摘要:

Adhesion to the vascular endothelium precedes or is a necessary prelude to leukocyte migration into the underlying tissue. Constitutive lymphocyte trafficking through lymphoid organs is controlled by tissue-specific interactions between molecules expressed on the surface of the lymphocyte (homing receptors) and ligands (vascular addressins) expressed on endothelial cells (HEV) within lymphoid tissues. Preliminary evidence suggests that lymphocytes may employ related but distinct interactions in their entry into some chronic sites of inflammation. Other leukocytes, such as neutrophils and monocytes, express molecules related or identical to lymphocyte homing receptors, and these molecules are exquisitely regulated by chemotactic factors and appear to be involved in the homing of these cells to inflamed tissues. In addition, inflammation in vivo induces increased endothelial cell adhesiveness for leukocytes that undoubtedly plays a key role in regulating leukocyte extravasation. Tissue- and inflammation-specific leukocyte/endothelial cell adhesion molecules constitute attractive targets for suppression or manipulation of the early stages of tissue inflammation.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The phenotype and function of T lymphocyte cell lines established in vitro from kidney biopsies at the time of acute cellular rejection were studied using a nonhuman primate renal allograft model. Our objectives were to investigate the function and surface phenotype of cells that infiltrate renal allografts in animals that were untreated, that were given subtherapeutic cyclosporin, or that developed rejection after treatment with monoclonal antibodies to IL-2R B chain (CD25), immune cell adhesion molecule-1 (ICAM-1), or CD8.Lines from allograft biopsies and peripheral blood were expanded in vitro using solely human recombinant IL-2 and analyzed after 6–20 days in culture. We found that the large majority of cells cultured from cynomolgus allografts at the time of acute rejection or, when possible, assayed directly without culture, were CD3+4−8+T lymphoblasts that possessed donor-specific cytolytic function and an NK-line, cytotoxic activity. In contrast, it was rarely possible to establish T cell lines exhibiting donor-specific cytotoxic activity from the blood except in the absence of immunosuppression or during CsA taper. A stable number of graft-derived CD4+8−cells was only observed in an unsuppressed animal 2 days after transplantation in the absence of manifest signs of rejection.Taken together, the above data indicate that similar T lymphocyte populations associated with allograft rejection are present in acutely rejecting allografts after the various types of immunosuppressive therapy. Since the infiltrating cells were similar to those obtained prior to therapy, recurrent rejection most likely represents cells that have escaped elimination. The T cells derived from monkey grafts differ from those from human renal allografts by the decreased frequency of CD4+cells. Whether this difference is species-related or therapy-related is not known.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

