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P J van Breda Vriesman

Publications and source records attributed to P J van Breda Vriesman.

At least 19 recordsLinked to original sources
PubMed2000

Effects of antibody reactivity to major histocompatibility complex (MHC) and non-MHC alloantigens on graft endothelial cells in heart allograft rejection.

BACKGROUND: To gain insight in the pathogenesis of vascular lesions in heart allograft rejection, we investigated effects of allosera reactive with major histocompatibility complex (MHC) or non-MHC alloantigens on graft endothelial cells (EC) in a rat transplantation model. METHODS: Anti-MHC and anti-non-MHC allosera were obtained from Brown Norway (RT.1(n)) recipients of a Lewis (RT.1(1)) or congenic LEW.1N (RT.1(n)) heart allograft respectively. Reactivity with endothelial alloantigens was studied in vitro using a series of three rat heart endothelial cell (RHEC) lines of Lewis origin. Phenotypic studies of MHC and non-MHC alloantigen expression, and adhesion molecule induction on EC were performed by immunostaining and fluorescence-activated cell sorting analysis. Complement-mediated cytotoxicity of allosera was studied using a 51Cr release assay. RESULTS: Both anti-MHC allosera and anti-non-MHC allosera showed reactivity with all three RHEC lines. EC stimulation with tumor necrosis factor-alpha and interferon-y resulted in increased reactivity of anti-MHC but not of anti-non-MHC allosera. Anti-MHC allosera showed complement-mediated cytotoxicity for EC, which was strongly increased when cytokine-stimulated EC were used. With anti-non-MHC allosera, only minor cytotoxicity was measured, irrespective of the activation of EC. Anti-MHC and anti-non-MHC allosera from the day of rejection (days 7-8 and days 29-35, respectively) had similar subclass profiles of allospecific IgG, except for allospecific IgM, which was only detected in anti-MHC allosera. Complement-mediated cytotoxicity of anti-MHC allosera from the day of rejection was effected mainly by IgM alloantibodies, whereas, in allosera taken 4 days after rejection, a predominance of cytotoxic alloantibodies of the IgG class was observed. No indications were found that either alloantibody reactivity alone or in combination with complement activation led to EC activation processes relevant to intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 induction. CONCLUSIONS: Our data show that, in heart allograft rejection, MHC but also non-MHC alloantigens on EC are target structures in the alloantibody response. Alloantibodies reactive with endothelial MHC, but not those reactive with non-MHC alloantigens, may significantly contribute to vasculopathy by complement-mediated cytotoxicity. Although no evidence was found that alloantibodies reactive with graft EC induce adhesion molecule expression, they may trigger other EC mechanisms relevant to graft vasculopathy.

Animals↗
PubMed2000

Complement activation by anti-endothelial cell antibodies in MHC-mismatched and MHC-matched heart allograft rejection: anti-MHC-, but not anti non-MHC alloantibodies are effective in complement activation.

Classical complement activation is a major effector mechanism in the development of vascular lesions contributing to allograft rejection. We investigated complement activation by alloantibodies reactive with graft endothelial cell (EC) alloantigens in settings of MHC-mismatched and MHC-matched (non-MHC-mismatched) rat heart transplantation (Tx). Allosera and heart allografts were collected at the day of rejection (day 7-8 and day 28-35 in MHC-mismatched and non-MHC-mismatched Tx respectively) or earlier. Allosera reactivity was studied in vitro using rat-heart-endothelial-cell (RHEC) lines expressing the appropriate donor MHC and non-MHC alloantigen profile. Immunohistochemical analysis of rejected heart allografts showed deposition of alloantibodies in both MHC-mismatched and MHC-matched heart allografts, but expression of C3 was only seen in the vasculature of MHC-mismatched grafts. FACS analysis showed that anti MHC as well as anti non-MHC allosera were reactive with donor EC cell surface antigens. Both sera had similar IgG subclass profiles of anti-endothelial cell antibodies. Complement activation by anti MHC and anti non-MHC alloantibodies on EC was measured by FACS analysis of C3 and C5b-9 (MAC) expression. Distinct expression of C3 was noticed for EC incubated with anti-MHC allosera, but hardly for EC incubated with anti non-MHC allosera. C5b-9 was low but showed no difference between the two allosera. However, complement-mediated cytotoxicity experiments showed that functional (lytic) MAC was induced with anti MHC allosera but hardly with anti non-MHC allosera. Our data show that in settings of MHC-matched heart transplantation alloantibodies against endothelial non-MHC alloantigens are generated, but, in contrast to alloantibodies to MHC alloantigens, these alloantibodies have only poor complement-activating and lytic potentials. Whether anti non-MHC allolantibodies effect other biological processes relevant for heart allograft vasculopathy, including development of graft arteriosclerosis, needs further elucidation.

