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N L Tilney

Publications and source records attributed to N L Tilney.

At least 55 records · Page 3Linked to original sources
PubMed1997

The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand.

Ischemia/reperfusion (I/R) injury associated with renal transplantation may influence both early graft function and late changes. The initial (</= 7 d) events of warm and in situ perfused cold ischemia of native kidneys in uninephrectomized rats were examined. mRNA expression of the early adhesion molecule, E-selectin, peaked within 6 h; PMNs infiltrated in parallel. T cells and macrophages entered the injured kidney by 2-5 d; the associated upregulation of MHC class II antigen expression suggested increased immunogenicity of the organ. Th1 products (IL-2, TNFalpha, IFNgamma) and macrophage-associated products (IL-1, IL-6, TGFbeta) remained highly expressed after 2 d. To examine directly the effects of selectins in I/R injury, a soluble P-selectin glycoprotein ligand (sPSGL) was used. Ischemic kidneys were perfused in situ with 5 microg of sPSGL in UW solution; 50 microg was administered intravenously 3 h after reperfusion. E-selectin mRNA remained at baseline, leukocytes did not infiltrate the injured organs throughout the 7-d period, and their associated products were markedly inhibited. Class II expression did not increase. No renal dysfunction secondary to I/R occurred. The early changes of I/R injury may be prevented by treatment with soluble P- and E-selectin ligand. This may reduce subsequent host inflammatory responses after transplantation.

Animals↗
PubMed1997

Sequential cellular and molecular kinetics in acutely rejecting renal allografts in rats.

The initial (0-24 hr), early (3-5 days), and late (7-14 days) events occurring in LBNF1 renal allografts transplanted into Lew recipients were examined to define precisely the sequential cellular and molecular kinetics during acute rejection. Grafts and spleens were harvested at 3, 6, 12, and 24 hr, and at 3, 5, 7, and 14 days and processed for morphology, immunohistology, and reverse transcriptase-polymerase chain reaction. Various factors (mRNA) were up-regulated sequentially in the allografts over time. In the initial phase, E-selectin and complement (C1 and C3) expression was noted within 6 hr, peaking by 24 hr. RANTES (regulated upon activation, normal T cell expressed and secreted) increased within 6 hr, and then again between 3 and 6 days. By immunohistology, MHC class II was up-regulated consistently after day 1. Intercellular adhesion molecule-1 expression increased after day 3; lymphocyte function-associated antigen-1+ infiltrating leukocytes peaked at day 5. Infiltrating CD8+ T lymphocytes increased strikingly between days 1 and 3, peaking at day 5; CD4+ cells infiltrated more slowly until day 5. The kinetics of ED1+ macrophages were similar to those of lymphocyte function-associated antigen-1+ cells. The CD4+ T cell-derived product, interleukin (IL)-2, peaked at 7 days. Interferon-gamma increased progressively up to 14 days. By 3 days, the macrophage-associated factor, transforming growth factor-beta, peaked; this was followed by increased IL-6 expression by day 5. IL-1, tumor necrosis factor-alpha, and inducible nitric oxide synthase increased slowly until day 7, declining thereafter. Endothelin increased progressively over the 14-day follow-up period. Cytokine dynamics occurring in host spleen were similar to those noted in the allografts. Although acute rejection is primarily T cell mediated, adhesion molecules, macrophages, and their associated products may influence initial and later changes. The brisk expression of complement, E-selectin, and RANTES within the first few hours after engraftment may occur secondary to ischemic injury and trigger subsequent immunological events. Macrophages and their products may play a larger role in the process than hitherto appreciated.

Animals↗
PubMed1997

Nephron mass modulates the hemodynamic, cellular, and molecular response of the rat renal allograft.

