Biomedical subjects

E de Heer

Publications and source records attributed to E de Heer.

At least 19 recordsLinked to original sources

PubMed2000

Distinctive roles of neutrophils and monocytes in anti-thy-1 nephritis.

Anti-Thy-1.1 glomerulonephritis as an experimental model for mesangial proliferative glomerulonephritis was induced in Wistar rats by a single injection of monoclonal IgG2a-anti-Thy-1.1 antibody (ER4G). This transient model is complement-mediated and leads to mesangial-cell (MC) lysis followed by MC proliferation, glomerular microaneurysm formation, glomerular influx of polymorphonuclear leukocytes (PMNs) and macrophages, proteinuria, and hematuria. In this study we investigated the distinctive roles of infiltrating PMNs or monocytes/macrophages by treating rats with an antibody against rat integrin CD11b/CD18 (ED7) or by depletion of monocytes with multilamellar clodronate liposomes, respectively. ED7 administration resulted in reduction of the influx of PMNs in glomeruli during the first 6 days after induction of Thy-1.1 nephritis, whereas treatment with an isotype-matched irrelevant antibody (PEN9) or with phosphate-buffered saline had no effect on macrophage influx. Increased glomerular C3 and C6 deposition on days 1 and 3 was seen in the ED7-treated rats but not seen in the control groups. In addition, the ED7-treated group showed an increased number of aneurysmatic glomeruli and more severe hematuria. Monocyte/macrophage depletion led to a significant reduction of mesangial matrix expansion, although mesangial proliferation, proteinuria, and hematuria remained unaltered. These results, together with the known effects of PMN-derived enzymes on C3 cleavage, suggest that a reduction in the influx of PMNs results in sparing of C3 and consequently of more complement activation in the glomerulus with increased complement-mediated damage. Our data indicate that infiltrating PMNs and monocytes/macrophages play distinctive roles during inflammation in this model of MC glomerulonephritis.

Animals↗

PubMed2000

Acute glomerular upregulation of ornithine decarboxylase is not essential for mesangial cell proliferation and matrix expansion in anti-Thy-1-nephritis.

BACKGROUND: Pathways of L-arginine metabolism including nitric oxide, agmatine and polyamine synthesis are upregulated during glomerular inflammation in experimental glomerulonephritis. In anti-Thy-1-glomerulonephritis L-arginine-deficient diets ameliorate the disease course in this model. However, it is unclear which metabolic pathway is affected by this substrate depletion. Since polyamines are important proproliferative molecules, we studied the effect of specific polyamine synthesis blockade in vivo on mesangial cell proliferation and glomerular fibrosis in this model. METHODS: Anti-Thy-1-glomerulonephritis was induced in male Sprague-Dawley rats by single-bolus injection of monoclonal ER4-antibodies. Rats were treated with difluoromethylornithine (0.5-2% in the drinking water), a selective inhibitor of the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC). Mesangial cell proliferation and matrix expansion were evaluated in PAS-stained kidney tissues. Glomerular TGF-beta and biglycan-mRNA-expression were determined by Northern blot analysis and albuminuria was measured using a competitive ELISA. Data were compared to untreated controls. RESULTS: Though complete inhibition of ODC activity was achieved at any time point, difluoromethlornithine treatment had no significant effect on albuminuria, glomerular matrix protein expression and mesangial cell count in this model. CONCLUSIONS: The acute upregulation of glomerular ODC activity above baseline in anti-Thy1-glomerulonephritis is not pathophysiologically important for disease development however, biological effects of available polyamine pools cannot be excluded by our study.

Animals↗

PubMed1999

Cellular localization and tissue distribution of polycystin-1.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of fluid-filled cysts in both kidneys, in addition to a variety of extra-renal manifestations. The PKD1 gene product, polycystin-1, encodes a novel protein with a putative role in cell-cell/cell-matrix interactions. The present study we focused on the (sub)cellular localization of polycystin-1 in cultured cells, and on its tissue distribution in various organs. In Madin Darby canine kidney (MDCK) cells, several polyclonal antibodies showed intense staining at the sites of interaction between adjacent cells, which remained after Triton extraction. Weak cytoplasmic staining was observed. No signal was detected at the free borders of cell aggregates, supporting a role for polycystin-1 in cell-cell interactions. At the tissue level, polycystin-1 expression was observed in specific cell types in tissues with known manifestations of the disease, but also in tissues of organs which have not been reported to be affected in ADPKD. Expression was frequently seen in epithelia, but also in endocrine cells (pancreatic islets, parathyroid-producing cells, clusters in the adenohypophysis, clusters in the adrenal gland, and Leydig cells in the testis). In addition, expression was observed in myocardium and more weakly in myocytes of cardiac valves, of the cerebral arteries, and of skeletal muscles.