We investigated the effect of donor pretreatment with chlorpromazine (CPZ), in rabbit livers cold-stored in University of Wisconsin (UW) cold storage solution for 48 hr. Three groups of livers were investigated: livers flushed with Perfadex and immediately thereafter re-perfused on an isolated circuit (controls), and livers cold stored in UW solution for 48 hr, with or without donor pretreatment with CPZ, 3 mg/kg. After preservation, reperfusion was performed in vitro, using an isolated circuit (IPL). The reperfusion medium consisted of an oxygenated Krebs-Henseleit bicarbonate solution supplemented with 5 mM glucose, 50 mg/L of streptomycin and penicillin G, and 3.5% Dextran 60 for oncotic support. Livers that were not pretreated with CPZ produced 5.3±1.2 ml bile/100 g (mean ± SD) during 2 hr of IPL reperfusion. CPZ donor pretreatment significantly improved the bile flow to 17.1±6.9 ml (P<0.01, Wilcoxon). This figure was not different from that in control livers without a storage period (18.3±3.8 ml). Alanine aspartate aminotransferase (ASAT) released into the perfusate was measured, and levels were increasing during 2 hr of reperfusion. ASAT values were moderately increased in the preserved groups compared with controls (P<0.01), with no discernible differences between livers with and without CPZ pretreatment. It is concluded that CPZ pretreatment of the donor improves preservation quality, as evidenced by improved bile formation. The present results suggest that 48 hr cold storage in UW solution may be safe for clinical preservation, if donors are pretreated with chlorpromazine.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Storage of rabbit kidneys at 0°C for periods of 72 hr after flushing with hypertonic citrate solution, or 24 hr when flushed with isotonic saline, resulted in significant increases in Schiff base and thiobarbituric acid-reactive markers of lipid peroxidation in vitro. The extent of lipid peroxidation was not significantly altered by addition of verapamil (100 μM), a Ca++channel blocking agent, or calcium 1 mM (CaCl2) to the HCA storage solution. In contrast, verapamil significantly reduced the extent of lipid peroxidation in kidneys stored in saline solution, and a significant increase in oxidative damage occurred when CaCl2was added to this storage solution. Thus the extent of lipid peroxidation in kidneys stored in saline was significantly mediated by extracellular Ca++, whereas in HCA this was probably chelated by the large excess of citrate (55 mM) in this medium that prevented, or at least slowed, its entry into the renal cells. Lipid peroxidation was however significantly increased in kidneys stored in both HCA and saline solutions by addition of the calcium ionophore A23187 (10 μM) or the polysaccharide dye ruthenium red (5 μM) that inhibits mitochondrial uptake of Ca++. This strongly suggested that altered intracellular Ca++homeostasis during the storage period played an important role in the development of oxidative damage to kidneys stored in both these media.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The role of humoral immunity in graft rejection in the rat model remains controversial. Passive transfer of cytotoxic alloantibody (CAA) has resulted either in hyperacute rejection or in graft enhancement. This study examines the effect of transfer of CAA on cardiac allograft survival in three rat strain combinations that are fully mismatched at the major histocompatibility (MHC) loci. Strain-specific immune responsiveness in donorrecipient pairs varied from low (Lewis-to-ACI) to high (ACI-to-Lewis) as measured by mixed lymphocyte reactions. CAA was obtained from rats sensitized by three successive skin grafts at weekly intervals. Group 1 (high responder recipients), which consisted of Lewis rats presensitized to ACI and had a lymphocytotoxicity titer of 1:512 to 1:2048, rejected ACI cardiac allografts in 10.8±7.2 hr compared with 6.5±0.5 days in naive controls (P<0.001). Injection of 1 ml of high-titer CAA into naive Lewis rats immediately after ACI cardiac grafting led to hyperacute rejection of ACI hearts in 2.1±0.8 hr while 1 ml of CAA followed by 2 ml of guinea pig complement (GPC) resulted in even faster rejection (mean survival time (MST) of 23.8±4.7 min). Injection of 2 ml GPC alone or in combination with 1 ml naive Lewis serum had no effect on graft survival. Multiple pretransplant injections of 1 ml of CAA on days —3, —2, —1, and 0 relative to transplantation resulted in significant prolongation of allograft survival (MST of 10.3± 0.3 days;P<0.01). In group 2 (intermediate responder recipients), where Lewis rats were presensitized to WF

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The cardiovascular effects of i.v. infusion of cyclosporine were studied in pentobarbital-anesthetized rabbits. In doses ranging from 0.5 to 120 mg/kg/hr, CsA induced significant, sustained, dose-dependent hypotension. At the 60 mg/kg/hr dose the average drop in diastolic blood pressure was 27 mmHg (n = 9). Possible mechanisms were investigated by comparison of heart rate and blood pressure responses to physiologic manipulation, metabolic inhibition, or receptor antagonism before and after infusion of CsA. CsA did not modify responses to vagal stimulation, decreases in heart rate and blood pressure,P< 0.001 andP< 0.002, respectively. However, the cardiovascular reflex response during recovery was significantly attenuated after CsA infusion,P< 0.05, n = 7. Response to bilateral carotid occlusion after CsA was decreased by 17 mmHg (n = 8,P< 0.01). There were no significant differences between CsA alone and CsA plus glycopyrrolate or CsA plus aspirin. In this cyclosporine-induced hypotensive rabbit model, the hypotensive response appears to be related to a decrease in the endogenous sympathetic adrenergic activity, not to alterations in cholinergic tone, ganglionic transmission, or vasodilatory prostaglandin metabolism.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The effect of pretreatment with cyclosporine on normothermic liver ischemia was studied in rats. The rats were divided into two groups. In group I, the animals were subjected to 60 min of warm liver ischemia. In group II, CsA (10 mg/kg, p.o.) was given daily for 4 days before induction of liver ischemia. The survival rates, serum biochemical parameters, and extent of necrosis (% liver necrosis), mitotic activities, and histology of the livers were investigated from days 1 to 7 following the release of hepatic vascular occlusion. CsA pretreatment significantly improved the survival of the animals (75.8%) in comparison with the control (42.5%). The highest levels of serum transaminases in group II had a tendency to be lower than in group I. The extent of liver necrosis reached a maximum in both groups one day postsurgery when the transaminases rose highest; however, the peak value of percentage of liver necrosis was significantly ameliorated by CsA treatment (27.1%) as compared with the control (48.3%). Furthermore, mitosis of hepatocytes in the group treated with CsA was substantially increased at day 3. Histological alterations of the livers coincided with the changes in other parameters.Our results demonstrate that CsA is capable of protecting the liver from ischemic insult. The mechanisms by which CsA exerts its beneficial effect on normothermic liver ischemia are discussed.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