Functioning nephron mass has recently been implicated as a risk factor for development of chronic "rejection" of kidney allografts. Reductions in nephron number below 50% may induce glomerular hypertension and hyperfiltration in surviving units, which in turn lead to graft injury. In the present study, which extends and amplifies our previous investigations, cellular and molecular characteristics of single allografts from F344 donors in bilaterally nephrectomized LEW recipients, our standard experimental model of chronic renal allograft dysfunction, were compared with allografts from recipients where total renal mass was reduced (by ligating branches of the graft renal artery) or restored to normal levels by transplanting or retaining a second kidney. Our findings in this study confirm that progressive proteinuria and structural injury in recipients of single allografts were accentuated in grafts with reduced mass but virtually absent in rats with increased kidney mass. A striking observation was that patterns of cell surface molecule expression, cellular infiltration, and expression of all T cell- and macrophage-associated products studied were all markedly modulated by changes in renal mass. Moreover, several molecules that are up-regulated before evidence of graft injury are down-regulated by providing increased renal mass. These data show that the quantity of functioning renal mass is not only an important independent determinant of the tempo and intensity of chronic renal allograft failure, but also a potent modulator of fundamental cellular and molecular components of a complex process. This phenomenon involves antigen-dependent and antigen-independent elements that ultimately result in chronic allograft failure.

Animals↗
PubMed1997

CD28-b7 blockade in organ dysfunction secondary to cold ischemia/reperfusion injury.

Ischemic injury to cadaver organs is a major risk factor for development of chronic organ dysfunction. We have recently shown that the B7 costimulatory pathway plays a critical role in early organ dysfunction developing after renal cold ischemia/reperfusion injury. We extended these observations to investigate the role of this pathway in the development and progression of chronic organ dysfunction following such injury. Uninephrectomized rats which underwent cold ischemia/reperfusion injury developed progressive proteinuria as compared to uninephrectomized controls. Animals treated with CTLA4Ig, which blocks B7 costimulation, starting on the day of injury had significantly better long-term survival and developed significantly less proteinuria than control animals treated with control Ig. RT-PCR analysis of kidney tissue showed significant reduction in expression of activation and inflammatory cytokines, chemoattractants, and growth factors, as compared to controls. Delaying administration of CTLA4Ig for one week, but not four weeks, after injury was still effective in ameliorating development of progressive proteinuria. Interestingly, selective blockade of B7-1 by a mutant form of CTLA4Ig had no effect on early or chronic organ dysfunction. These findings indicate the long-term functional and molecular consequences of experimental cold ischemia/reperfusion injury, and suggest that B7-2 is critical in the development of organ dysfunction following ischemic injury, even in the absence of alloantigen.

Abatacept↗
PubMed1997

Chronic allograft failure: the clinical problem.

Long-term survival statistics for organ allografts have not improved substantially over time, despite improved immunosuppression and organ preservation and better surgical and perioperative management. Chronic rejection is the most important long-term limitation in allografts and increasingly seems to be caused by a multifactorial series of antigen-dependent and antigen-independent factors. Early injury is critical to late events, whether antigen driven (early acute rejection episodes and human leukocyte antigen mismatching) or antigen independent (ischemia/reperfusion injury and brain death). Ongoing alloimmunologic injury to the host and inadequate organ mass functioning (donor age, gender, race, and organ size) also seem to be important to this persisting process. Associated recipient conditions, which includes hypertension and hyperlipidemia, and postoperative complications, which include drug nephrotoxicity and infections, may affect this late-phase graft loss. These deleterious risk factors for chronic rejection of long-functioning allografts are an important subject for future investigation.

Graft Rejection↗
PubMed1997

Candesartan cilexetil reduces chronic renal allograft injury in Fisher-->Lewis rats.