Animals↗
PubMed1999

A dominant role for the thymus and MHC genes in determining the peripheral CD4/CD8 T cell ratio in the rat.

During their development, immature CD4CD8 double positive thymocytes become committed to either the CD4 or CD8 lineage. The final size of the peripheral CD4 and CD8 T cell compartments depends on thymic output and on the differential survival and proliferation of the respective T cell subsets in the periphery. Our results reveal that the development of the distinct peripheral CD4/CD8 T cell ratio between Lewis and Brown Norway rats originates in the thymus and, as shown by the use of radiation bone marrow chimeras, is determined by selection on radio-resistant stromal cells. Furthermore, this difference is strictly correlated with the MHC haplotype and is the result of a reduction in the absolute number of CD8 T cells in Brown Norway rats. These data suggest that the distinct CD4/CD8 T cell ratio between these two rat strains is the consequence of differential interactions of the TCR/CD8 coreceptor complex with the respective MHC class I haplotypes during selection in the thymus.

Animals↗
PubMed1998

Comparison of detection techniques for cytokine reverse transcriptase polymerase chain reaction; digoxigenin-labeled polymerase chain reaction permits sensitive detection of cytokine mRNA in rat heart allografts.

The polymerase chain reaction (PCR) is a sensitive method for the analysis of cytokine mRNA expression. The amount of specific mRNA in tissues involved in an inflammatory immune response can be low and therefore requires highly sensitive detection of the PCR products. In our study we have compared different detection techniques in order to replace the commonly used detection by means of radiolabeled probes. Besides the detection of DNA in agarose gels by ethidium bromide (EB), we used detection by digoxigenin (DIG)-labeled probes, as well as the direct incorporation of DIG-labeled nucleotides in the PCR, in comparison to detection by means of 32P-labeled probes. In vitro activated rat lymph node cells, lymph node tissue, and acutely or chronically rejected rat heart allografts were examined for expression of mRNA of the cytokines IL-2 and IFNgamma. The directly DIG-labeled PCR appeared to be the best alternative for detection of PCR products by means of radiolabeled probes. While IL-2 mRNA was not detected by means of EB and IFNgamma mRNA was only detected at the highest PCR cycle numbers in acutely and chronically rejected rat heart allografts, both cytokine mRNA's were readily detected by directly DIG-labeled PCR.

Animals↗
PubMed1998

Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients.

Interleukin-12 (IL-12) is a cytokine that promotes cell-mediated immunity to intracellular pathogens by inducing type 1 helper T cell (TH1) responses and interferon-gamma (IFN-gamma) production. IL-12 binds to high-affinity beta1/beta2 heterodimeric IL-12 receptor (IL-12R) complexes on T cell and natural killer cells. Three unrelated individuals with severe, idiopathic mycobacterial and Salmonella infections were found to lack IL-12Rbeta1 chain expression. Their cells were deficient in IL-12R signaling and IFN-gamma production, and their remaining T cell responses were independent of endogenous IL-12. IL-12Rbeta1 sequence analysis revealed genetic mutations that resulted in premature stop codons in the extracellular domain. The lack of IL-12Rbeta1 expression results in a human immunodeficiency and shows the essential role of IL-12 in resistance to infections due to intracellular bacteria.

Adult↗
PubMed1998

Selection of recombinant anti-HuD Fab fragments from a phage display antibody library of a lung cancer patient with paraneoplastic encephalomyelitis.

