Tumor necrosis factor production during human renal allograft rejection is associated with depression of plasma protein C and free protein S levels and decreased intragraft thrombomodulin expression.

Abstract

SummaryFibrin deposition is a common accompaniment of renal allograft rejection, indicating disruption of the normal physiologic balance between procoagulant and anticoagulant pathways. In vitro, tumor necrosis factor (TNF) induces endothelial expression of the procoagulant, tissue factor, and downregulation of thrombomodulin, a key component of the thrombomodulin/protein C (PC)/protein S (PS) pathway, which normally maintains an anticoagulant state by inactivating thrombin, preventing further thrombin formation by degrading factors Va and VIIIa, and decreasing plasminogen activator inhibitor activity. Raised levels of TNF were recently demonstrated within the blood of patients during episodes of renal allograft injection, and may be an early and discriminatory marker of rejection. This led us to investigate prospectively whether monitoring of serum TNF levels was of value dinically, and was associated with effects on circulating PC and PS levels, or alterations in intragraft thrombomodulin expression. Plasma samples (n = 454) were collected three times/week from all patients (n = 25) undergoing renal transplantation during a 9-month consecutive period, and assayed by ELISA and functional assays for TNF, PC, and free PS (FPS). Portions of renal biopsies, taken to evaluate episodes of acute deterioration of renal function, were evaluated by immunoperoxidase labding for the presence and distribution of TNF, thrombomodulin, PC, PS, thrombin, fibrin, and factors V and VIII. Comparison of 78 plasma samples collected during 26 episodes of biopsy-proven acute cellular rejection with samples collected during periods of stable renal function (n = 349) showed that TNF levels rose significantly (390 +_ 242 pg/ml, p < 0.01) above background levels 3 days before rising serum creatinine concentrations, and peaked (2,426 _+ 978 pg/ml) on the day of clinical rejection. PC-antigen (Ag) concentrations also decreased 3 days before rejection (68 _+ 13%, p < 0.05), and were maximally depressed (49% _+ 16%, p < 0.001) on the day of rejection. FPS levels were normal until the day before rejection (63% +_ 8%, p < 0.01) and, like PC, were maximally depressed (43 + 10%) at rejection. Plasma TNF levels were significantly and inversely correlated with PC-Ag (p < 0.001) and FPS (p < 0.005) levels during rejection, regardless of whether such rejection episodes were steroid responsive or required OKT3 monoclonal antibody therapy. TNF, PC, and FPS levels were normal during episodes of cydosporine toxicity and viral infection. Immunoperoxidase studies showed that rejection was associated with a intrarenal production of TNF, decreased microvascular labeling for thrombomodulin, and widespread endothelial and interstitial deposition of PC, PS, thrombin, fibrin, and factors V and VIII. These findings suggest that TNF is an important mediator of renal allografr rejection, causing depression of the intragraft thrombomodulin/PC/PS pathway and thereby contributing to intragraft fibrin deposition. Moreover, these results indicate that monitoring of circ...

Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain.

“…Activation of mononuclear or endothelial cells was assessed using antibodies to class II antigens (OX-3) ; p-55 chain of the IL-2R (CD25, ART18 ; courtesy of Dr. T Diamantstein, Berlin, Germany) ; intercellular adhesion molecule-1 (ICAM-1, CD54, 1A29 ; courtesy of Dr . M. Miyasaka, Tokyo, Japan) ; proliferating cell nuclear antigen (PCNA; Dako Corp ., Carpinteria, CA); tissue factor (Al-3) (13) and thrombomodulin (TM-4; courtesy of Dr. H. Salem, Melbourne, Australia) (14) ; and by labeling for the cytokines IL lei (C42, Olympus Corp ., Lake Success, NY); IL-2 (1D10) (15) ;11,4 (Genzyme Corp.,…”

Initial Inhibition of Tissue Factor Signalling Reduces Chronic Vascular Changes in Isogenic Rat Aortic Transplants

“…The possible role of the coagulation system in acute rejection and chronic renal graft failure is still poorly investigated, but studies performed so far imply that the hemostatic balance is altered in these conditions (8)(9)(10)(11). Tissue factor (TF), the primary initiator of coagulation, is a 47-kDa integral glycoprotein belonging to the cytokine-receptor superfamily (12).…”

Urine Cytology and the Diagnosis of Renal Allograft Rejection

“…9,20,21 The tubular expression of ICAM-1 is probably induced by the high levels of interferon-gamma and TNF-α in the circulation of patients with AR. [11][12][13] Receptors for these cytokines have been demonstrated in human tissue. 22 In the present study, we attempted to correlate ICAM-1 expression with the expression of cytokine receptors.…”

“…ICAM-1 expression, in turn, may be induced by the cytokines interferon-gamma and TNF-α, 9,10 both present at high concentration in the circulation of patients with AR. [11][12][13] We wondered if the expression of receptors for these cytokines could be studied using urine immunocytology. We have now investigated this hypothesis and found a close correlation between the regulation of these receptors and clinical events.…”