OBJECTIVES: To determine the effects of the angiotensin II receptor antagonist, candesartan cilexetil, on glomerular and systemic blood pressures and the development of renal injury in Lewis rat recipients of a single Fisher kidney (F334--> LEW transplantation), an established rat model of chronic renal allograft failure. DESIGN: Recent studies have shown that chronic injury of renal allografts in F334-->LEW rats may be virtually abrogated by supplying the Lewis recipients with two Fisher kidneys or, alternatively, by retaining a native kidney. These findings imply a major contribution from processes associated with nephron loss to the pathogenesis of chronic renal allograft failure, a notion supported by the observation that transplanting two kidneys also normalizes glomerular capillary pressure (PGC) in F344-->LEW rats. Thus, a pharmacological reduction in PGC, by blocking the effects of angiotensin II, should also lessen renal injury in F344-->LEW rats. MATERIALS AND METHODS: Bilaterally nephrectomized F344--> LEW rats were treated with the angiotensin II receptor blocker candesartan cilexetil (TCV-116) at 40 mg/l or with vehicle, administered in drinking water. Proteinuria and systolic blood pressure were assessed monthly, and histological studies were carried out after 24 weeks. The glomerular filtration rate and glomerular pressures were determined after 10 weeks in additional rats by clearance and micropuncture studies. RESULTS: Treatment with candesartan cilexetil lowered systemic blood pressure, normalized PGC at 10 weeks and greatly reduced proteinuria and allograft glomerulosclerosis at 24 weeks. CONCLUSIONS: These data indicate that the development of renal injury in F344-->LEW renal allografts can be prevented by the pharmacological blockade of angiotensin II receptors using candesartan cilexetil. This suggests that angiotensin-dependent processes contribute significantly to chronic injury in this model of late renal allograft failure.

Angiotensin Receptor Antagonists↗
PubMed1997

Colonic perforations after renal transplantation.

BACKGROUND: Perforation of the colon is a rare but serious complication in renal transplantation; allograft recipients constitute a patient population uniquely at risk with end-stage renal failure, maintenance therapy with dialysis before transplantation, and then chronic immunosuppression thereafter. STUDY DESIGN: In 1,401 consecutive transplants performed between 1951 and 1995 at the Brigham and Women's Hospital, 30 recipients (2.1 percent) experienced 34 episodes of colonic perforations, 13 of which (38 percent) were fatal. The medical records and clinic charts of each person were analyzed for variables between those who survived and those who died of the colon perforation. RESULTS: Significant differences in patient demography and clinical and laboratory findings including age, mean corticosteroid dose, and nutritional status were noted between the two groups. Early diagnosis and intervention improved the prognosis; 22 percent of those operated on within 24 hours died; 47 percent died after delayed intervention. Excision of the lesion with end-to-end anastomosis was effective in most right colon perforations, and removal of the lesion and formation of an end-colostomy and Hartmann pouch was preferred in rectosigmoid perforations. The incidence and outcome of posttransplant colonic perforations were associated with the intensity of immunosuppression, with 28 percent of perforations occurring within the first month after engraftment and 47 percent within the first 3 months; the mean daily dose of corticosteroids was three times higher in those who died compared with those who survived. The levels of serum albumin were significantly lower among nonsurvivors. CONCLUSIONS: Colon perforation is a catastrophic event in immunosuppressed renal transplant recipients. Prompt diagnosis and treatment are critical; because of the masking effects of corticosteroids on symptoms and signs, a high index of suspicion and urgent investigation are indicated. Prompt surgical intervention and attention to the nutritional status are essential for survival.

Adult↗
PubMed1996

Sequential cytokine expression in renal allografts in rats immunosuppressed with maintenance cyclosporine or mycophenolate mofetil.

Although the immunosuppressive agents used clinically modulate acute rejection of organ allografts, their ability to prevent chronic rejection has been less clear. To ascertain the effects of prolonged maintenance treatment with cyclosporine (CsA) and mycophenolate mofetil, we examined sequential patterns of cytokine regulation by reverse transcriptase polymerase chain reaction in long-surviving renal allografts in treated recipients. In renal allografts in animals on long-term CsA therapy, there is important up-regulation of transforming growth factor-beta, Hsp70, and endothelin as compared with control animals. Conversely, interleukin-2 receptor, interferon-gamma, and tumor necrosis factor-alpha in kidney grafts in this group were expressed at lower levels compared with those noted in chronically rejecting grafts in control animals that had received only CsA for 10 days after transplantation. Morphologically, the long-term CsA-treated kidneys had more extensive arterial obliterative changes and glomerulosclerosis after 24 weeks than control organs; these changes can presumably be attributed to the nephrotoxic effects of this drug combined with the progressive changes of chronic rejection. In contrast, mycophenolate mofetil inhibited the production of all lymphocyte and macrophage-derived cytokines throughout the entire follow-up period. Allograft kidneys in these latter recipients showed no late morphological abnormalities. This agent may be important clinically in preventing chronic rejection.

Animals↗
PubMed1996

Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection.