Antibodies against the HuD antigen expressed in small-cell lung cancer (SCLC) cross-react with proteins expressed in neurons of the central and peripheral nervous system and are associated with paraneoplastic encephalomyelitis and sensory neuropathy (PEM/SN). We isolated anti-HuD Fab fragments from an antibody phage display library that was constructed from mRNA of a metastatic lymph node from a patient with SCLC and Pem/SN. Fab GLN495 recognized HuD and other related proteins (HuC and Hel-N1, or Hu antigens) in immunoblots of these recombinant proteins and in immunohistochemical and Western blot analysis of SCLC and neurons. Fab GLN495 inhibited up to 75% of the anti-Hu antibodies of the patient from which it was derived, suggesting that recognizes a dominant epitope in the polyclonal anti-Hu antibody response. Fab GLN495 also competed with anti-Hu sera from most but not all patients with PEM/SN, indicating that the same epitope is recognized by a large subgroup of patients. Human monoclonal anti-HuD antibodies may be useful in diagnosis of HuD expressing tumors and in clarifying the autoimmune etiology of PEM/SN. This study, the first to demonstrate that tumor specific recombinant antibodies can be isolated from metastatic lymph node tissue, shows that this approach may be generally applicable to isolate human antibodies against tumor specific antigens.

Amino Acid Sequence↗
PubMed1998

Costimulatory molecules CD80 and CD86 in the rat; tissue distribution and expression by antigen-presenting cells.

The CD28-CD80/CD86 costimulatory pathway provides a critical signal for T cell activation. Only recently rat CD80 and CD86 have been cloned and monoclonal antibodies have been generated. In this study we examined the expression of these molecules in lymphoid tissue and on purified subsets of antigen-presenting cells (APC). The target tissue of cyclosporin A-induced autoimmunity, i.e. the skin and tongue, were also examined for expression of CD80 and CD86. Whereas CD80 was hardly detected in the lymphoid tissues, CD86 was clearly expressed by non-lymphoid cells in the thymus, as well as in the secondary lymphoid organs. With respect to lymphoid cells, only germinal center B cells exhibited clear CD86 expression. Phenotypic analysis by flow cytometry revealed that only dendritic cells, both of thymic and splenic origin, expressed the full array of stimulatory molecules required for the proper activation of naive T cells. On development of cyclosporin A-induced autoimmunity, non-professional APC, i.e. epithelial cells, started to express MHC class II, but not the costimulatory ligands CD80 and CD86. However, CD86 staining was observed in the target tissue and was associated with Langerhans cells as well as infiltrating leukocytes. Altogether, our results show that also in the rat strong stimulatory capacity for primary immune responses is associated with the expression of the costimulatory ligands CD80 and CD86. As concluded from the in situ expression CD86 may be the predominant costimulatory ligand early in immune responses.

Animals↗
PubMed1998

A dominant role for non-MHC gene effects in susceptibility to cyclosporin A (CsA)-induced autoimmunity.

Lethally irradiated LEW rats reconstituted with syngeneic bone marrow and given CsA for a 4-week period develop a graft-versus-host-like disease upon withdrawal of CsA. This T cell-mediated autoimmune disease is referred to as CsA-induced autoimmunity (CsA-AI). CsA-AI-susceptible LEW rats and resistant BN rats differ greatly in the composition of their peripheral T cell compartment. To dissect the role of MHC and non-MHC genes in the development of peripheral T cell subsets in combination with susceptibility to CsA-AI the respective MHC congenic strains (LEW-1N and BN-1L) were examined for their T cell subsets and for their ability to develop CsA-AI. In this study we show that the Th1/Th2-like cell ratio as well as susceptibility to CsA-AI are under control of the non-MHC genes. This suggests that the Th1/Th2-like cell ratio is a critical determinant for development of CsA-AI. Alternatively, resistance can be attributed to lack of target organ susceptibility due to the absence of the target autoantigen in resistant rat strains. This interpretation is rejected, since both BN as well as BN-1L rats consistently develop the characteristic macroscopic and microscopic signs of CsA-AI upon adoptive transfer with autoreactive LEW-1N and LEW T cells, respectively. Therefore, it can be concluded that the non-MHC genes encode for immune deviation and thereby determine susceptibility or resistance to CsA-AI.

Adoptive Transfer↗
PubMed1998

Chronicity index and mesangial IgG deposition are risk factors for hypertension and renal failure in early IgA nephropathy.

To determine the natural history in early immunoglobulin A (IgA) nephropathy, we evaluated the long-term follow-up of 27 normotensive nonazotemic adult idiopathic IgA nephropathy patients with chronic hematuria who derived from a prospective regional epidemiological study of glomerulonephritis conducted between 1978 and 1984. As controls, 17 thin glomerular basement membrane (GBM) patients, 24 patients with normal renal tissue, and nine patients with miscellaneous nephropathies were followed up. Median follow-up was 11 years (range, 8 to 14 years). Renal biopsies, performed within 2 years after patient identification, were scored semiquantitatively in terms of activity and chronicity indices, using a modified National Institutes of Health (NIH) scoring system. During follow-up, two patients with IgA nephropathy went into histological remission, and 12 IgA nephropathy patients showed disease progression, of whom three developed renal failure. Initial proteinuria over 1 g/d was associated with a high activity score, extracapillary lesions, and late onset of uremia. Mesangial IgG deposition and a higher initial chronicity index were associated with development of hypertension during follow-up. In the multivariate analysis, a high initial chronicity index, erythrocyturia, and mesangial IgG deposition are independent determinants of progression of disease. We conclude that in patients with IgA nephropathy, identified early in the course of disease, erythrocyturia, a high chronicity index, and mesangial IgG deposition in the presence of normal renal function are risk factors for decreased renal survival. Disappearance of hematuria is associated with remission of IgA nephropathy immunopathologically and low activity and chronicity indices at initial biopsy.

Adult↗
PubMed1998

Pathogenesis of cyclosporin A-induced autoimmunity: absence of T-cell reactivity towards syngeneic antigen presenting cells.

Cyclosporin A-induced autoimmunity (CsA-AI) is a T-cell mediated inflammatory autoimmune disease of the skin resembling human scleroderma and is often referred to as syngeneic-Graft-versus-Host Disease. Induction of CsA-AI is obtained by total body irradiation in combination with syngeneic bone marrow transplantation (BMT) and subsequent administration of CsA for 4 weeks; about 2 weeks after withdrawal of CsA disease develops. In CsA-AI, irradiation is thought to eliminate peripheral autoregulatory T-cells, whereas CsA interferes with selection in the thymus giving rise to putative autoreactive T-cells. MHC class II-self-peptide complexes have been thought to function as autoantigen(s). Moreover, induction of CsA-AI is used in humans to achieve a Graft-versus-Leukemia effect based on this anti-MHC class II reactivity. In this study we therefore have examined whether T-cells of CsA-AI rats respond to syngeneic dendritic cells (DC). Furthermore we determined the in vitro stimulatory capacity of the presumptive antigen presenting cell (APC) in the target organs, i.e. the keratinocytes. In contrast to keratinocytes of control rats the keratinocytes of CsA-AI rats show in situ a strong reactivity with anti-MHC class II specific monoclonal antibody (mAb) and therefore might induce local T-cell activation. Results reveal that T-cells of CsA-AI rats have no increased response to syngeneic DC. This indicates that MHC class II is not the autoantigen and that the autoantigen(s) are not presented by peripheral APC of control animals. With respect to possible APC in the target organ flow cytometry showed a strong induction of MHC class II and upregulation of MHC class I on keratinocytes of CsA-AI rats. However, these cells were unable to give any stimulatory signal to T-cells of control or diseased animals, indicating that the autoantigen(s) are not presented by keratinocytes of CsA-AI rats and that the MHC induction is probably secondary to the inflammatory reaction in the skin. The nature of the autoantigen(s) therefore remains to be determined.

Animals↗
PubMed1998

Cyclosporin A-induced autoimmunity: the result of defective de novo T-cell development.

Cyclosporin A-induced autoimmunity (CsA-AI) is an autoimmune disease, caused by the combinatory treatment with irradiation and cyclosporin A (CsA). CsA-AI is the result of defective T-cell maturation leading to disturbed T-cell balances in the periphery. Increases in Th1 cells and reduction of autoregulatory cells eventually enable the enumerated autoreactive CD4 and CD8 T cells to disturb the homeostasis in the target organs. In unravelling the effect of CsA on T-cell maturation and the role of T cells in CsA-AI many pieces have been put in their places; nevertheless, some remain the topic of debate. The identity of the autoantigen(s) remains elusive, the working mechanism of the autoregulatory cells still is to be determined, and the interplay between CD4 and CD8 T-cell subsets in relation to type-1 and type-2 responses is a matter of interest. In spite of all these unknowns, the CsA-AI autoimmune model is, in contrast to many autoimmune models induced by immunization with a foreign protein in adjuvant, an interesting physiological model based on defective T-cell development including aberrant selection in the thymus and disturbed T-cell balances in the periphery.

Animals↗
PubMed1997

Malignant neoplasms in cyclosporin A-induced autoimmunity (CyA-AI).

Lethally X-irradiated LEW rats reconstituted with syngeneic bone marrow and given low-dose Cyclosporine A (CyA) for 5 weeks develop, after withdrawal of CyA, symptoms of disease resembling graft-vs.-host disease (GVHD) as seen after allogeneic bone-marrow transplantation. Symptoms of disease may include acute dermatitis and chronic disease resembling scleroderma. Since anti-class II MHC cytotoxic lymphocytes are generated in this model, it has been proposed as an anti-tumor regimen in humans. We now report that LEW rats treated according to this protocol may, after cessation of CyA administration, paradoxically develop malignant neoplasms. Of 48 experimental animals, 31 developed rapidly progressive subcutaneous and/or intracutaneous tumors commencing at 6 weeks, 13 weeks and 6 months after cessation of CyA. Tumors were of mesenchymal origin, usually high-grade sarcoma, adenocarcinoma or both mesenchymal and epithelial tumors. Such tumor incidence exceeded the incidence of tumor growth in X-irradiated controls, and in rats subjected to thymectomy prior to X-irradiation and CyA administration. CyA by itself induced no tumors. Our results show that total body X-irradiation is required for tumor development but that the presence of CyA-induced autoimmune disease increases the incidence significantly.

Alopecia↗
PubMed1997

Anti-acetylcholine receptor Fab fragments isolated from thymus-derived phage display libraries from myasthenia gravis patients reflect predominant specificities in serum and block the action of pathogenic serum antibodies.

Myasthenia gravis (MG) is a prototype antibody-mediated autoimmune disease in which antibodies against nicotinic acetylcholine receptors (AChR) induce loss of functional receptors at the neuromuscular junction. Germinal centers present in MG hyperplastic thymus contain activated B-cells spontaneously producing anti-human AChR (huAChR) Ab in vitro. In order to access the anti-huAChR repertoire phage display Fab libraries of thymic lymphocytes were constructed from two MG patients. A total of four Fabs highly specific for huAChR were isolated that bind to determinants in or near the main immunogenic region (MIR). These anti-huAChR Fabs showed evidence of significant somatic mutations supporting the notion that the anti-huAChR Ab response in MG patients is driven by antigen. A total of two Fabs were able to inhibit up to 90% of donor serum anti-huAChR antibodies. Competition with serum anti-huAChR Ab was also observed in unrelated MG patients and indicate that anti-huAChR Fabs bind to epitopes on huAChR recognized by the majority of MG patients. In vitro antigenic modulation studies demonstrated that anti-huAChR Fabs were able to induce AChR loss when cross-linked by an anti-Fab antibody but not as monovalent Fab. Moreover, anti-huAChR Fabs were able to protect against AChR loss by antigenic modulation induced by MG serum antibodies suggesting a potential therapeutic role for these recombinant Fabs in patients with a myasthenic crisis.

Antibody Specificity↗
PubMed1997

Human anti-nicotinic acetylcholine receptor recombinant Fab fragments isolated from thymus-derived phage display libraries from myasthenia gravis patients reflect predominant specificities in serum and block the action of pathogenic serum antibodies.

Myasthenia gravis (MG) is a prototype Ab-mediated autoimmune disease in which Abs against nicotinic acetylcholine receptors (AChR) induce loss of functional receptors at the neuromuscular junction. Germinal centers present in MG hyperplastic thymus contain activated B cells spontaneously producing anti-human AChR (anti-huAChR) Ab in vitro. To access the anti-huAChR repertoire, phage display Fab libraries of thymic lymphocytes were constructed from two MG patients. Four Fabs highly specific for huAChR were isolated that bind to determinants in or near the main immunogenic region. These anti-huAChR Fabs showed evidence of significant somatic mutations, supporting the idea that the anti-huAChR Ab response in MG patients is driven by Ag. Two Fabs were able to inhibit up to 90% of donor serum anti-huAChR Abs. Competition with serum anti-huAChR Ab was also observed in unrelated MG patients and indicate that anti-huAChR Fabs bind to epitopes on huAChR recognized by the majority of MG patients. In vitro antigenic modulation studies demonstrated that anti-huAChR Fabs were able to induce AChR loss when cross-linked by an anti-Fab Ab but not as monovalent Fab. Moreover, anti-huAChR Fabs were able to protect against AChR loss by antigenic modulation induced by MG serum Abs, suggesting a potential therapeutic role for these recombinant Fabs in patients with a myasthenic crisis.

Adult↗
PubMed1997

Age-related susceptibility to experimental autoimmune myasthenia gravis: immunological and electrophysiological aspects.

Susceptibility to experimental autoimmune myasthenia gravis (EAMG) was found to decrease with aging in both Lewis and Brown Norway (BN) rats. In this study, the difference in susceptibility between young and aged Lewis and BN rats was used to analyze factors determining the clinical severity of EAMG. The incidence and severity of muscular weakness did not correlate with acetylcholine receptor (AChR) loss nor with the ability of antibodies to interfere with AChR function. Aged rats showed significantly lower anti-rat AChR antibody titers than young rats and developed less severe or no clinical signs of disease. In individual young or aged rats, however, no significant correlation was found between the clinical signs of disease and anti-rat AChR titer. Neuromuscular transmission was found to change with aging as measured by single-fiber electromyography (SFEMG). In aged BN rats, increased jitter and blockings were found even before EAMG induction. Despite this disturbed neuromuscular transmission, these aged BN rats were clinically resistant against induction of EAMG. The results of this study indicate that the age-related susceptibility to EAMG is influenced by factors determined by the immune attack as well as mechanisms at the level of the neuromuscular junction.

Aging↗
PubMed1997

Multiple effects of cyclosporin A on the thymus in relation to T-cell development and autoimmunity.

The immunosuppressive reagent cyclosporin A paradoxically is able to generate autoimmunity. Cyclosporin A is known to interfere with the signal transduction upon T-cell receptor cross-linking, an event required not only for T-cell activation in the periphery but also for T-cell maturation and selection in the thymus. In this review the multiple effects of cyclosporin A on the thymus are explained in terms of a differential response of thymocyte subsets upon recognition of MHC-peptide complexes. This hypothesis holds the effects of cyclosporin A on the thymic stromal cells to be secondary to its effect on the thymocytes: generation of autoreactive cells is the result of direct interference with negative selection and is not due to the partial disappearance or alteration of thymic stromal cells and, depending on the concomitant reestablishment of the autoregulatory T-cell circuit in the periphery, autoimmunity may develop.

Animals↗
PubMed1997

Myasthenia gravis as a prototype autoimmune receptor disease.

Myasthenia gravis (MG) is an organ-specific autoimmune disease in which autoantibodies against nicotinic acetylcholine receptors (AChR) at the postsynaptic membrane cause loss of functional AChR and disturbed neuromuscular transmission. The immunopathogenic mechanisms responsible for loss of functional AChR include antigenic modulation by anti-AChR antibodies, complement-mediated focal lysis of the postsynaptic membrane, and direct interference with binding of acetylcholine to the AChR or with ion channel function. The loss of AChR and subsequent defective neuromuscular transmission is accompanied by increased expression of the different AChR subunit genes, suggesting a role for the target organ itself in determining susceptibility and severity of disease. Experimental autoimmune myasthenia gravis (EAMG) is an animal model for the disease MG, and is very suitable to study the immunopathogenic mechanisms leading to AChR loss and the response of the AChR to this attack. In this article the current concepts of the structure and function of the AChR and the immunopathological mechanisms in MG and EAMG are reviewed.

Animals↗