Biomedical subjects

Cees van Kooten

Publications and source records attributed to Cees van Kooten.

At least 37 records · Page 2Linked to original sources

PubMed2005

Antibody response against the glomerular basement membrane protein agrin in patients with transplant glomerulopathy.

Chronic allograft nephropathy (CAN) of renal allografts is still the most important cause of graft loss. A subset of these patients have transplant glomerulopathy (TGP), characterized by glomerular basement membrane (GBM) duplications, but of unknown etiology. Recently, a role for the immune system in the pathogenesis of TGP has been suggested. In 11 of 16 patients with TGP and in 3 of 16 controls with CAN in the absence of TGP we demonstrate circulating antibodies reactive with GBM isolates. The presence of anti-GBM antibodies was associated with the number of rejection episodes prior to diagnosis of TGP. Sera from the TGP patients also reacted with highly purified GBM heparan sulphate proteoglycans (HSPG). Indirect immunofluorescence with patient IgG showed a GBM-like staining pattern and colocalization with the HSPGs perlecan and especially agrin. Using patient IgG, we affinity purified the antigen and identified it as agrin. Reactivity with agrin was found in 7 of 16 (44%) of patients with TGP and in 7 of 11 (64%) patients with anti-GBM reactivity. In conclusion, we have identified a humoral response against the GBM-HSPG agrin in patients with TGP, which may play a role in the pathogenesis of TGP.

Agrin↗

PubMed2005

MIP-3alpha/CCL20 in renal transplantation and its possible involvement as dendritic cell chemoattractant in allograft rejection.

Graft-infiltrating dendritic cells (DC) and alloreactive T lymphocytes play a critical role in renal allograft rejection. Renal proximal tubular epithelial cells (TEC) are considered as active players in the attraction of leukocytes during renal inflammatory responses. Macrophage inflammatory protein (MIP)-3alpha/CCL20 is a major chemokine expressed by epithelial cells that attracts immature DC. In the present study, we present evidence that also the transplanted kidney can be a major source of MIP-3alpha/CCL20. Renal transplant recipients with rejection showed significantly increased excretion of urinary MIP-3alpha/CCL20 that correlated with transplant function. The tubular staining for MIP-3alpha/CCL20 in renal biopsies of patients with rejection as well as in vitro studies with primary human TEC indicated that TEC might be responsible for the increased urinary MIP-3alpha/CCL20. Furthermore, MIP-3alpha/CCL20 produced by activated TEC was highly potent in the attraction of CD1a+CD34+-derived DC precursors. These data suggest a role for MIP-3alpha/CCL20 in amplification of the immune response during renal allograft rejection by attraction of CCR6+ inflammatory cells, which may include DC, to the site of inflammation.

Adult↗

PubMed2004

Opsonization with C1q and mannose-binding lectin targets apoptotic cells to dendritic cells.

Deficiencies of early components of the classical complement pathway, particularly C1q, are strongly associated with susceptibility to systemic lupus erythematosus. Recent data link this predisposal to autoimmunity to an inappropriate clearance of apoptotic cells, which could lead to a loss of self-tolerance. In the present study, we demonstrate that opsonization of apoptotic cells with C1q and mannose-binding lectin allows and facilitates their uptake not only by macrophages but also by human immature dendritic cells (DCs). Both C1q and mannose-binding lectin enhance the uptake of apoptotic cells by DCs in a dose-dependent way. The uptake of C1q-opsonized apoptotic cells, but not nonopsonized apoptotic cells, by DCs stimulated the production of IL-6, IL-10, and TNF-alpha, without an effect on IL-12p70. We conclude that these recognition molecules of the complement system do not sequester apoptotic cells from DCs, but rather promote their uptake by immature DCs. Therefore, we propose that early complement components support safe clearance of cellular debris by facilitating phagocytosis and possibly by immunomodulatory mechanisms, thus preventing autoimmunity.

Apoptosis↗

PubMed2004

Injection of recombinant FcalphaRI/CD89 in mice does not induce mesangial IgA deposition.

