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Biomedical subjects

Steven H Sacks

Publications and source records attributed to Steven H Sacks.

28 records · Page 2Linked to original sources
PubMed2004

Minireview: functions of the renal tract epithelium in coordinating the innate immune response to infection.

Infection of the urinary tract remains one of the most common infections affecting mankind. Renal epithelial cells, being one of the first cells to come into contact with invading organisms, are in a key position to coordinate host defense. The epithelium not only provides a physical barrier to infection, but can also augment the immune response via the production of a number of inflammatory mediators and antimicrobial proteins. Recent work has demonstrated that cells of the innate immune system, including epithelial cells, express toll-like receptors (TLRs), with the capacity to recognize bacterial components. Although the exact mechanisms remain unclear, engagement of TLRs can lead to epithelial cell activation and the production of inflammatory mediators. These include complement proteins, other bactericidal peptides, and chemotactic cytokines. The resulting inflammatory infiltrate serves to aid bacterial clearance, but can also lead to renal damage. In this review, we describe how renal epithelial cells contribute to the innate immune response to ascending urinary tract infection. We specifically relate previous work to more recent developments in this field. An improved understanding of the mechanisms involved may highlight potential therapeutic avenues to aid bacterial clearance and prevent the renal scarring associated with infection.

Animals↗
PubMed2003

Natural killer-cell activity after human renal transplantation in relation to killer immunoglobulin-like receptors and human leukocyte antigen mismatch.

BACKGROUND: Natural killer (NK) cells use killer immunoglobulin-like receptors (KIR) that bind to self-class I major histocompatibility complex (MHC) molecules to prevent killing of autologous cells. Mismatched allografts, which do not express recipient MHC class I molecules, can therefore be potential targets for NK-cell killing. In our living related-unrelated renal transplantation program, donor-recipient pairs vary in the amount of both HLA and KIR genes they share. This provides us with a unique opportunity to dissect the influence of KIR on NK-cell function after transplantation. METHODS: Recipient NK cells were used in a cytotoxicity assay against donor peripheral blood mononuclear cells 2 days before, on the day of, and 3 days after transplantation. Results were correlated to HLA-KIR compatibility between donor and recipient. RESULTS: NK killing, in a direct ex vivo setting, was demonstrated to be HLA mismatch dependent. Recipient NK antidonor cytotoxicity was unaltered despite having received 2 days' treatment with cyclosporine A before transplantation. However, cytotoxicity increased 3 days after transplantation in 71% of recipients. Recipients exhibiting increased NK cytotoxicity against their donors after transplantation were found to possess more activating KIR genes specific for donor class I MHC molecules than those in whom killing activity did not increase (P<0.04). CONCLUSIONS: NK cells are activated after transplantation despite quadruple immunosuppression, suggesting that recipient NK-cell cytotoxicity against the donor may be a previously unrecognized area of the rejection process, especially in poorly matched donor-recipient pairs where the recipient may not express the correct repertoire of inhibitory receptors to prevent killing of donor cells.

Adult↗
PubMed2003

Fc-dependent depletion of activated T cells occurs through CD40L-specific antibody rather than costimulation blockade.

Although the underlying mechanisms are not well understood, it is generally believed that antigen recognition by T cells in the absence of costimulation may alter the immune response, leading to anergy or tolerance. Further support for this concept comes from animal models of autoimmunity and transplantation, where treatments based on costimulation blockade, in particular CD40 ligand (CD40L)-specific antibodies, have been highly effective. We investigated the mechanisms of action of an antibody to CD40L and provide evidence that its effects are dependent on the constant (Fc) region. Prolongation of graft survival is dependent on both complement- and Fc receptor-mediated mechanisms in a major histocompatibility complex (MHC)-mismatched skin transplant model. These data suggest that antibodies to CD40L act through selective depletion of activated T cells, rather than exerting immune modulation by costimulation blockade as currently postulated. This finding opens new avenues for treatment of immune disorders based on selective targeting of activated T cells.

Animals↗
PubMed2003

Nontransgenic hyperexpression of a complement regulator in donor kidney modulates transplant ischemia/reperfusion damage, acute rejection, and chronic nephropathy.

Complement activation during ischemia and reperfusion contributes to the development of tissue injury with severe negative impact on outcomes in transplantation. To counter the effect of complement, we present a strategy to deliver a novel complement regulator stabilized on cell surfaces within donor organs. The membrane-bound complement regulator is able to inhibit complement activation when the donor organ is revascularized and exposed to host-circulating complement. Application of this construct to donor kidneys protected transplanted tissues from ischemia/reperfusion injury and reduced the deposition of activated complement and histological signs of damage under conditions in which a nontargeted control construct was ineffective. Treatment of donor organs in this way improved graft performance in the short and long term. An analysis of the immune response in allograft recipients showed that reducing graft damage at the time of transplantation through complement regulation also modulated the alloresponse. Additionally, the results of perfusion studies with human kidneys demonstrated the feasibility of targeting endothelial and epithelial surfaces with this construct, to allow investigation in clinical transplantation.

Acute Disease↗
PubMed2003

Role of the complement system in rejection.