Animals↗

PubMed1999

Differential expression of collagen type IV alpha-chains in the tubulointerstitial compartment in experimental chronic serum sickness nephritis.

The expression of collagen type IV chains in the renal tubulointerstitium was investigated during the development of chronic serum sickness (CSS) in rats, a model for immune complex-mediated renal disease. Immunohistochemical studies showed increased expression of alpha4(IV) collagen early during disease development, followed by an increase in alpha1(IV) through alpha3(IV) collagen subchain expression, especially in the tubular basement membrane. Dot-blot and in situ hybridization analysis showed a transient increase in steady-state mRNA levels for all collagen IV subchains during the development of CSS, which was most abundant for alpha1(IV), alpha2(IV), and alpha4(IV). Statistical correlations were found between the mRNA levels of alpha1(IV) and alpha2(IV) collagen and between alpha3(IV) and alpha4(IV), in line with the results of others which showed that these chains are co-distributed as heterotrimer collagen type IV molecules. However, additional correlations were found between the mRNA levels coding for alpha1(IV) and alpha3(IV) collagen, and between alpha1(IV) and alpha4(IV) mRNAs in the course of CSS. These abnormal correlations support the hypothesis that changes occur in the co-expression of the collagen IV subchains during the development of CSS. In addition, a strong correlation was found between the presence in the tubulointerstitium of alpha1(IV) and alpha2(IV) collagen chains, on the one hand, and the tubulointerstitial influx of R73+ and ED1+ cells, on the other, suggesting the involvement of inflammatory cells in the observed alterations in matrix production. Changes in the relative abundance of collagen IV chains in disease states may perturb the collagen IV network in the tubulointerstitial compartment and thereby play a role in the development of renal failure.

Animals↗

PubMed1999

Combined administration of IgA and IgG anti-Thy-1 antibodies enhances renal inflammation in rats.

BACKGROUND: IgA nephropathy (IgAN) is the most common type of immunologically mediated glomerulonephritis (GN) and is characterized by deposition in the glomerular mesangium of IgA together with C3, C5b-9, and properdin. In patients, the codeposition of IgA together with IgG and/or IgM can lead to a more progressive course of disease. In Wistar rats, mesangial proliferative GN can be induced by the injection of mouse IgG anti-Thy-1 antibodies (ER4G). In contrast, the administration of mouse IgA anti-Thy-1 antibodies (ER4A) to rats results in isolated hematuria without detectable albuminuria and without detectable complement deposition. METHODS: To investigate the effect of the combination of IgA and IgG on glomerular injury, Wistar rats were injected with a limiting dose of ER4G in the presence or absence of ER4A in a dose able to induce hematuria. RESULTS: Although the limiting dose of ER4G or the dose of ER4A used did not induce significant albuminuria, the combination of ER4G and ER4A resulted in a synergistic increase in albuminuria. Microhematuria occurred in rats receiving either ER4A or ER4G alone or in combination. Although both ER4A or a limiting dose of ER4G induced minor increases in extracellular matrix expansion, the combination resulted in a pronounced, additive increased matrix expansion. CONCLUSION: We conclude that in this model of IgA-mediated glomerulopathy, a selective complement-dependent synergistic renal injury is induced in Wistar rats by glomerular codeposition of mouse anti-Thy-1 monoclonal isotypes.

Animals↗

PubMed1998

Association between leukocyte infiltration and development of glomerulosclerosis in experimental lupus nephritis.

Mice with chronic graft-versus-host disease (GvHD) induced by injection of DBA/2 lymphocytes into (DBA/2 x C57BL/10) F1 hybrids (DBA/2 GvHD) develop a lupus-like glomerulonephritis with global glomerulosclerosis 12 weeks after induction of the disease. In two other strain combinations with similar H-2 incompatibilities [BALB/c into BALB/c x BL10 (BALB/c GvHD) and BALB.D2 into BALB.D2 x BL10 (BALB.D2 GvHD)], GvHD induction leads to lupus nephritis without global glomerulosclerosis. This study investigated the identity of kidney-infiltrating leukocytes and their involvement in the development of glomerulosclerosis in these three strain combinations. In mice with DBA/2 GvHD, a significant increase in glomerular CD11a-positive cells was found 4 weeks after disease induction. Mice with BALB/c or BALB.D2 GvHD did not show an increase in glomerular CD11a-positive cells at any time point. In the interstitium, CD11a-positive cells were observed 4 weeks after disease induction only in mice with DBA/2 GvHD. In mice with BALB.D2 GvHD, no increase was found in interstitial CD11a-positive cells. In mice with BALB/c GvHD, interstitial CD11a-positive cells were found from week 4 onward. Further immunohistochemical analysis of the glomerular CD11a-positive cells in mice with DBA/2 GvHD showed that these cells were neither polymorphonuclear leukocytes (PMN), nor CD3-positive (T cells), B220-positive (B cells), or F4/80-positive (macrophages). They were all CD45-positive (leukocytes) and MHC class II-positive. In conclusion, we have shown in this model of chronic lupus nephritis that glomerular influx of as yet unidentified CD11a-positive leukocytes is associated with the development of glomerulosclerosis.

Animals↗

PubMed1998

Differential expression of collagen IV isoforms in experimental glomerulosclerosis.

Expansion of the glomerular mesangial matrix (MM), thickening of the glomerular basement membrane (GBM), and eventually the development of glomerulosclerosis are often seen in immunologically mediated kidney diseases. In addition to quantitative changes in the extracellular matrix (ECM), qualitative changes in ECM molecules may contribute to alterations in the composition of the glomerular matrix. The expression of collagen IV, alpha 1-5(IV) mRNA, and polypeptides was therefore investigated during the development of chronic graft-versus-host disease (GvHD) in mice, a model for lupus nephritis, and in chronic serum sickness (CSS) in rats, a model for membranous nephropathy. Immunohistochemical studies showed increased mesangial expression of alpha 1 and alpha 2 early in the disease, but only late in the GBM. In contrast, alpha 3 and alpha 4 increased in the GBM during disease, but not in the MM. The mRNA levels for all collagen IV chains were increased in isolated glomeruli before morphological alterations were detectable. The mRNA increase was earlier and more profound for alpha 3, alpha 4 and alpha 5 than for alpha 1 and alpha 2. Expression of alpha 3(IV) was greatest in GvHD, whereas expression of alpha 4 was greatest in CSS. As determined by in situ hybridization (ISH), alpha 1 mRNA was observed dispersed in the glomerulus, but alpha 3, alpha 4, and alpha 5 mRNAs were mainly located in cells at the periphery of the glomerular tuft. The changes in the relative abundance of collagen IV mRNA in disease states may perturb the collagen IV network, altering glomerular structure and function, and may thereby play a central role in the development of glomerulonephritis and glomerulosclerosis.

Animals↗

PubMed1998

Experimental glomerulonephritis is attenuated by CD8+ T cell chimerism and prevented by Mls-1-incompatible thymocytes.

Chronic graft-versus-host disease (GvHD) in mice is a model resembling glomerulonephritis in human systemic lupus erythematosus. In the present study congenic mouse strains were used to investigate the pathogenetic role of (1) donor T cell subset chimerism and (2) donor thymocytes in this model. In GvHD employing minor lymphocyte-stimulating-1 (Mls-1)-compatible donors and recipients, full-blown immune complex glomerulonephritis was associated with a low-donor CD8(+) T cell chimerism. Injection of lymphocytes from Mls-1-negative donors (Mls-1(b)) into Mls-1-positive recipients (Mls-1(a)) induces a type of GvHD characterized by rapid self-limitation accompanied by the immediate inhibition of donor T cell chimerism and the absence of glomerulonephritis. However, omission of thymocytes from the donor inoculate does result in glomerular depositions containing immunoglobulins. These results suggest that donor CD8(+) T cell chimerism is associated with attenuation of immune complex glomerulonephritis, whereas Mls-1-incompatible donor T cell precursors prevent the disease.

Animals↗

PubMed1998

Tissue chimerism in human cryopreserved homograft valve explants demonstrated by in situ hybridization.

BACKGROUND: The presence of viable cells may contribute to increased homograft valve durability. These cells may be of infiltrating recipient or persisting donor origin. In this study, in situ hybridization was used to assess the origin of cells in cryopreserved homograft valve explants. METHODS: A total of 10 homografts with a donor-recipient gender mismatch were acquired from patients whose graft had been explanted at reoperation or at autopsy. The period of implantation varied from 14 days to 70 months. Frozen sections were made and alternately examined with hematoxylin and eosin staining and in situ hybridization. Male cells were distinguished from female using a biotinylated Y-chromosome-specific deoxyribonucleic acid probe. RESULTS: No endothelial cells were found. Thirty percent of the leaflets showed large acellular zones and 30% were completely acellular. The homograft arterial wall was occupied by a vast majority of penetrating host fibroblasts in 80% of the studied specimens. Donor and recipient cells were coexistent in the wall in 60% of the studied specimens and in 50% of the leaflets. In 30% only host cells could be identified. CONCLUSIONS: This finding of tissue chimerism may lead to new insights in homograft pathology. The technique of in situ hybridization may provide an indispensable contribution in further homograft research.

Adolescent↗

PubMed1998

Disproportionate enlargement of the pulmonary autograft in the aortic position in the growing pig.

PURPOSE: This study was aimed to demonstrate growth in the pulmonary autograft after transplantation to the aortic position. METHODS AND MATERIALS: In 20 piglets (weight 25.4 +/- 3.5 kg) (mean +/- standard deviation) a Ross operation was performed and in five piglets (weight 9.3 +/- 0.7 kg) (mean +/- standard deviation) the ascending aorta was replaced with a valveless pulmonary autograft. Animals were allowed to grow as much as possible. Postmortem explanted autografts were studied by direct measurements of the valve cusps in the Ross group and of the wall segments in the valveless autograft group. Measurements of the first group were compared with the values of a separate control group, and values of the second group were compared with values of samples taken at operation. RESULTS: In the Ross group, cuspal weight, height, and width increased significantly by comparison with body weight (p < or = 0.003). The rate of increase did not differ significantly from that of the control group with a native pulmonary valve. However, there was a rapid adaptation of the autograft valves resulting in a significantly higher mean cuspal weight, height, and width. In the valveless autograft group, wall circumference, thickness, and height increased significantly (p < or = 0.001). The circumference increased significantly more than that of the native pulmonary wall. Compared with the native aortic wall, the pulmonary autograft media showed retained pulmonary architecture on microscopic study. CONCLUSION: These data suggest that the dimensional increase of the pulmonary autograft in the aortic position in the growing pig is determined by growth and dilatation, that the valve mass increases more than that of the native pulmonary valve, and that the characteristic pulmonary microscopic architecture is retained.

Aging↗

PubMed1998

Antibodies against mesangial cells and their secretory products in chronic renal allograft rejection in the rat.

Antibodies or cell-mediated immunity can cause chronic rejection of vascularized organ grafts, but the nature and specificity of the antigen(s) involved has remained elusive. We have previously demonstrated the presence of antibodies against cryptic glomerular basement membrane antigens and undefined antigens in the mesangial area in rats with chronic renal allograft rejection. Current experiments were designed to study the post-transplant antibody response against cultured mesangial and endothelial cells in rats with chronic rejection using flow cytometry, indirect immunofluorescent staining, immunoelectron microscopy, confocal microscopy, and Western blots. The results were compared with those obtained with alloantisera raised by immunization with cultured mesangial cells. Post-transplant and post-immunization sera contained IgG antibodies against trypsinized mesangial cells detected by flow cytometry. Indirect immunofluorescent studies using mesangial cells grown on coverslips showed autoantibody binding to cytoplasmic granules in cultures early after plating whereas staining of later cultures showed antibody binding in an interrupted, web-like pattern on the outside of the cells. Immunoelectron microscopy showed autoantibody binding to intracellular secretory granules and to cell surface focal adhesion plaques. The latter finding was confirmed in double-labeling experiments with an antiserum against vinculin. Western blots with mesangial cell culture supernatants demonstrated autoantibody reactivity with antigens in the 40-kd and 60- to 70-kd range, and immunoprecipitation identified these molecules as biglycan and decorin. Absorption of the sera with mesangial cell culture supernatant removed most of the antibodies except those that gave a punctate staining with the mesangial cell surface. However, not all immunostaining of mesangial cells could be explained by antibodies against biglycan and decorin. Post-transplant sera, furthermore, contained low-titered antibodies against endothelial cells. We conclude that rats with chronic renal transplant rejection produce a strong autoantibody response against mesangial cell focal adhesion plaques and proteins secreted by these cells in culture. Such antibodies may cause local damage and interfere in the tissue repair process after injury.

Animals↗

PubMed1997

Fatal attraction: adhesion molecules and disease.

Knowledge of molecular mechanisms in cell-cell and cell-matrix adhesion has increased rapidly in the past decade. Adhesion mechanisms are of prime importance in both physiology and pathology. With respect to the kidney, expression of adhesion molecules has been studied in a variety of diseases, including various forms of glomerulonephritis. Hitherto, these descriptive studies have merely launched extensive speculation regarding the role of adhesion mechanisms in renal pathology. A logical next step is to correlate adhesion molecule expression to alterations in structures which may possibly be affected by altered adhesion, for example gap junctions. Current studies linking structural to functional adhesion expand our understanding of cell biology in health and disease.

Cell Adhesion↗

PubMed1997

Matrix and adhesion molecules in kidney pathology: recent observations.

The purpose of this article is to review a set of recently obtained data concerning matrix and matrix adhesion molecules in renal disease. Our goal is not to cover the entire topic, but rather to focus on findings obtained with an experimental model for chronic lupus nephritis, evoked in mice by inducing graft-versus-host disease (GVHD). The overall aim of these studies was to investigate the role of adhesion molecules as targets for autoantibodies, in the recruitment of inflammatory cells, and in the accumulation of matrix in kidney disorders. In addition, we set out to discover how matrix proteins in renal diseases differ from normal matrix molecules both quantitatively, in their increased frequency, and qualitatively, in their intramolecular structure. The advances in understanding and methodology described in this review imply a substantial capability for greater insight into the pathogenesis of kidney disease; for making better use of renal biopsies, such as in applying competitive reverse-transcriptase-polymerase chain reaction (RT-PCR) in RNA analysis for matrix; and in developing more effective treatment strategies for patients with kidney disease.

Animals↗

PubMed1997

Expression of the transcriptional regulator Egr-1 in experimental glomerulonephritis: requirement for mesangial cell proliferation.

The early growth response gene-1 (Egr-1), a zinc finger transcriptional regulator, was induced in a rat model of mesangioproliferative glomerulonephritis (GN). Northern blot analysis revealed a maximal 14.9-fold increase in glomerular Egr-1 mRNA at day 6 of GN. By immunohistochemistry Egr-1 protein expression was demonstrated to be mainly confined to glomerular mesangial cells (MC). To test whether Egr-1 directly regulates MC proliferation, cultured MCs were stimulated with platelet-derived growth factor (PDGF) after preincubation with different Egr-1 antisense oligonucleotides (ASOs). PDGF-induced rise in 3H-thymidine uptake by 83% and almost completely abrogated increase in MC number. We conclude that Egr-1 induction is of critical importance for PDGF-induced mitogenic signaling in MCs, and inhibition of Egr-1 in vivo may offer an approach to oppose glomerular MC proliferation in glomerular inflammatory disease.

Animals↗

PubMed1997

Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain.

Cisplatin-induced nephrotoxicity was studied in porcine proximal tubular cells, focusing on the relationship between mitochondrial damage, reactive oxygen species (ROS) and cell death. Cisplatin specifically affected mitochondrial functions: complexes I to IV of the respiratory chain were inhibited 15 to 55% after 20 min of incubation with 50 to 500 microM, respectively. As a result, intracellular ATP was decreased to 70%. The mitochondrial glutathione (reduced form) (GSH)-regenerating enzyme GSH-reductase (GSH-Rd) activity was reduced by 20%, which contributed to a 70% reduction of GSH levels and ROS formation. The residual electron flow through the mitochondrial respiratory chain was the source of ROS because additional inhibition of the complexes I to IV reduced ROS formation. Because cisplatin affects both GSH-Rd and complexes I to IV, cells were incubated with N,N'-bis(2-chloroethyl)-N-nitrosourea (inhibitor of GSH-Rd) and inhibitors of the different complexes. Only N,N'-bis(2-chloroethyl)-N-nitrosourea with rotenone (complex I inhibitor) induced ROS formation, which indicates that inhibition of complex I and inhibition of the GSH-Rd is probably the cause of ROS formation. However, the resulting ROS is not the cause of cell death because diphenyl-p-phenylene-diamine and deferoxamine, which completely prevented ROS, could not prevent cell death. Similarly, the antioxidants did not completely prevent the decrease in activity of complexes I to IV, ATP or GSH levels. In conclusion, ROS formation does occur during cisplatin-induced toxicity, but it is not the direct cause of cell death.

Adenosine Triphosphate↗

PubMed1997

T cell subsets in immunologically-mediated glomerulonephritis.

Until recently, research on the pathogenesis of glomerulonephritis has been mainly focused on the characterization of humoral immune responses in the initiation of glomerular injury. However, there is a growing recognition that both cellular and humoral immune responses, in varying proportions, are involved in the pathogenesis of immunologically-mediated glomerulonephritis. T lymphocytes are essential cellular elements of cell-mediated immunity. Both in experimental models of immune-mediated renal disease and in histopathological analyses of human nephropathies, the involvement of T cells has been demonstrated in the immunoregulation of nephritogenic immune responses and in the immune injury in the kidney. T cell activation resulting in either delayed-type hypersensitivity, cytolytic reactions, abnormal expression of major histocompatibility complex (MHC) molecules, or B cell activation can result in glomerulonephritis. These different types of responses are exerted by distinct T cell subsets defined by cell surface markers and cytokine profiles. CD4+ T cells in vivo are functionally heterogeneous with respect to cytokine production and the CD45 isoforms that are found on their surface. Like CD4+ T cells, CD8+ T cells may also be heterogeneous at the level of cytokine production. The roles of CD4+ and CD8+ cells and their cytokine profiles in glomerulonephritis have not been extensively investigated yet, but such studies might improve the understanding of the pathogenesis and possibly lead to new therapeutic approaches of human glomerulonephritis. In this review the role of distinct T lymphocyte subsets in experimental and human glomerulonephritis will be discussed.

Animals↗

PubMed1997

Collagen types VIII and X, two non-fibrillar, short-chain collagens. Structure homologies, functions and involvement in pathology.

Collagens can be divided into two groups, i.e., fibrillar and non-fibrillar collagens. Short-chain collagens, a subgroup of non-fibrillar collagens, comprises collagen type VIII and type X. These two collagen types show several similarities in structure and possibly also in function. Type VIII collagen appears to be secreted by rapidly proliferating cells. It can be found in basement membranes and may serve as a molecular bridge between different types of matrix molecules. In different tissues this collagen type may serve different functions. Stabilization of membranes, angiogenesis, and interactions with other extracellular matrix molecules. Since collagen type X is produced by hypertrophic chondrocytes, this collagen type can only be found in matrix of the hypertrophic zone of the epiphyseal growth plate cartilage. Collagen type X is probably involved in the process of mineralization, endochondral ossification, and is also proposed to play a role in angiogenesis. Collagen types VII and X may be involved in matrix and bone disorders. Their structure, function, and involvement in pathology are discussed in this review.

Animals↗

PubMed1997

Blocking of alpha 1 beta 1 integrin strongly improves survival of hepatocytes in allogeneic transplantation.

The survival rate of hepatocytes after allogeneic hepatocyte transplatation (HTX) is low, possibly because of formation of intravascular hepatocyte aggregates. The aim of this study was to determine the role of integrins in intravascular aggregation and intraparenchymal survival of transplanted hepatocytes in a fully allogeneic rat model. First, the expression profile of various integrins was determined on both isolated hepatocytes in vitro and on hepatocyte aggregates in recipient livers after intraportal transplantation of allogeneic hepatocytes. Next, the role of these integrins in hepatocyte aggregation was determined in an in vitro attachment assay on liver sections with function-blocking anti-integrin monoclonal antibodies (mAb). The results showed that anti-alpha 1 beta 1 integrin mAb significantly block hepatocyte attachment to vessel walls and liver parenchyma in vitro. Subsequently, the effect of preincubation of hepatocytes with anti-integrin mAb on their intravascular aggregation and on intraparenchymal survival was studied in an allogeneic HTX model. Preincubation with anti-leukocyte function-associated antigen-1 alpha or anti-beta 2 mAb significantly intravascular hepatocyte aggregation, and anti-leukocyte function-associated antigen-1 alpha mAb enhanced intraparenchymal survival. Preincubation with anti-alpha 1 or anti-beta 1 mAb did not inhibit aggregation but significantly improved survival from 2% to up to 45% at Day 2 after transplantation (p < 0.001). In conclusion, our results suggest that the blocking of alpha 1 beta 1 integrin significantly improves survival of allotransplanted hepatocytes.

Animals↗