Blocking CD28-B7 T-cell costimulation by systemic administration of CTLA4Ig, a fusion protein which binds B7 molecules on the surface of antigen-presenting cells, prevents rejection and induces tolerance in experimental acute allograft rejection models. We tested the effect of CTLA4Ig therapy on the process of chronic renal allograft rejection using an established experimental transplantation model. F344 kidneys were transplanted orthotopically into bilaterally nephrectomized LEW recipients. Control animals received low dose cyclosporine for 10 days posttransplantation. Administration of a single injection of CTLA4Ig on day 2 posttransplant alone or in addition to the low dose cyclosporine protocol resulted in improvement of long-term graft survival as compared with controls. More importantly, control recipients which received cyclosporine only developed progressive proteinuria by 8-12 weeks, and morphological evidence of chronic rejection by 16-24 weeks, including widespread transplant arteriosclerosis and focal and segmental glomerulosclerosis, while animals treated with CTLA4Ig alone or in addition to cyclosporine did not. Competitive reverse transcriptase-PCR and immunohistological analysis of allografts at 8, 16, and 24 weeks showed attenuation of lymphocyte and macrophage infiltration and activation in the CTLA4Ig-treated animals, as compared with cyclosporine-alone treated controls. These data confirm that early blockade of the CD28-B7 T-cell costimulatory pathway prevents later development and evolution of chronic renal allograft rejection. Our results indicate that T-cell recognition of alloantigen is a central event in initiating the process of chronic rejection, and that strategies targeted at blocking T-cell costimulation may prove to be a valuable clinical approach to preventing development of the process.

Abatacept↗
PubMed1996

Retransplantation reverses mononuclear infiltration but not myointimal proliferation in a rat model of chronic cardiac allograft rejection.

Episodes of acute rejection seem to play an important role in the development of chronic allograft failure. Whereas acute rejection appears to be fully reversible, at least at early stages, reversibility of chronic graft alterations is still unclear. Male Fisher F344 rat hearts were heterotopically transplanted into Lewis recipients (n=8/group). Minimal immunosuppression (rapamycin 0.5 mg/kg for 14 days) guaranteed allograft survival during the observation period (group 1). Allografted hearts were retransplanted into syngeneic recipients after 14 days (group 2) and 50 days (group 3) and compared with F344 isografts undergoing retransplantation after 4 days (group 4) and with F344 isografts without a second procedure (group 5). All organs were removed after 100 days and morphologically and immunohistologically assessed. Allografts of group 1 developed concentric myointimal proliferation with dense intramural and perivascular mononuclear infiltration and intravascular thrombosis in 59 +/- 7% of coronary arteries. Retransplantation into syngeneic recipients almost completely abolished mononuclear infiltration, but did not affect the development of myointimal proliferation (groups 2/3: 46 +/- 7%/31 +/- 24%, NS). Isograft retransplantation resulted in a similar incidence of coronary lotions (group 4: 37 +/- 9%, NS), whereas coronary arteries of isografts without a second transplant procedure (group 5) remained normal (0%, P<0.001). In conclusion, syngeneic retransplantation of allografts reverses mononuclear infiltration but not myointimal proliferation. The development of coronary lesions in retransplanted isografts underlines the participation of antigen-independent stimuli in the development of myointimal proliferation. These experiments further support the hypothesis of an interaction of antigen-dependent and antigen-independent factors for the development of coronary myointimal proliferation.

Animals↗
PubMed1996

Infection-associated cellular activation accelerates chronic renal allograft rejection in rats.

The etiology of chronic rejection is unknown, although acute rejection, viral infection, and initial graft ischemia have been implicated. To test the effects of infections on the process of chronic rejection, we simulated bacterial infection by the administration of the endotoxin lipopolysaccharide (LPS), a potent activator of various cell types in an established rat model of chronic rejection. Lewis recipients of Fisher 344 kidneys were treated with a single dose of LPS or vehicle 8 weeks following transplantation and grafts were examined at various time points. In the chronically rejecting controls, leukocytic infiltration and the expression of cytokines peaked at 16 weeks. In LPS-treated hosts, leukocyte infiltration and cytokine expression peaked at 12 weeks. By 16 weeks, glomeruli in LPS-treated recipients had become far more sclerotic than those in controls, mimicking the changes observed in controls at 24 weeks. We conclude that infections may play an important role in the development of chronic rejection.

Animals↗
PubMed1996

Augmenting kidney mass at transplantation abrogates chronic renal allograft injury in rats.

Conventional renal transplantation, which substitutes a single allograft for two native kidneys, imposes an imbalance between nephron supply and the metabolic and excretory demands of the recipient. This discrepancy, which stimulates hyperfunction and hypertrophy of viable allograft nephrons, may be intensified by nephron loss through ischemia-reperfusion injury or acute rejection episodes occurring soon after transplantation. In other settings where less than 50% of the total renal mass remains, progressive glomerular injury develops through mechanisms associated with compensatory nephron hyperfiltration and hypertrophy. To determine whether responses to nephron loss contribute to chronic injury in renal allografts, nephron supply was restored to near-normal levels by transplanting Lewis recipients with two Fisher 344 kidneys (group 2A) compared with the standard single allograft F344 --> LEW rat model of late renal allograft failure (group 1A). At 20 weeks, indices of injury were observed in 1A but not 2A rats. These indices included proteinuria (1A: 45 +/- 13; 2A: 4.0 +/- 0.29 mg/day) and glomerulosclerosis (1A: 23 +/- 4.9%, 2A: 0.7 +/- 0.3%) (p < .05). Double-allograft recipients maintained near normal renal structure and function, whereas 1A rats showed evidence of compensatory hyperfiltration (single-nephron glomerular filtration rate of 63 +/- 10 versus 44 +/- 2.0 nl/min in 2A rats) and hypertrophy (mean glomerular volume of 2.64 +/- 0.15 versus 1.52 +/- 0.05 microns3 x 10(6) in 2A rats) (p < .05). Thus, we conclude that a major component of late allograft injury is attributable to processes associated with inadequate transplanted renal mass, a finding that has major implications for kidney transplantation biology and policy.

Animals↗
PubMed1996

Infections and reduced functioning kidney mass induce chronic rejection in rat kidney allografts.

The etiology of chronic rejection of kidney allografts is unknown, although hyperfiltration, acute rejection, viral infection and initial graft ischemia have been implicated. To test whether endothelial activation may be the link between these factors and chronic rejection, the endotoxin (lipopolysaccharide-LPS), a potent activator of endothelial cells, was evaluated in an established chronic rejection model. Bilaterally nephrectomized Lewis recipients of orthotopically transplanted Fisher 344 kidneys were treated briefly with low dose cyclosporine (1.5 mg/kg/day x 10). Recipients were given a non-lethal dose of LPS (2 mg) i.p. at 8 weeks and compared to allografted controls treated with vehicle. Urine protein was measured every 4 weeks. Rats in the treated group were sacrificed at 12 and 16 weeks, control animals at 12, 16 and 24 weeks (20/group) and examined histologically. In the chronically rejecting control allografts, progressive interstitial and glomerular sclerosis and vascular intimal proliferation had become apparent by 12 weeks. Infiltration of glomeruli, particularly by macrophages (M phi), and the coincident presence of cytokines were prominent, peaking at 16 weeks. LPS treatment accelerated and intensified these changes; proteinuria was more pronounced (16 weeks: 79 mg/24 h vs. 49 mg/24 h, p < 0.05). Numbers of infiltrating M phi peaked at 12 weeks in LPS treated hosts (69 c/FV vs. 27 c/FV in untreated controls, p < 0.01), accompanied by an increased upregulation of MHC class II and cytokine expression, particularly TNF alpha and PDGF around arteries and areas of infiltration. BY 16 weeks, 35 +/- 3% of glomeruli in LPS treated recipients had become sclerotic vs. 15 +/- 6% (p < 0.05) in controls, again associated with increased expression of cytokines (PDGF, TNF alpha, TGF beta), adhesion molecules (ICAM-1) and extracellular matrix proteins. Overall, the extent of chronic rejection of grafts in LPS treated rats at 16 weeks was similar to that developing in non-treated rats at 24 weeks. Activation of graft endothelium and/or host leucocytes increased the pace of graft infiltration and the expression of cytokines and other molecules. These events accelerate the process of chronic rejection.

Analysis of Variance↗
PubMed1995

Prevention of functional, structural, and molecular changes of chronic rejection of rat renal allografts by a specific macrophage inhibitor.

Chronic rejection is the primary cause of long-term allograft loss. Macrophages and their products have been shown to be critical in the development of this process in an established kidney allograft rat model. A new synthetic agent, Gamma lactone, is a specific inhibitor of macrophages and monocytes that inhibits the generation of these populations in vitro and their activities in the effector phase of host alloresponsiveness. We tested its effects on the development of chronic changes in the model. Untreated control allograft recipients developed increasing proteinuria after 12 weeks; progressive glomerulosclerosis, interstitial fibrosis, and arterial obliteration developed thereafter. Infiltrating ED1+ macrophages as noted by immunohistology increased dramatically between 12 and 16 weeks, localizing preferentially in glomeruli and perivascular areas. The presence of these cells was associated with dense expression of their products. Reverse transcription polymerase chain reaction confirmed and expanded the immunohistological findings, showing significant gene expression of macrophage-derived mediators. In contrast, recipients treated with G-Lac daily for 32 weeks never developed proteinuria; macrophage infiltration was dramatically reduced, and expression of their products was virtually absent. At 32 weeks, most glomeruli and arteries remained histologically normal. In another group in which treatment was stopped at 24 weeks, however, proteinuria began to develop by 32 weeks; macrophages infiltrated the organs and expression of their products became manifest. These results confirm the importance of macrophages and macrophage-derived factors in chronic rejection and suggest that a specific inhibitor of macrophage activation may be useful in the prevention of the process over the long term.

Animals↗
PubMed1995

Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts.

We have examined the effects of rapamycin (RPM) on transplant vasculopathy in long-surviving F344 rat heart allografts transplanted heterotopically into Lewis recipients. RPM was administered intraperitoneally for the first 14 days in groups 1 and 2 (0.5 and 2 mg/kg/day), and daily throughout the follow-up period in groups 3 (0.5 mg/kg/day) and 4 (5 mg/kg for 14 days, followed by a maintenance dose of 2.5 mg/kg/day). Treatment with low dose cyclosporine (CsA; 1.5 mg/kg/day) in combination with RPM (0.5 mg/kg/day for 14 days) (group 5) and immunosuppression with CsA only (5 mg/kg for 14 days, followed by 1.5 mg/kg/day) (group 6) were also examined. F344 isograft recipients treated with RPM (0.5 mg/kg/day for 14 days) (group 7), those that were untreated (group 8), and hearts in naive F344 animals (group 9) served as controls. Grafts of group 1 were removed at 50, 75, 100, 150, and 200 days and infiltrating cell populations and surface molecules were compared with those of the other groups at 100 days. All allografts in treated hosts functioned > 100 days; in contrast, grafts in untreated recipients were rejected acutely by 8 +/- 1 days (MST +/- SD). The incidence of transplant vasculopathy in group 1 increased progressively (MST +/- SD = 10 +/- 2%, 59 +/- 7%, 85 +/- 15%, and 80 +/- 12% at 50, 100, 150, and 200 days, respectively), as manifested by myointimal proliferation with dense mononuclear infiltration (predominantly ED1+ macrophages). Numbers of MHC class II+ infiltrating cells were prominent, as was expression of adhesion molecules and cytokines. The incidence of graft disease and extent of cellular infiltration at 100 days was significantly lower in animals receiving increased maintenance doses of RPM (for groups 2, 3, and 4: 25 +/- 15%, 22 +/- 11%, and 10 +/- 3%, respectively; P < 0.005). CsA treatment either in combination with RPM or alone (groups 5 and 6) failed to improve transplant vasculopathy, but reduced mononuclear cell infiltration. Isografts (groups 7 and 8) and naive hearts (group 9) developed no structural abnormalities throughout the follow-up period, regardless of RPM treatment. We conclude that the extent of transplant vasculopathy can be reduced markedly in this rat cardiac transplant model with maintenance RPM. Addition of CsA modifies the morphological picture but does not improve myointimal proliferation.

Animals↗