The complement system plays a complex role in transplantation, beginning with effects on reperfusion injury and continuing with stimulation of the adaptive immune response. Recent evidence has emphasised the importance of the late components of the complement cascade in the mediation of post-ischaemic damage, which are apparently triggered by the classical, alternative or lectin pathways of complement activation, depending on the organ affected. In studies of renal allograft rejection, the local synthesis of complement component C3 seems to influence the T-cell response more strongly than circulating complement protein, raising the possibility that there is co-operation between locally derived C3 and antigen presentation in the graft. Class switching of alloantibody to a high-affinity IgG response is also highly dependent on C3. In addition, the finding that capillary-bound C4d is a robust marker for humoral rejection has started a new investigation into the significance of alloantibodies in acute and chronic allograft rejection. There are several selective and nonselective inhibitors suitable for clinical development; clearly it is time for more concerted effort to evaluate their role in clinical transplantation.

Complement Activation↗
PubMed2003

Locally produced complement and its role in renal allograft rejection.

The role of innate immunity in allograft injury is just beginning to become clear, and complement is probably one of a number of factors that are activated very early in the course of transplantation. Kidney transplantation into complement-inhibited rats reduces subsequent inflammation of the graft, probably as a result of reduction of ischemia reperfusion damage as well as diminution of immune mediated damage. Closer analysis of the role of locally synthesised components in mice has suggested that regional synthesis of complement proteins, in particular by the renal tubule, may play a more important role than circulating components. A marked effect on the antidonor T cell response may be explained by the triggering of complement receptors present on antigen presenting cells or T cells infiltrating the graft, or by a more direct effect of complement on the liaison between proximal tubule cells and T cells. Therapeutic control is likely to require a shift to a more targeted approach, directed at complement components produced in the extravascular tissue compartment.

Animals↗
PubMed2002

Local synthesis of complement component C3 regulates acute renal transplant rejection.

Accumulating evidence suggests that innate immunity interacts with the adaptive immune system to identify potentially harmful antigens and eliminate them from the host. A central facet of innate immunity is complement, which for some time has been recognized as a contributor to inflammation in transplant rejection but without detailed analysis of its role in what is principally a T cell mediated process. Moreover, epithelial and vascular tissues at local sites of inflammation secrete complement components; however, the role of such local synthesis remains unclear. Here we show that the absence of locally synthesized complement component C3 is capable of modulating the rejection of renal allografts in vivo and regulating T-cell responses in vivo and in vitro. The results indicate that improved success in kidney transplantation could come from therapeutic manipulation of innate immunity in concert with T cell directed immunosuppression.

Acute Disease↗
PubMed2002

Triptolide is a potent suppressant of C3, CD40 and B7h expression in activated human proximal tubular epithelial cells.

BACKGROUND: Previous studies have shown that triptolide possesses potent immunosuppressive and anti-inflammatory properties. Increasing recognition of the importance of the proximal tubular epithelial cells (PTEC) in renal disease and renal transplantation raises the question of whether triptolide suppresses the pro-inflammatory activity of PTEC. METHODS: Cultured human PTEC were exposed to tumor necrosis factor-alpha (TNF-alpha) and immunosuppressant (triptolide or CsA or FK506) for 24 hours, followed by RT-PCR, ELISA, flow cytometry and Western blotting analysis for complement C3, CD40, B7h expression. RESULTS: TNF-alpha up-regulated C3, CD40 and B7h production by PTEC. This up-regulation was inhibited by all three immunosuppressants with different intensity. Firstly, triptolide (4 to 8 ng/mL), CsA (4000 to 6000 ng/mL) and FK506 (2000 ng/mL) inhibited up-regulation of C3 mRNA, but CsA and FK506 had less of an effect than triptolide. Secondly, triptolide (4 to 8 ng/mL) completely inhibited C3 expression at both mRNA and protein levels. In contrast, CsA and FK506 had only slight effects on C3 expression at the protein level. Thirdly, triptolide (4 to 8 ng/mL), CsA (500 to 2500 ng/mL) and FK506 (1250 ng/mL) inhibited up-regulation of CD40 and B7h mRNA, the effect on B7h and CD40 mRNA expression by CsA and FK506 being greater than that on C3 mRNA expression. CONCLUSION: Triptolide effectively inhibited up-regulation of C3, CD40 and B7h on PTEC. Triptolide was more effective than CsA and FK506 at inhibiting C3 expression. This suggests that triptolide, at non-cytotoxic concentrations, has the potential to reduce the inflammatory and immunostimulatory properties of PTEC, in addition to any of the previously reported actions on T cell or B cell function.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Role of complement in tubulointerstitial injury from proteinuria.

The complement system is being increasingly implicated in the pathogenesis of progressive renal disease resulting from persistent proteinuria. It has recently been established that renal tubular cells can produce complement, activate complement, and respond to complement activation. Complement proteins that pass through the glomerular barrier along with other serum proteins in the proteinuric state may become activated at the tubular epithelial brush border, and lead to a cascade of events culminating in cell injury. Furthermore, nephrotic components in the urinary space may cause direct activation of the tubular cells to overexpress complement and contribute to local tissue injury. In this review, we will discuss the current evidence supporting a role for complement in the pathogenesis of progressive tubulointerstitial damage in the proteinuric state. The possibility of complement inhibition intervening in progressive tubulointerstitial injury due to proteinuric glomerular disease will also be considered.

Complement System Proteins↗