BACKGROUND: Earlier studies have suggested that complexes of the human IgA receptor FcalphaRI/CD89 with mouse IgA are pathogenic upon deposition in the renal mesangium. Transgenic mice expressing FcalphaRI/CD89 on macrophages/monocytes developed massive mesangial IgA deposition and a clinical picture of IgA nephropathy (IgAN). Based on these findings, the purpose of this study was to design an experimental model of IgAN by injection of human CD89 in mice. The interaction of mouse IgA with CD89 was investigated further. METHODS: Recombinant human soluble CD89 and a chimeric CD89-Fc protein were generated, produced, purified and injected in mice. Renal cryosections were stained for IgA and CD89. The interaction of mouse IgA with CD89 was analysed by fluorescence-activated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA) and plasmon resonance technology. RESULTS: Injection of recombinant human CD89 did not result in significant IgA or CD89 deposition in the renal mesangium. However, CD89 staining in the liver was found to be positive. CD89 was rapidly cleared from circulation without signs of complex formation with IgA. FACS analysis, ELISA and plasmon resonance techniques all revealed a dose-dependent binding of human IgA to recombinant CD89, while no detectable binding was seen of mouse IgA, either of serum IgA or of different monoclonal mouse IgA preparations. CONCLUSIONS: An experimental model for IgAN in mice could not be obtained by injection of recombinant CD89. This is compatible with our in vitro biochemical data showing a lack of binding between recombinant human CD89 and mouse IgA.

Animals↗

PubMed2004

An increased polymeric IgA level is not a prognostic marker for progressive IgA nephropathy.

BACKGROUND: Elution of IgA from renal biopsies of patients with primary IgA nephropathy (IgAN) has suggested that mesangial IgA deposits are mainly multimeric in nature. This macromolecular IgA consists of dimeric and polymeric IgA and may be derived from the circulation. In children with IgAN, circulating macromolecular IgA levels correlate with bouts of macroscopic haematuria, but in adults a correlation with disease activity is less clear. Therefore, we have designed a novel method to assess the levels of polymeric IgA (pIgA) in sera from patients and controls. METHODS: A novel precipitation assay using recombinant CD89 was developed to measure pIgA. Polymeric IgA levels were measured in serum samples obtained from healthy volunteers (n = 21) and patients with IgAN (n = 51). Subsequently, serum pIgA levels were correlated with clinical parameters of disease. RESULTS: Serum pIgA levels were significantly increased in patients with IgAN. However, pIgA concentrations relative to total IgA were significantly lower in sera of patients with IgAN. No correlation was found between serum pIgA levels and clinical parameters of IgAN, such as decline of glomerular filtration rate, haematuria or proteinuria. CONCLUSIONS: Although absolute levels of serum pIgA are increased in patients with IgAN as compared with controls, levels of pIgA relative to total serum IgA are lower. No significant correlation was found between serum concentrations of pIgA and clinical parameters of disease. These data support the notion that it is not the size alone, but the physicochemical composition of the macromolecular IgA that is the key factor leading to mesangial deposition.

Adult↗

PubMed2004

Secretion of collagen type IV by human renal fibroblasts is increased by high glucose via a TGF-beta-independent pathway.

BACKGROUND: Tubulointerstitial fibrosis is an important component of diabetic nephropathy, which is characterized by increased expression of interstitial extracellular matrix components and aberrant expression of the basement membrane component collagen type IV. The present study examined the effect of high ambient glucose and transforming growth factor-beta1 (TGF-beta1) on collagen secretion by human renal fibroblasts and proximal tubular epithelial cells (PTECs). METHODS: Human renal fibroblasts (TK173) and PTECs (HK2) were used to examine the effects of high glucose (25 mM d-glucose) and TGF-beta1 (1 ng/ml) on collagen type I, III and IV secretion compared with control medium (5.5 mM glucose). Matrix components were measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Renal fibroblasts are the main producers of the interstitial components collagen type I and type III, while collagen type IV was secreted predominantly by PTECs. However, renal fibroblasts were also able to secrete collagen type IV. Secretion of collagen type IV by fibroblasts was increased upon stimulation with TGF-beta1, reaching levels comparable with those secreted by TGF-beta1-induced PTECs. Moreover, high glucose stimulated increased collagen type IV secretion. Importantly, this could not be attenuated by neutralizing pan-specific anti-TGF-beta antibodies. CONCLUSIONS: These data show that renal fibroblasts secrete collagen type IV, which can be increased by high glucose independent of endogenous TGF-beta. This suggests that as well as the increased expression of interstitial components, renal fibroblasts can contribute to the increased expression of the basement membrane component collagen type IV in tubulointerstitial fibrosis observed during diabetic nephropathy.

Cells, Cultured↗

PubMed2004

The novel cyclophilin-binding drug sanglifehrin A specifically affects antigen uptake receptor expression and endocytic capacity of human dendritic cells.

Sanglifehrin A (SFA) is a recently developed immunosuppressant that belongs to the family of immunophilin-binding ligands. SFA is a cyclophilin A-binding immunosuppressive drug with a novel, but unidentified, mechanism of action. Several reports exist about the effect of SFA on T cells, but its effect on the initiators of the immune response, i.e., dendritic cells (DCs), is relatively unknown. Therefore, we examined the effect of SFA on the differentiation and function of human monocyte-derived DCs. Unlike the well-known cyclophilin A-binding immunosuppressant cyclosporin A, which did not affect DC phenotype, differentiation of DCs in the presence of SFA resulted in CD14-CD1a DCs with normal DC morphology, viability, and a proper capacity to activate allogeneic T cells. However, DCs generated in the presence of SFA demonstrated reduced macropinocytosis and lectin-mediated endocytosis, which was in line with a decreased expression of C-type lectins, including mannose receptor, C1qRP, DC-ASGPR, and especially, DC-SIGN. In contrast, FcalphaRI (CD89) and FcgammaRII (CD32) were increased by SFA. The explicit effect of SFA on the expression of Ag uptake receptors and Ag capture by DCs makes SFA unique among immunophilin-binding immunosuppressive drugs.

Antigens, CD↗

PubMed2004

Anti-tubular basement membrane antibodies and giant cell formation in a model of chronic renal allograft rejection.

BACKGROUND: In the Fisher (F344)-to-Lewis (LEW) kidney transplantation (Tx) model of chronic rejection, antibodies reactive with tubular basement membranes have been found. We investigated whether giant cells, typical for a granulomatous inflammatory reaction, can be found during allograft rejection. METHODS: F344-to-LEW renal Txs were performed, and kidneys were removed at various time points. Kidneys were analyzed by histology and immunohistochemistry. Interferon-gamma levels were measured by reverse-transcriptase polymerase chain reaction. RESULTS: Multinucleated Langhans'-type giant cells were found in F344 allografts at days 21 and 30 and disappeared thereafter. Giant cells were not observed in LEW allografts. The giant cells were ED1, OX-43, and major histocompatibility complex class II positive. All grafts showed transient expression of interferon-gamma, peaking at days 7 to 14 post-Tx. CONCLUSION: Granulomatous inflammation with giant cell formation occurs in the F344-to-LEW model and may represent an alloimmune response against tissue-specific antigens.

Animals↗

PubMed2004

Effective targeting of pathogens to neutrophils via chimeric surfactant protein D/anti-CD89 protein.

Targeting of specific pathogens to FcRs on immune effector cells by using bispecific Abs was reported to result in effective killing of the pathogens, both in vitro and in vivo. Instead of targeting a specific pathogen to an FcR, we assessed whether a broad spectrum of pathogens can be targeted to an FcR using surfactant protein D (SP-D). SP-D is a collectin that binds a great variety of pathogens via its carbohydrate recognition domain. A recombinant trimeric fragment of SP-D (rfSP-D), consisting of the carbohydrate recognition domain and neck domain of human SP-D, was chemically cross-linked to the Fab' of an Ab directed against the human Fc alpha RI (CD89). In vitro, the chimeric rfSP-D/anti-CD89 protein enhanced uptake of Escherichia coli, Candida albicans, and influenza A virus by human neutrophils. Blocking of the interaction between rfSP-D/anti-CD89 and either the pathogen or CD89 abolished its stimulatory effect on pathogen uptake by neutrophils. In addition, rfSP-D/anti-CD89 stimulated killing of E. coli and C. albicans by neutrophils and enhanced neutrophil activation by influenza A virus. In conclusion, rfSP-D/anti-CD89 effectively targeted three structurally unrelated pathogens to neutrophils. (Col)lectin-based chimeric proteins may thus offer promise for therapy of infectious disease.

Animals↗

PubMed2004

Maturation of dendritic cells abrogates C1q production in vivo and in vitro.

