the treatment protocols were redesigned to include one or two additional doses of antibody, given as CD4 molecules were either released from blockade (KT6) or re-expressed following modulation (YTS177.9), the YTS 177.9 protocol led only to a slight improvement in graft survival (MST 51 days), whereas the modified KT6 regimen gave indefinite survival in 100% of the recipients. These data clearly show that modulating anti-CD4 antibodies may be far less effective than antibodies that effect prolonged CD4 occupation, a significant observation especially in relation to the proposed clinical use of the antibody OKT4A, which appears to cause modulation rather than CD4 blockade.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Trophism between transplanted hepatocytes and pancreatic endocrine tissue has been demonstrated with both adult and late gestational fetal tissue. Since this effect has not been looked for with fetal tissue obtained early in pregnancy, we conducted a series of experiments transplanting human liver and pancreas, which was obtained early in the second trimester (15–20 weeks gestation), beneath the renal capsule of athymic mice. Fetal pancreatic explants increased in size after transplantation into nondiabetic mice, but their insulin content 11 weeks later was not different from that of grafts that included liver explants. Reversal of diabetes was achieved in 2 of 5 diabetic mice transplanted with pancreas alone, but none of the mice that received pancreas and liver became normoglycemic. Histological examination of grafted liver explants, which consist of hepatocytes and hematopoietic cells, showed that hepatocytes survived for only two weeks regardless of the presence of pancreatic explants. Bile ducts differentiated by this time in both groups and were still present at 7 weeks. In conclusion, there was no trophic effect observed between transplanted fetal human liver and pancreatic endocrine tissue obtained early in pregnancy; bile duct differentiation is a feature of fetal human liver xenografted into the athymic mouse.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Liver allografts in pigs and in rats elicit a substantial cellular immune response that can resolve spontaneously with the induction of donor-specific systemic tolerance. Self-limiting interactions between host and donor (graft)-derived leukocytes may be the basis for tolerogenesis. We have attempted to reproduce this effect of liver grafting in pigs by peroperative infusion of donor leukocytes into kidney graft recipients given an interrupted short course of CsA designed to promote donor leukocyte survival and interaction with host cells. This protocol can secure long-term kidney graft survival resistant to challenge by donor skin grafting. Donor skin is, however, rejected, but more slowly than third-party skin, indicating a degree of systemic specific unresponsiveness in these long-term kidney graft recipients.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Since IL-10 was recently shown to inhibit several T cell functions in vitro, we investigated the effects of IL-10 on the cytokine release syndrome induced in mice by the 145–2C11 anti-CD3 mAb. As OKT3 in man, this mAb induces a massive polyclonal T cell activation before to induce immunosuppression. First, we found that administration of 1000 U of recombinant mouse IL-10 (mIL-10) 30 min before injection of 10 μg of the 145–2C11 antimouse CD3 mAb markedly reduced the systemic release of IFN-γ and TNF. In contrast, IL-10 pretreatment did not significantly modify the release of IL-6. To determine the effect of IL-10 pretreatment on the endogenous secretion of IL-10 induced by the 145–2C11 mAb, mice were injected with human IL-10 (hIL-10) which does not cross-react in the ELISA for mIL-10 determination. While hIL-10 was as efficient as mIL-10 in reducing TNF and IFN-γ release, it did not modify peak serum levels of IL-10. The modulation of cytokine production by mIL-10 was associated with a significant reduction of the toxicity of the 145–2C11 mAb, as assessed by the attenuation of hypothermia and by the reduced lethality in D-galac-tosamine-sensitized mice. We conclude that IL-10 differentially regulates the in vivo production of cytokines and decreases the systemic toxicity induced by the 145–2C11 mAb. These observations suggest potential therapeutic applications of IL-10 in organ transplantation, especially in association with anti-CD3 mAb.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The inflammatory response to trauma induces release of platelet activating factor (PAF), which promotes leukocyte adherence to the vascular endothelium. Ischemia and reperfusion induces inflammatory reactions that play a role in reperfusion injury, and here we investigate the role of both PAF and of leukocytes in damage to reperfused rat liver. The experimental procedure consisted of the temporary interruption of blood flow to the left lateral and medial lobes of the rat liver in vivo, and subsequent reperfusion after defined periods. Rats were pretreated either with the PAF-antagonist WEB-2170 or with vinblastine to induce leukopenia, and compared with controls. The postischemic liver blood flow and liver oxyhemoglobin saturation were recorded using an He-Ne Laser doppler flowmeter and photometer. Reperfusion after 30 and 45 min of ischemia was associated with partial recovery to normal values and was inversely proportional to the duration of ischemia. In the WEB-2170-treated group, liver flow and hemoglobin saturation upon reperfusion did not show significant differences when compared with the untreated control groups, suggesting that inhibition of PAF activity did not protect against the microcirculatory disturbance induced by ischemia and reperfusion in the liver. In contrast, rats made leukopenic by treatment with vinblastine showed significantly better recovery of blood flow and hemoglobin saturation than the control group after 45 min of ischemia. Thus, we found that although PAF alone did not appear to have a pivotal role in the cascade of reperfusion injury, the effect of leukocytes is critical.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