To determine the nature and sequence of the histologic changes in the early rejection of pancreaticoduodenal allografts and to assess the correlation between pancreaticoduodenal biopsy findings and the pathologic changes in the graft, we performed serial cystoscopically directed needle biopsies of pancreaticoduodenal allografts in 18 dogs and compared the findings with the histologic changes in 16 autografts as controls. Tissue adequate for evaluation was obtained by the biopsy technique in 70% of instances. The earliest and most characteristic manifestation of rejection was diffuse mixed inflammatory infiltrates involving the pancreatic acinar tissue and duodenum. The biopsy findings correlated well with the changes in the resected pancreatic specimens. Cellular rejection in the duodenum correlated with rejection in the pancreatic graft. There were no changes in the autografts that resembled cellular rejection. We conclude that, in the canine model, cystoscopically directed needle biopsy of pancreaticoduodenal allografts consistently provides adequate tissue for the diagnosis of rejection; the status of the graft can be monitored by serial biopsies of pancreatic acinar tissue and, possibly, by serial biopsies of the duodenal wall alone.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

We have studied organ allograft survival in rhesus monkeys conditioned with myeloablative total-body irradiation and T cell-depleted autologous bone marrow transplantation then given a heterotopic MHC-mismatched cardiac allograft in the immediate postmyeloablative period. This model has enabled us to investigate the role of T cells in vascularized organ allograft rejection. We previously reported (1) that recipients of marrow depleted of T cells below a critical threshold (0.16% residual marrow T cells, or 0.14×l05infused T cells/kg) experienced a period of freedom from acute rejection associated with a profound nonspecific immune deficiency (determined by skin grafting). Resolution of the nonspecific immune deficiency was associated with late graft rejection. In the present report, we correlate the results of peripheral immune reconstitution studies and direct immunohistochemical analysis with allograft status in order to study T cell subsets involved in late rejection. We report that, in contrast with CD8+/CD28−T cells, CD16+NK cells, and CD20+B cells, late allograft rejection was associated with the return of peripheral CD4+T cells and CD8+/CD28+T cells, suggesting a critical role for one or both of these subsets in late allograft rejection in this model.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Studies of postmyeloablative immune reconstitution have been reported for allogeneic bone marrow transplantation and also for non-T cell-depleted autologous/syngeneic BMT. However, there is a paucity of information regarding immune recovery following T cell-depleted autologous/syngeneic BMT. We have developed a primate transplantation tolerance model in which rhesus monkeys were conditioned with total-body irradiation and extensively T cell-depleted autologous BMT and given a major histocompatibility complex—mismatched heterotopic cardiac allograft. This model provided an opportunity to study peripheral immune recovery following T cell-depleted autologous BMT. Limiting dilution analysis was used to quantify marrow T cells following depletion (2.8% to 25.6% marrow T cells predepletion, 0.00014% to 0.036% residual marrow T cells postdepletion). We found that (1) hematopoietic engraftment was prompt despite extensive marrow T cell depletion, (2) reconstitution of CD4+helper T cells and CD8+cytotoxic T cells were substantially delayed (6–12 months) compared with the recovery of CD8+suppressor T cells, CD16+NK cells, and CD20+B cells, (3) distinction between CD8+cytotoxic T cells and CD8+suppressor T cells by the CD28 marker was critical in revealing the markedly discrepant recoveries of those subsets, and (4) immune reconstitution resembled that observed in recipients of T cell-depleted allogeneic and non-T cell-depleted autologous/syngeneic BMT, suggesting that the pattern of immune recovery following BMT is not substantially influenced by either allogeneic effects or the number of transferred T cells over a range of values.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID