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S H Sacks

Publications and source records attributed to S H Sacks.

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

Evidence for increased synthesis of complement C4 in the renal epithelium of rats with passive Heymann nephritis.

Passive Heymann nephritis (PHN) is a complement-dependent model of immune complex glomerulonephritis. This study investigated the contribution of local complement synthesis by studying gene expression of the classical pathway component C4 in relation to the site of the tissue injury and the development of proteinuria induced by the pathogenic antibody (sheep anti-GP330). This study, using in situ hybridization, found that C4 mRNA expression was increased in the glomerular epithelium and the proximal renal tubular epithelium in a distribution similar to that of the targeted GP330 antigen. The total cortical C4 mRNA expression assessed by semiquantitative polymerase chain reaction (PCR) increased in a time-dependent manner (P < 0.05), coincident with the onset and progression of proteinuria, and peaking 11 to 14 days after the induction of the disease. These data suggest a link, in place and time, between local complement gene expression and glomerular barrier dysfunction induced by anti-GP330. It is postulated that increased epithelial synthesis of C4 stimulated by the engagement of GP330 enhances the formation of the membrane attack complex of complement through its classical pathway, and, hence, the formation of complement-mediated injury.

Animals↗
PubMed1997

Intraglomerular C3 synthesis in rats with passive Heymann nephritis.

Passive Heymann nephritis (PHN), a model of human membranous nephropathy, is an immune-complex-mediated glomerulonephritis characterized by the presence of complement-dependent tissue injury. Recent studies have confirmed the synthesis of C3, involved in both the classical and alternative pathways of complement, in injured human and animal renal tissues. However, there is little clear information on the role of local C3 synthesis in the pathogenesis of nephritides such as PHN. In the present study, using nonradioactive in situ hybridization and semiquantitative reverse transcriptase polymerase chain reaction, we examined C3 synthesis in the kidney and its contribution to tissue injury in a rat model of PHN induced by the injection of polyclonal anti-gp330 antibody. C3 mRNA was localized in mesangial cells, glomerular epithelial cells, and cells of Bowman's capsule. During the early stages of PHN, C3 mRNA expression was detected in mesangial cells and glomerular epithelial cells, whereas such expression was limited to mesangial cells during the late stages of the disease. Focal, weak C3 mRNA expression was detected in tubular epithelial cells and occasionally in the interstitium. Semiquantitative polymerase chain reaction demonstrated that the level of C3 mRNA expression correlated with that of proteinuria. Our results suggest that renal cells synthesize C3 mRNA in PHN in a site-specific manner and that locally produced C3 is associated with the development of proteinuria in this model.

Animals↗
PubMed1996

Up-regulation of type 1 plasminogen activator inhibitor messenger RNA with thrombotic changes in renal grafts.

Small vessel thrombosis is a prominent feature in kidneys undergoing vascular rejection. Type I and type 2 plasminogen activator inhibitors (PAI-1 and PAI-2, respectively) are known to mediate thrombosis. To examine the potential role of PAI-1 and PAI-2 in the mediation of vascular injury, the relationship and the time course of gene expression of PAI-1 and PAI-2 with the thrombotic changes in renal grafts were investigated in an unmodified rejection model in rats. Orthotopic renal transplantation was performed from Lewis to dark agouti (DA) rats and from DA to DA isografts; untreated normal rat kidneys were used as controls. The rats were killed on days 1-9 posttransplantation (n=18 in each allograft and isograft group). The grafts were analyzed by histopathology, in situ mRNA hybridization and Northern blot methods. The results show that PAM mRNA was first detected at day 4, when the thrombotic changes in the grafts were first seen, and that this relationship persisted during the time course observed to day 9. There was no detectable PAI-1 mRNA in the control groups and no PAI-2 in either group. In situ hybridization showed that PAI-1 positive cells were predominantly located in the cortical interstitium, consistent with the distribution of interstitial microthrombi. These results provide experimental evidence that the thrombotic changes in rejecting allografts are associated with the up-regulation of PAI-1 in the donor tissue, whereas PAI-2, from our results, does not seem to influence these changes. The data are consistent with a role for PAI-1 in the pathogenesis of vascular rejection.

Animals↗
PubMed1996

Rhesus immunization after renal transplantation.

Previous reports, before the advent of cyclosporine, suggest that the small amount of blood transplanted with a kidney can result in rhesus D (RhD) antibody production. We looked for retrospective and current evidence of primary RhD antibody production following renal transplantation in RhD-negative recipients of an RhD-positive kidney. Of 42 patients, all on triple immunosuppressive therapy, 2 (5%) were found to have an RhD antibody identified for the first time after transplantation. As the number of pregnancies in transplant recipients increases, the small risk of primary immunization and subsequent risk of hemolytic disease of the newborn will become more important. Therefore, we recommend that all RhD-negative women of child-bearing age receiving an RhD-positive solid organ transplant are given a prophylactic dose of 500 IU of anti-D immunoglobulin intramuscularly at the time of transplantation.

Antibodies↗
PubMed1996

Allograft immune response with sCR1 intervention.

The deposition of complement (C) components on tissues of transplanted organs may induce many proinflammatory responses. The role of such C activation in allograft rejection is uncertain. We addressed this question by inhibiting C at the level of the C3 and C5 convertases, preventing C activation and progression of its cascade, using recombinant human soluble complement receptor 1 (sCR1) in an unsensitized rat renal allograft model. Fully MHC disparate Lewis to DA rat renal allograft recipients given 25 mg/kg sCR1 daily, with saline-treated allograft recipients as controls (n = 15 in each group), were sacrificed from day 1 to day 5 post-transplant, and examined histopathologically, and for the deposition of C3 and C5b-9 membrane attack complex (MAC), and for the presence of leucocyte antigen markers. Treated animals demonstrated a reduction in vascular injury and cellular infiltration, coincident with reduced C deposition. Flow cytometric analysis of leucocyte subpopulations in the spleen showed a reduction in activated (CD25 positive) B and T cells in treated animals, compared to saline treated controls. The results suggest that C inhibition with sCR1, in an unsensitized model of allograft rejection, was able to suppress the vascular and cell mediated components of tissue injury. The data support not only a role for C in antibody and possibly cell mediated cytotoxicity in the graft, but also suggest a role in the primary immune response leading to both T cell and B cell activation.

Animals↗
PubMed1996

Complement synthesis in the injured kidney: does it have a role in immune complex glomerulonephritis?

On pages 2428 to 2433 of this issue, Miyazaki et al. provide evidence that complement component C3 is synthesized within the glomeruli of patients with mesangial glomerulonephritis. Although it has been known for several years that cells isolated from the human kidney can synthesize a range of complement components, and that immune complex disease can increase the expression of these genes, it is only now that the link between intraglomerular synthesis of complement and human glomerulonephritis can be made. In view of the long interest in the role of complement in the pathogenesis of glomerulonephritis, this begs the question to what extent local complement synthesis may be involved in the generation of tissue injury. Given also the double-sided nature of complement-proinflammatory and protective-It remains to be seen if the roles of local and systemic complement differ in these respects. To weigh these questions, we examine the current evidence that connects local complement synthesis with renal injury, and ask what studies are needed to provide more definitive answers.

Animals↗
PubMed1996

Effects of complement inhibition with soluble complement receptor-1 on vascular injury and inflammation during renal allograft rejection in the rat.

Complement is both an effector of the humoral immune response and a stimulator of leukocyte activation. To examine the influence of complement on the allograft response, we inhibited complement using recombinant human soluble complement receptor-1 (sCR1; TP10), in an unsensitized model of rat renal allograft rejection. Lewis to DA renal transplant recipients were treated daily with 25 mg/kg sCR1 or saline and sacrificed on days 1 to 5 after transplant. Transplanted organs were examined histologically and immunohistochemically for leukocyte subset markers and for the third component of complement, C3, and membrane attack complex deposition. A second set of recipients was followed from day 5 to day 9 to assess graft survival. sCR1-treated recipients displayed > 90% inhibition of plasma complement activity and a marked reduction in tissue C3 and membrane attack complex deposition. Inactivation of complement reduced the vascular injury such that there was almost complete sparing of vascular damage in day 5 sCR1-treated rats. There was a significant reduction in infiltrating leukocytes by day 5 after transplant, and complement inhibition delayed the time to reach a histologically defined end point of graft survival from 5 days in controls to 9 days in the sCR1-treated group. These results imply that the vascular and cell-mediated injury arises, in part, from complement activation. The partial inhibition of these injuries by sCR1 may have functional implications for strategies to inhibit allograft rejection.

Acute Disease↗
PubMed1995

Molecular analysis of C3 allotypes related to transplant outcome in human renal allografts.

The third component of complement (C3) exists in two main allotypic forms, C3S and C3F, which can be distinguished at the molecular level using a variation of the polymerase chain reaction. An increased frequency of the C3F allele has been noted in a number of autoimmune and inflammatory conditions affecting the kidney, including systemic vasculitis, IgA nephropathy, and type II mesangiocapillary nephritis. Recently, in an unrelated study, we found (with small numbers) an increased incidence of graft loss associated with the presence of the C3F allele. To further assess this, we analyzed the S/F polymorphism in 183 donor-recipient pairs of patients undergoing renal transplantation. Forty-one of 183 grafts were lost, but graft loss was not associated with the C3F allele over 14-month follow-up. However, the presence of the C3F allele predicted an increased risk of graft dysfunction (defined as serum creatinine > 150 mumol/L): 61/105 versus 36/78, with a relative risk of 1.4 (P < 0.05). The C3F allele predisposed toward graft dysfunction when present in either donor or recipient. The presence of two C3F alleles gave a relative risk for graft dysfunction of 1.8, suggesting a dose-dependent effect, although numbers were small. The presence of the C3F allele was not significantly correlated with the number of rejection episodes, serum creatinine, or duration of primary nonfunction. These findings suggest that C3F may be a susceptibility allele for allograft injury. Possible mechanisms for this association are discussed.

Alleles↗
PubMed1995

Expression and tissue localization of donor-specific complement C3 synthesized in human renal allografts.

Recent evidence suggests that the third component of complement, C3, is synthesized in renal tissue, and that increased C3 synthesis occurs in allograft rejection and immune complex-mediated nephritis. However, it is unclear whether intrinsic renal cells or migratory cells in the inflammatory infiltrate, possibly of recipient bone marrow origin, are the source of the C3 detected. This was investigated by determining the C3 allotypes of mRNA and protein produced by transplanted human kidney. Twenty donor-recipient pairs were examined, of which nine pairs had C3 allotypes that were informatively mismatched at the C3 F/S locus. Reverse transcriptase polymerase chain reaction (RT-PCR) followed by amplification refractory mutation system analysis showed intracellular donor-specific mRNA expression in six of these nine cases, at up to 61 days post-transplantation. Nested PCR reactions and the size of PCR products excluded contamination by genomic DNA. Allotype-specific staining of frozen sections of renal cortex demonstrated donor-derived C3 protein in both glomeruli and tubules of all biopsies examined, in a predominantly tubular distribution. These results imply that at least some of the pro-inflammatory effects of complement arise from intrinsic tissue synthesis of donor C3, and that this may represent a previously unrecognized source of tissue injury. The occurrence of local synthesis of C3 of donor allotype may have functional implications related to C3 allotype, and may also be relevant to strategies to inhibit intrarenal complement-mediated injury.

Alleles↗
PubMed1995

Tissue synthesis of complement as an immune regulator.

Evidence is accumulating that a variety of tissues produce complement components, and that production in each tissue is differentially regulated by inflammatory cytokines. This locally produced complement could have protective or injurious actions, depending upon local circumstances. Techniques for analysing separately the contributions of local complement synthesis and complement derived from the circulation are now becoming available. We argue that an appreciation of the role of local complement synthesis may help to explain many features of organ- and tissue-specific immunological disease.

Animals↗
PubMed1995

Unusual presentations of anti-glomerular basement membrane antibody mediated disease are associated with delayed diagnosis and poor outcome.

Anti-glomerular basement membrane antibody mediated disease (anti-GBM disease) is an uncommon cause of renal failure. Presentation is usually dramatic, with renal failure and alveolar hemorrhage leading to an early diagnosis. In contrast, we here describe 3 cases which presented with atypical features, and where diagnosis was delayed due to the presence of other factors which were initially felt sufficient to explain the clinical status. No patient recovered renal function, and one died from sepsis. We also present data on 15 patients presenting to Guy's Hospital over the past 10 years with anti-GBM disease and creatinine > 500 mumol/l. The median delay from presentation to diagnosis was 7 days, range 1-81 days. Two patients died, and only one recovered renal function. We speculate that earlier referral and renal biopsy might have improved outcome in these patients, and recommend a policy of early biopsy in all cases of acute renal failure with atypical feature, delay in recovery, or where a clearcut cause is not established.

Aged↗
PubMed1995

Early prediction of treatment outcome in idiopathic membranous nephropathy.

Most patients with idiopathic membranous nephropathy have a benign course, but a minority develop severe persistent nephrotic syndrome or endstage renal failure. The disease appears to have an immunological basis and immunosuppression has been used with some benefit. Unfortunately, treatment can be toxic and not all patients respond. For this reason it would be useful to identify at an early stage those patients who might benefit from treatment. This information could be used to minimize the exposure of patients to unnecessary treatment toxicity. We studied a cohort of 128 patients over a 2-year period. A clear relationship exists between the early response to treatment at one month and the long-term outcome from treatment across a number of treatment types. Those patients who might benefit from treatment and those who are unlikely to benefit, can be clearly distinguished at an early stage.

Adult↗
PubMed1994

Sparing of first dose effect of monovalent anti-CD3 antibody used in allograft rejection is associated with diminished release of pro-inflammatory cytokines.

The murine monoclonal antibody OKT3 is the best known of the anti-CD3 antibodies used for the prevention and treatment of renal allograft rejection. Use of this antibody is associated with improved graft outcome but it has a number of adverse effects thought to result from the massive release of pro-inflammatory cytokines. It has been postulated that OKT3 causes cytokine release because of cross-linking of CD3 molecules on the cell surface by bivalent anti-CD3 antibodies, such as OKT3, and the simultaneous binding of the Fc regions of these monoclonal antibodies to Fc receptors on other cells resulting in cell activation. Monovalent antibodies directed against the CD3 antigen should not, in theory, cause cell activation and cytokine release by this postulated mechanism. This study details the use of a monovalent anti-CD3 monoclonal antibody in the treatment of allograft rejection in five renal transplant recipients and documents the degree of TNF, IFN-g and IL6 release generated after antibody injection. Monovalent anti-CD3 monoclonal antibody reversed the rejection episode for which it was used and was well tolerated in all patients. TNF, IFN-g and IL6 measurement showed that little pro-inflammatory cytokine release occurred after this drug. It is likely that the relative lack of side-effects of monovalent anti-CD3 reflects the blunted release of pro-inflammatory cytokines. Monovalent anti-CD3 monoclonal antibody may be a useful addition to the reagents available to treat allograft rejection.

Acute Disease↗