There is at present no noninvasive method that reliably measures blood flow in the poorly functioning renal allograft. The present study was designed to evaluate phase-contrast cine magnetic resonance imaging (PC-cine-MRI) for this purpose. We recruited for study 18 patients who had received kidney transplants 13–66 months earlier from closely related living donors. As judged by the glomerular filtration rate, which was elevated for a single kidney (76±4 ml/min/ 1.73 m2), allograft function was excellent, permitting the assumption of unimpaired renal extraction of paminohippuric acid (PAH). Allograft blood flow was determined consecutively on the same day, first by the standard PAH clearance technique and they by the product of the velocity of protons and renal vein cross-sectional area using PC-cine-MRI. MRI determinations could not be completed because of claustrophobia in two patients and failure to image the terminus of the allograft vein in another two. Comparison of blood flow in the remaining 14 subjects revealed the two techniques to be strongly related (r=0.91, P<0.001). On the average, the renal blood flow rate was similar by each method; 732 ± 62 by PAH clearance and 703 ±69 ml/min by PC-cine-MRI, but the agreement among individuals between the two methods was only modest, with a 95% confidence interval of agreement from −214 to +254 ml/min. We conclude that PC-cine-MRI provides a fairly accurate and noninvasive method for determining the rate of blood flow in the transplanted kidney. With further refinement it should permit the role of depressed blood flow in a variety of acute and chronic forms of human allograft dysfunction to be elucidated in humans for the first time.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The hyperfiltration hypothesis postulates that kidneys with reduced renal mass will progress toward failure due to hypertrophy of the remaining nephron to meet the excess load, eventually leading to nephron exhaustion. Five conditions in which hyperfiltration might be suspected were studied in human kidney transplantation: (1) small kidneys from donors aged 4 to 6; (2) transplants into large recipients (over 100 kg); (3) grafts from females to males compared with males to females; (4) kidneys that experience rejection episodes; and (5) cadaveric grafts compared with living-unrelated donor grafts. In all 5 instances, the requirement for dialysis and discharge serum creatinine level were both high—and, correspondingly, the 1− and 3-year graft survival rates were lower than the controls. The discharge SCr was the best indicator of 1–3-year graft survival and may serve to measure the “fit” of the kidney to the recipient—for even in patients requiring no dialysis graft survival was related to the discharge SCr levels. One consequence of this hypothesis is that many late graft losses currently attributed to rejections may, in fact, be hyperfiltration failures. As evidence, a progressively higher incidence of reported late rejections was noted even in patients who had been rejection-free at the time of discharge if they had higher discharge SCr values. We conclude that the 5 conditions under which hyperfiltration damage might be suspected had increased failure rates. Such failures are almost never reported as “due to hyperfiltration” and are probably recorded as rejections.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

This prospective study investigated the urodynamics of the urinary bladder prior to renal transplantation in 57 patients and related this to graft function and transplantation outcome. The study demonstrated a clear deterioration in the pretransplant urodynamic characteristics in all subgroups, with male patients in the hemodialysis group (HD) showing a more substantial decline: 1st sensation volume (ml) in male HD patients = 112 (120) vs. 171 (173) in male CAPD patients, P<0.05; and corresponding average flow rate for same groups 3 (3) ml/sec vs. 5 (5) ml/sec, P<0.05. Figures are median (interquartile range). We have identified a subgroup of patients with a small bladder capacity (less than 100 ml) who have a reduced graft survival (55% vs. 92% for bladders larger than 100 ml at 2 years) apparently unrelated to immunological processes.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Fluorescent in situ hybridization (FISH) is a reliable, rapid, sensitive, and quantitative method for detection of residual host cells following sex-mismatched bone marrow transplantation. Recently, donor-derived long-term multilineage hematopoiesis was detected in a sex-mismatched liver transplant recipient. We therefore assessed chimeric status in 12 patients (F 9, M 3), mean age 42.5 years (range 16–57), for a median period of 18 months (range 7–32) following sex-mismatched liver transplantation. Peripheral blood he-matolymphoid cells were hybridized with Y- or X-chro-mosome fluorescently labeled specific probes, and the donor-typed hematopoietic cells were enumerated. In two F recipients 4–5% male hematolymphoid cells were detected in the peripheral blood at 15 and 22 months after sex-mismatched liver transplantation, respectively. These two patients with systemic chimerism suffered from primary biliary cirrhosis and fulminant Wilson's disease before transplantation. One of them had evidence of graft rejection only once during the posttransplant course and the other had no episode of graft rejection. Two other female patients who were found to have ∼2% male hematolymphoid cells, which is considered to be in the false-positive range, also had no signs of graft rejection during the post-transplant follow-up period. Among the remaining eight patients, in whom systemic chimerism was un-detectable, there was at least one episode of acute cellular rejection during the posttransplant period. In summary, the FISH technique enables us to detect systemic chimerism following sex-mismatched liver allografts. Inasmuch as balanced systemic chimerism after organ transplantation is of major importance for self tolerance, our findings may enable us to treat patients after liver transplantation without the need for immunosuppression.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID