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J Rozing

Publications and source records attributed to J Rozing.

At least 19 recordsLinked to original sources
PubMed2006

Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes?

AIMS/HYPOTHESIS: Accumulating data suggest that the gut immune system plays a role in the development of type 1 diabetes. The intestinal flora is essential for the development of the (gut) immune system and the establishment of tolerance. It has been reported that oral administration of food and bacterial antigens early in life suppresses later development of diabetes in the Bio-Breeding diabetes-prone (BB-DP) rat. This study was designed to investigate the possible relationship between the development of diabetes and the composition of intestinal flora. MATERIALS AND METHODS: The intestinal flora of BB-DP rats, a rat model for type 1 diabetes, was characterised long before the clinical onset of diabetes by fluorescent in situ hybridisation. In a separate experiment, BB-DP rats were treated with antibiotics and the effect on diabetes incidence and level of insulitis was analysed. RESULTS: We observed a difference in bacterial composition between rats that eventually did and those that did not develop diabetes. This difference was detectable long before clinical onset of the disease. Rats that did not develop diabetes at a later age displayed a lower amount of Bacteroides sp. Modulation of the intestinal flora through antibiotic treatment decreased the incidence and delayed the onset of diabetes. A combination of antibiotic treatment and a protective hydrolysed casein diet completely prevented diabetes in the BB-DP rat. CONCLUSIONS/INTERPRETATION: Our data suggest that the intestinal flora is involved in the development of type 1 diabetes. Factors influencing composition of the intestinal flora could be a target for therapeutic intervention.

Animals↗
PubMed2006

Costimulation and autoimmune diabetes in BB rats.

Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55-120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.

Animals↗
PubMed2004

Neonatal oral administration of DiaPep277, combined with hydrolysed casein diet, protects against Type 1 diabetes in BB-DP rats. An experimental study.

AIMS/HYPOTHESIS: Environmental factors such as diet and bacterial antigens play an important role in the onset of Type 1 diabetes. Different self-antigens are suggested to play a role in the development of diabetes. Antibodies against the 60-kDa heat shock protein 60, which have a high homology to bacterial heat shock protein 65, have been found in the circulation at the onset of diabetes in humans and in pre-diabetic NOD-mice. One of the immunodominant epitopes in autoimmune diabetes is p277, a specific peptide of human heat shock protein 60 corresponding to positions 437-460. In this study we investigated whether neonatal oral administration of DiaPep277 (a synthetic peptide analogue of p277) affected the development of diabetes in the BioBreeding-Diabetes Prone (BB-DP) rat, and whether this could potentiate the effect of a protective hydrolysed casein-diet. METHODS: BB-DP rats were orally inoculated once per day with placebo or DiaPep277 at days 4, 5, 6 and 7 of life. At the age of 21 days rats were weaned on to a conventional, cereal-based diet or on to the hydrolysed casein-diet. RESULTS: The development of diabetes in animals receiving DiaPep277 in combination with the hydrolysed casein-diet was delayed by 17 days, and a relative reduction of the incidence by 64% was seen. Non-diabetic animals did not show any sign of insulitis. CONCLUSIONS/INTERPRETATION: Short-term neonatal feeding with p277 in early life, combined with diet adaptation, appears to provide a procedure to significantly reduce the development of Type 1 diabetes in later life.

Administration, Oral↗
PubMed2004

Enteropathy precedes type 1 diabetes in the BB rat.

BACKGROUND AND AIMS: There is increasing evidence implicating intestinal immune responses to dietary proteins in the pathogenesis of type 1 autoimmune diabetes (T1D). Here we investigated the association between intestinal pathology and dietary factors in T1D by examining the mucosal architecture in the BB rat model. METHODS: BB control (BBc) and diabetes prone (BBdp) rats were fed either a diabetes retardant hydrolysed casein based diet or one of two cereal based diets that promote the development of diabetes. Intestinal architecture was assessed in the jejunum by microdissection, histology, and immunohistology, and by measuring peroxidase activity and brush border invertase levels. RESULTS: Enteropathy was present in BBdp rats soon after weaning, as assessed by increases in crypt length and in the proliferative activity of crypt epithelial cells in the jejunum, and this remained constant until 120 days of age. There was also a decrease in invertase activity, as well as increased numbers of intraepithelial lymphocytes, increased levels of mucosal peroxidase activity, and infiltration of the mucosa by CD4(+) T lymphocytes. Equivalent enteropathy was present at all times in BBdp rats and was not influenced by the nature of the diet or by thymectomy at three weeks at age, procedures which prevent the development of diabetes. CONCLUSION: Enteropathy is a consistent feature in the diabetes prone BB rat but it precedes the onset of insulitis and appears to be due to mechanisms distinct from those which cause diabetes. The beneficial effects of the diabetes retardant hydrolysed casein diet on diabetes are not due to an effect on intestinal architecture per se but mucosal damage may be necessary for the development of autoreactivity in the pancreas.

Animals↗
PubMed2003

Dissemination of rat cytomegalovirus through infected granulocytes and monocytes in vitro and in vivo.

The role of leukocytes in the in vivo dissemination of cytomegalovirus was studied in this experiment. Rat cytomegalovirus (RCMV) could be transferred to rat granulocytes and monocytes by cocultivation with RCMV-infected fibroblasts in vitro. Intravenous injection of purified infected granulocytes or monocytes resulted in a systemic infection in rats, indicating that our model is a powerful tool to gain further insight into CMV dissemination and the development of new antivirals.

Animals↗
PubMed2003

Long-term prophylactic insulin treatment can prevent spontaneous diabetes and thyroiditis development in the diabetes-prone bio-breeding rat, while short-term treatment is ineffective.

OBJECTIVE: Prophylactic insulin treatment has been demonstrated to reduce diabetes development in the diabetes-prone bio-breeding (DP-BB) rat. These prophylactic insulin treatments were given from 50 to 150 days of age. However, several data indicate that the diabetogenic process in DP-BB rats starts well before day 50. DESIGN AND METHODS: DP-BB rats were given bovine insulin pellets from 21 to 60 days of age, from 21 to 100 days of age and from 60 to 100 days of age. At 160 days of age a glucose tolerance test was performed to establish beta-cell function and pancreata collected for histological analysis. RESULTS: Prophylactic insulin treatment from 21 to 100 days of age gave a 42% reduction of diabetes incidence. The other treatment protocols had no effect. Non-diabetic rats treated with insulin from day 21 to 100 showed normal glucose tolerance and no sign of insulitis at 160 days of age. Non-diabetic rats of the control group and the other treatment groups showed normal glucose tolerance, but a slight increase of insulitis. Interestingly, the 21-100 day treated rats showed reduced serum levels of anti-colloid antibodies as compared with the control group. CONCLUSIONS: These results show that short-term prophylactic insulin treatment cannot prevent diabetes and thyroiditis development in DP-BB rats. The prophylactic treatment must start well before 60 days of age and be prolonged into the phase when the rats normally become diabetic to reduce diabetes incidence. These findings imply that in the human situation prophylactic insulin treatment must be prolonged over the normal range of diabetes onset.

Animals↗
PubMed2001

Intrathymic immune modulation prevents acute rejection but not the development of graft arteriosclerosis (chronic rejection).

BACKGROUND: We showed previously that our intrathymic immune modulation protocol induces virtually permanent graft survival of simultaneously transplanted cardiac allografts in MHC-incompatible rat strain combinations. It is, however, unknown whether this procedure prevents the development of graft arterial disease (GAD). METHODS: Male AO recipient rats were intrathymically inoculated with 2.5x10(7) PVG splenocytes immediately followed by heterotopic transplantation of a PVG cardiac allograft (day 0). Immunosuppression consisted of 1 ml of antilymphocyte serum i.p. (day 0) and cyclosporine i.m. (15 mg/kg body weight) on days 1, 2, and 3 posttransplantation. Histological analysis, mixed lymphocyte reactions, and intragraft cytokine mRNA expression were performed at several time points after engraftment. RESULTS: Histological analysis revealed that GAD was already present 14 days after transplantation. At 200 days, virtually all vessels were affected and over 80% of the vessels showed severe intimal lesions. Infiltrate analysis displayed massive parenchymatous infiltrates (CD8+ cells and ED1+ macrophages) 2 weeks after transplantation. At later time points, infiltrates became epicardial and/or blood vessel associated and mainly consisted of CD4+, CD8+, and B cells. Mixed lymphocyte reactions showed nonspecifically decreased responses at 60 days but complete restoration of these responses at later time points (120 to 280 days). Intragraft cytokine mRNA expression showed decreased interleukin-2/interferon-gamma and sustained interleukin-10 expression 2 weeks after transplantation. Transforming growth factor-beta mRNA expression was increased >200 days after transplantation. CONCLUSIONS: Intrathymic immune modulation does not abolish alloreactivity, and despite induction of long-lasting graft survival, this procedure does not prevent and may even facilitate the development of GAD.

Acute Disease↗
PubMed2001

Origin of neointimal endothelium and alpha-actin-positive smooth muscle cells in transplant arteriosclerosis.

The development of transplant arteriosclerosis (TA) is today's most important problem in clinical organ transplantation. Histologically, TA is characterized by perivascular inflammation and progressive intimal thickening. Current thought on this process of vascular remodeling assumes that neointimal vascular smooth muscle (VSM) cells and endothelium in TA are graft-derived, holding that medial VSM cells proliferate and migrate into the subendothelial space in response to signals from inflammatory cells and damaged graft endothelium. Using MHC class I haplotype-specific immunohistochemical staining and single-cell PCR analyses, we show that the neointimal alpha-actin-positive VSM cells in rat aortic or cardiac allografts are of recipient and not of donor origin. In aortic but not in cardiac allografts, recipient-derived endothelial cells (ECs) replaced donor endothelium. Cyclosporine treatment prevents neointima formation and preserves the vascular media in aortic allografts. Recipient-derived ECs do not replace graft endothelium after cyclosporine treatment. We propose that, although it progresses beyond the needs of functional repair, TA reflects the activity of a normal healing process that restores vascular wall function following allograft-induced immunological injury.

Actins↗
PubMed2000

Rat cytomegalovirus replication in the salivary glands is exclusively confined to striated duct cells.

The salivary gland is the preferred organ for cytomegalovirus (CMV) replication and viral persistence. In order to identify the nature of infected cells and to study viral replication in more detail, several experiments were conducted. Using the rat CMV (RCMV) model, acutely infected young adult rats (6 weeks of age) and new-born rats (3 days of age) were infected, and submandibular, parotid and sublingual glands were harvested at different time points after infection. For identification of the nature of infected cells, immunohistochemistry, in situ hybridisation and electron microscopic techniques were used. In young adult animals, the submandibular gland was the preferred organ for RCMV replication. The parotid and sublingual glands contained fewer viruses than the submandibular gland. In contrast, in new-born rats, the main site of RCMV replication was the sublingual gland, while the submandibular and parotid glands contained low amounts of virus. No virus could be detected in the parotid glands. In all glands of RCMV-infected animals, the infection was exclusively confined to striated duct cells. Infection resulted in a cellular inflammatory response which was mostly located in the interlobular duct region, whereas only few inflammatory cells were found in the neighbourhood of infected striated duct cells. This phenomenon may contribute to the long persistence of the virus in this organ.

Animals↗
PubMed2000

Recipient origin of neointimal vascular smooth muscle cells in cardiac allografts with transplant arteriosclerosis.

BACKGROUND: Coronary artery disease is today's most important post-heart transplantation problem after the first perioperative year. Histologically, coronary artery disease is characterized by transplant arteriosclerosis. The current view on this vasculopathy is that vascular smooth muscle (VSM) cells from the media of affected arteries proliferate and migrate into the sub-endothelial space (intima) in response to signals from inflammatory cells and damaged graft endothelium. According to this model, the intimal VSM cells in transplant arteriosclerotic lesions should originate from donor tissue. Using recipient-specific polymerase chain reaction (PCR) analysis of microdissected, single, neointimal VSM nuclei, we recently showed that after allogeneic aorta transplantation the neointimal VSM cells are of recipient and not of donor origin. In this study, we analyzed whether VSM-cell replacement with recipient-derived cells also takes place after allogeneic heart transplantation. METHODS: Cardiac allografts, when transplanted from female donors to male immune-modulated recipient rats, eventually developed transplant arteriosclerosis. We microdissected alpha-actin positive neointimal VSM cells from tissue sections and determined the origin (donor or recipient) using recipient-specific (male), single-cell, PCR analysis. RESULTS: In total, we analyzed 35 VSM-cell nuclei from 3 allografts, and PCR analysis revealed that 30/35 (86%) of the samples displayed the male-specific 128 base pair DNA fragment. These results indicate that after allogeneic cardiac transplantation, at least 86% of VSM cells in transplant arteriosclerotic lesions are of recipient origin. CONCLUSIONS: In contrast to current thought, the neointimal VSM cells in cardiac allografts that show transplant arteriosclerosis are of recipient and not of donor origin.

Actins↗
PubMed2000

Chronic allograft rejection associated vasculopathy and synthetic biodegradable vascular grafts: a lesson to learn?

In chronic allografts, graft vessels eventually develop so-called "transplant vascular sclerosis" or "intimal hyperplasia". A major question is whether the cells in the neointima are donor or recipient derived. The process of transplant vascular sclerosis closely resembles the remodeling of the vascular wall as seen when synthetic biodegradable small caliber vascular grafts are implanted. In this model, the cells in the newly developing neointima as well as neomedia are, by definition, recipient derived. By using cardiac allografts as well as aortic allografts exchanged between a female donor and a male recipient (rats), the origin of the neointimal vascular smooth muscle cells could be traced by looking for the Y-chromosome in isolated (alpha-actin positive) intimal cells using PCR. In both models these intimal cells were found to be of recipient-origin. It is proposed, that, basically, this remodeling process is part of a normal healing process. Whereas in biodegradable grafts this "healing process" appears to be self limiting, in allografts the process goes on beyond the needs of functional repair, eventually, in some cases, leading to total vascular occlusion. Future therapeutic protocols might try and aim at controlling this essentially normal repair process.

Absorbable Implants↗
PubMed1999

The role of thymus-dependent T cells in hexachlorobenzene-induced inflammatory skin and lung lesions.

The involvement of thymus-dependent T cells in the inflammatory skin and lung lesions and spleen effects induced by hexachlorobenzene (HCB) was investigated by using genetically athymic and euthymic WAG/Rij rats and Brown Norway (BN) rats with or without depletion of T cells by adult thymectomy, lethal irradiation, and bone marrow reconstitution. Rats were exposed to diets with no supplementation or diets supplemented with 150 or 450 mg HCB per kg diet for 4 (BN) or 6 (WAG/Rij) weeks. Skin lesion development and body weight gains were assessed during exposure and spleen and liver weights as well as histopathologic changes in skin, lung, and spleen were assessed after exposure. Oral HCB exposure of athymic and euthymic rats of both rat strains resulted in a dose-dependent increase of relative liver weight at doses of 150 and 450 mg/kg HCB and increased relative spleen weights at a dose of 450 mg/kg. HCB exposure of both strains further resulted in inflammatory changes in skin, lungs, and splenic red pulp independent of the T cell status except for skin lesions in the BN strain. HCB-exposed T cell-competent BN rats showed faster skin lesion development than the T cell-depleted rats, although qualitatively and quantitatively similar skin pathology was observed at the end of the 4-week exposure in both groups. In the WAG/Rij strain skin lesions could not be comparatively assessed due to preexistent inflammatory skin pathology in the nude rats. This study showed that thymus-derived T cells are not required for the induction of skin and lung pathology and splenic changes by HCB and therefore it is suggested that HCB acts differently from many allergenic and autoimmunogenic low molecular weight compounds that trigger pathology via thymus-dependent mechanisms. A role for mononuclear phagocytes and, in BN rats, eosinophilic granulocytes, in the HCB-induced pathology is suggested since these cells were prominently present in the HCB-induced lesions.

Animals↗
PubMed1998

Cytomegalovirus infection enhances the neointima formation in rat aortic allografts: effect of major histocompatibility complex class I and class II antigen differences.

BACKGROUND: The development of chronic rejection has emerged as a major cause of long-term graft failure. Previous studies have demonstrated that cytomegalovirus (CMV) infection is associated with an increased incidence of chronic allograft rejection in renal, cardiac, and aortic allografts. This study was designed to investigate the effects of the major histocompatibility complex (MHC) class I or class II mismatches on CMV-enhanced chronic rejection. METHODS: Aortic transplantation was performed between different inbred rat strain combinations; the Lewis to RP combination was class I-mismatched and Wag/Rij to RP class II-mismatched. At 7, 28, and 90 days after transplantation, the intensity of chronic rejection in mismatched grafts with or without CMV infection was evaluated using histological and immunohistological analysis. RESULTS: The results of this study demonstrated that CMV infection led to an increased influx of monocytes/ macrophages in class I-mismatched grafts at 1 week after transplantation and enhanced infiltration of T lymphocytes in class II-mismatched grafts at 4 weeks. Although more vascular lesions were observed in the class II-mismatched combinations, an intensified neointima formation by CMV infection was observed only in the MHC class I-mismatched allografts. CONCLUSIONS: CMV infection may increase neointima formation of allografts when an MHC class I disparity between donor and recipient is present. This may be associated with the increased perivascular influx of monocytes/macrophages observed in CMV-infected animals early after transplantation.

Animals↗