Dendritic cells (DCs) and complement are essential components of the innate immune system. Immature DCs (immDCs) and mature DCs (mDCs) can migrate to lymphoid areas inducing, respectively, tolerance and immune responses. Primary deficiency of complement component C1q (C1q) leads to autoimmunity, suggesting a role in the maintenance of tolerance. In the present study, we investigated the production of C1q by immDCs, mDCs, and macrophages. We demonstrated that monocyte-derived and CD34(+)-derived interstitial DCs are a rich source of C1q. C1q produced by immDCs is functionally active in complement activation and binding to apoptotic cells. The production of C1q is completely down-regulated upon DC maturation in vitro. Moreover, we found that DC differentiation in the presence of interferon-alpha (IFN-alpha) accelerated DC maturation and strongly impaired overall C1q production. Finally, we demonstrated the presence, in significant numbers, of DC-SIGN(+)/C1q(+) cells in T-cell areas of tonsils, next to DC-LAMP(+) mDCs lacking C1q. We conclude from these results that immDC, a cell with tolerogenic properties, is a rich source of active C1q in vitro and in vivo, which is down-regulated on maturation. Therefore, immDCs may be considered an additional source of C1q in humans.

Cell Differentiation↗

PubMed2004

Mini-review: A pivotal role for innate immunity in the clearance of apoptotic cells.

Apoptotic cells can be recognized and taken up by both macrophages and dendritic cells. Phagocytosis of apoptotic cells generally leads to active suppression of cytokine production by professional phagocytes. This is different from the response towards cells that die by necrosis, which induce a pro-inflammatory cytokine profile. Uptake of apoptotic cells involves a large number of receptors and opsonins, which bind to cellular ligands exposed during the various stages of apoptotic cell death. Among the opsonins of apoptotic cells, complement factors, including C1q, and complement-activating members of the pentraxin family play an important role. This is indicated by in vitro phagocytosis studies and supported by the susceptibility to systemic autoimmunity of carriers of genetic deficiencies for early complement proteins. The present review summarizes the role of molecules of innate immunity in the handling of apoptotic cells by macrophages and dendritic cells. It is proposed that C1q and other opsonins prevent autoimmunity and maintain self-tolerance by supporting the efficient clearance of apoptotic material, as well as by actively modulating phagocyte function.

Animals↗

PubMed2004

Dendritic cells and complement: at the cross road of innate and adaptive immunity.

The interaction between different components of the immune system plays a pivotal role in the overall development of immune responses. Dendritic cells (DCs) and complement are essential components of innate immunity. They have been shown to be relevant both in the induction of adaptive immune responses and in maintenance of tolerance. However, hyperactivity of these systems has also been demonstrated to be detrimental in various disease states. Despite increased insight into dendritic cell biology, relatively little is known about possible interactions between dendritic cells and complement. This review focuses on novel findings, which have started to shed light on these intriguing components of the innate immune system.

Animals↗

PubMed2004

Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells.

Recent studies have shown inflammatory markers in affected neural tissues of amyotrophic lateral sclerosis (ALS) patients. We examined immunocytochemically spinal cord tissues of six patients with ALS, two with corticospinal tract degeneration secondary to cerebral infarcts and three control subjects without neuropathologic abnormalities. ALS spinal cords had dense macrophage infiltration (one log greater than control spinal cords) involving the white and gray matter, with heaviest infiltration of lateral and ventral columns and, in one patient, prefrontal gyrus and the occipital lobes of the brain. Macrophages in ALS spinal cord showed strong expression of cyclooxygenase-2 (COX-2) (one log greater than control tissues) and inducible nitric oxide synthase. In the gray matter, macrophages surrounded and appeared to phagocytize neurons (NeuN-positive) that appeared to be dying. Vessels showed damage to the tight junction protein ZO-1 in relation to perivascular CD40 receptor-positive macrophages and CD40 ligand-positive T lymphocytes. ALS spinal cords, but not control cords, were sparsely infiltrated with mast cells. In control cases with corticospinal tract degeneration following hemispheric cerebral infarction, macrophage infiltration of the white matter was COX-2-negative and restricted to lateral and anterior corticospinal tracts. Our data suggest that inflammation in ALS spinal cord and cortex is based on innate immune responses by macrophages and mast cells and adaptive immune responses by T cells.

Aged↗

PubMed2004

Mechanism of steroid action in renal epithelial cells.

Renal tubular epithelial cells (TEC) are thought to play an active role in tubulointerstitial inflammation. Various immune and non-immune factors activate TEC to produce a variety of cytokines and chemokines, contributing to attraction of inflammatory cells to the kidney. The proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) appears to be a key player in these responses and tubular expression of NF-kappaB has been demonstrated in vitro and in vivo. Although glucocorticoids are known to inhibit NF-kappaB activation at different levels, the proinflammatory capacity of TEC was not inhibited. In contrast, glucocorticoids seemed to enhance the profibrotic response of TEC, emphasizing the cell-type specific characteristics of glucocorticoid action. We propose that specific inhibition of NF-kappaB activation in TEC might be an attractive strategy for therapeutic intervention in renal inflammation.

Animals↗

PubMed2004

The pathobiology of chronic allograft nephropathy: immune-mediated damage and accelerated aging.

Chronic allograft nephropathy includes chronic calcineurin nephrotoxicity, recurrent and de novo glomerulonephritis and a group of disorders with graft dysfunction of unknown etiology designated chronic rejection. Review of risk factors of the latter category show that the chronic rejection lesions emerge in organs that have undergone injury. Despite the relevance of nonalloantigen-dependent progression factors in the tissue injury, alloantigen-dependent factors predominate in the pathogenesis. Lately, B cell responses have received increasing interest in transplant rejection and include responses against both major histocompatibility complex (MHC) and tissue-specific antigens, mainly on the endothelium and in the glomeruli. These humoral responses are thought to be involved in the development of vascular and glomerular lesions. Furthermore, at the tissue level, markers of senescence are found in the tubular epithelium contributing to the lesions of tubular atrophy and interstitial fibrosis.

Aging↗

PubMed2004

Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes.

Anti-C1q autoantibodies are present in sera of patients with several autoimmune diseases, including systemic lupus erythematosus (SLE). Strikingly, in SLE the presence of anti-C1q is associated with the occurrence of nephritis. We have generated mouse anti-mouse C1q mAb's and used murine models to investigate whether anti-C1q autoantibodies actually contribute to renal pathology in glomerular immune complex disease. Administration of anti-C1q mAb JL-1, which recognizes the collagen-like region of C1q, resulted in glomerular deposition of C1q and anti-C1q autoantibodies and mild granulocyte influx, but no overt renal damage. However, combination of JL-1 with a subnephritogenic dose of C1q-fixing anti-glomerular basement membrane (anti-GBM) antibodies enhanced renal damage characterized by persistently increased levels of infiltrating granulocytes, major histological changes, and increased albuminuria. This was not observed when a non-C1q-fixing anti-GBM preparation was used. Experiments with different knockout mice showed that renal damage was dependent not only on glomerular C1q and complement activation but also on Fcgamma receptors. In conclusion, anti-C1q autoantibodies deposit in glomeruli together with C1q but induce overt renal disease only in the context of glomerular immune complex disease. This provides an explanation why anti-C1q antibodies are especially pathogenic in patients with SLE.

Animals↗

PubMed2003

Pathogenesis of chronic allograft rejection.

Chronic allograft nephropathy (CAN) is, besides death of the recipient with graft function, the most common cause of renal transplant loss. It is characterized by loss of function and replacement of tissue by fibrotic material. The pathogenesis is not clear, but seems to be multifactorial and involves events both early and late after transplantation. Alloantigen-dependent mechanisms seem to be crucial for the development of chronic rejection (CR). Although modern immunosuppressive drugs have reduced the number and severity of acute rejection episodes, their effects on CR are less obvious. In this review we discuss the role of direct and indirect antigen presentation in the development of CR, and we will focus on the production of antibodies directed against HLA and non-HLA antigens on the graft and their influence on CR.

Acute Disease↗

PubMed2003

Telomere shortening and cellular senescence in a model of chronic renal allograft rejection.

Cellular senescence has been suggested to play a role in the deterioration of renal graft function and has been linked to telomere shortening. We have investigated markers of cellular senescence in the F344 to LEW rat model of chronic renal transplant rejection. Syngeneic and LEW to F344 transplants were used as controls. Substantial telomere shortening was observed in all transplants, including allogeneic and syngeneic grafts from day 7 post-transplant onwards. Ischemia of native F344 kidneys was already sufficient to induce telomere shortening. It is known that shortened telomeres can activate cell cycle regulators, such as p21 and p16. Accordingly, all cases showed a transient p21 increase, with a maximum at day 7 and a sustained expression of p16. Importantly, senescence-associated beta-galactosidase staining, a cytological marker for senescence, was only observed in tubular epithelial cells of chronically rejecting F344 allografts from day 30 post-transplantation onwards. Long-term surviving LEW allografts or syngeneic F344 grafts were negative for senescence-associated beta-galactosidase. In conclusion, ischemia during transplantation results in telomere shortening and subsequent activation of p21 and p16, whereas senescence-associated beta-galactosidase staining is only present in chronically rejecting kidney grafts.

Animals↗