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J D Bignon

Publications and source records attributed to J D Bignon.

At least 19 recordsLinked to original sources
PubMed2000

Highly altered V beta repertoire of T cells infiltrating long-term rejected kidney allografts.

Chronic rejection represents a major cause of long-term kidney graft loss. T cells that are predominant in long-term rejected kidney allografts (35 +/- 10% of area infiltrate) may thus be instrumental in this phenomenon, which is likely to be dependent on the indirect pathway of allorecognition only. We have analyzed the variations in T cell repertoire usage of the V beta chain at the complementary determining region 3 (CDR3) level in 18 human kidney grafts lost due to chronic rejection. We observed a strongly biased intragraft TCR V beta usage for the majority of V beta families and also a very high percentage (55%) of V beta families exhibiting common and oligoclonal V beta-C beta rearrangements in the grafts of patients with chronic rejection associated with superimposed histologically acute lesions. Furthermore, V beta 8 and V beta 23 families exhibited common and oligoclonal V beta-J beta rearrangements in 4 of 18 patients (22%). Several CDR3 amino acid sequences were found for the common and oligoclonal V beta 8-J beta 1.4 rearrangement. Quantitative PCR showed that biased V beta transcripts were also overexpressed in chronically rejected kidneys with superimposed acute lesions. In contrast, T lymphocytes infiltrating rejected allografts with chronic rejection only showed an unaltered Gaussian-type CDR3 length distribution. This pattern suggests that late graft failure associated with histological lesions restricted to Banff-defined chronic rejection does not involve T cell-mediated injury. Thus, our observation suggests that a limited number of determinants stimulates the recipient immune system in long-term allograft failure. The possibility of a local response against viral or parenchymatous cell-derived determinants is discussed.

Acute Disease↗
PubMed2000

Interaction of anti-HLA antibodies with pig xenoantigens.

BACKGROUND: Many patients with renal failure are condemned to long-term dialysis with little prospect of transplantation because they are highly sensitized with immunoglobulin G (IgG) directed against class I human leukocyte antigens (HLA) of virtually all donors. Xenotransplantation could represent an attractive solution providing their alloantibodies (alloAb) do not recognize porcine motifs. Hitherto there has been no in vivo demonstration of any cross-reactivity and the objective of this work was to investigate this problem using a technique of extracorporeal pig kidney perfusion as a model of clinical xenografting. METHODS: Pig kidneys were perfused ex vivo with plasma from both a group of highly sensitized patients and healthy individuals. Sequential plasma samples were analyzed for the titer of anti-Galalpha1-3Gal antibody (Ab) (major natural xenoreactive Ab) by enzyme-linked immunosorbent assay and anti-HLA class I Ab against a cell panel. At the end of perfusion, kidneys were perfused with a citric acid buffer to elute bound Ab. RESULTS: Galalpha1-3Gal Ab were shown to decrease rapidly in the plasma (in less than 10 min) and then reached a plateau. A fractional decrease in anti-HLA Ab was also found in some of the perfused plasma samples. Anti-Gal Ab were readily detected in all citric acid perfusates and anti-HLA Ab in 8 of 10. The HLA specificities of eluted Ab were mainly concordant with the originally designated specificities for each patient. CONCLUSION: Anti-HLA class I Ab presumably cross-react with pig class I homologues. However, some plasma samples did not cross-react, suggesting that negatively cross-matched pig kidneys could be identified in the pig population for xenotransplantation in these patients. Further studies are required to precisely describe these cross-reactivities and to understand their functional significance in xenotransplantation.

Animals↗
PubMed1999

Frequent enrichment for CD8 T cells reactive against common herpes viruses in chronic inflammatory lesions: towards a reassessment of the physiopathological significance of T cell clonal expansions found in autoimmune inflammatory processes.

We recently evidenced a dramatic enrichment for T cells reactive against Epstein-Barr virus (EBV) within inflamed joints of two rheumatoid arthritis patients. To assess the generality of this phenomenon and its relevance to autoimmunity, we studied the responses of CD8 T cells from patients with either acute or chronic inflammatory diseases (rheumatoid arthritis: n = 18, ankylosing spondylitis: n = 5, psoriatic arthritis: n = 4, Reiter's syndrome: n = 3, arthrosis: n = 2, uveitis: n = 2, multiple sclerosis: n = 2, encephalitis: n = 1) against viral proteins derived from EBV and another common herpes virus, human cytomegalovirus (CMV). T cell responses against EBV and/or CMV epitopes were frequently observed within CD8 T cells derived from chronic inflammatory lesions, irrespective of their location (knee, eye, brain) and autoimmune features. In most cases, CD8 T cells derived from affected organs yielded stronger anti-viral T cell responses than CD8 T cells derived from patients' PBL, even in chronic inflammatory diseases devoid of autoimmune features or induced by defined bacterial agents. Taken together, these results suggest that the presence of virus-specific T cells within inflamed lesions of patients suffering from autoimmune diseases is a general phenomenon associated with chronic inflammation rather than the initiating cause of the autoimmune process. Since this phenomenon was sometimes associated with long-term T repertoire biases within inflamed lesions, the physiopathological significance of T cell clonal expansions found in a recurrent fashion within chronically inflamed autoimmune lesions should be interpreted with caution.

Adult↗
PubMed1999

Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis.

Hereditary pancreatitis (HP) is a rare inherited disorder, characterised by recurrent episodes of pancreatitis often beginning in early childhood. The mode of inheritance suggests an autosomal dominant trait with incomplete penetrance. The gene, or at least one of the genes, responsible for hereditary pancreatitis has been mapped to the long arm of chromosome 7 and a missense mutation, an arginine to histidine substitution at residue 117 in the trypsinogen cationic gene (try4) has been shown to segregate with the HP phenotype. The aim of this work was to investigate the molecular basis of hereditary pancreatitis. This study was performed on 14 HP families. The five exons of the trypsinogen cationic gene were studied using a specific gene amplification assay combined with denaturing gradient gel electrophoresis (DGGE). The present paper describes three novel mutations, namely K23R and N29I and a deletion -28delTCC in the promoter region. We also found a polymorphism in exon 4, D162D. In eight of these families we found a mutation which segregates with the disease. A segregation analysis using microsatellite markers carried out on the other families suggests genetic heterogeneity in at least one of them. Our findings confirm the implication of the cationic trypsinogen gene in HP and highlight allelic diversity associated with this phenotype. We also show that the pattern of inheritance of HP is probably complex and that other genes may be involved in this genetic disease.

Cations↗
PubMed1998

Impact of the MHC-encoded HLA-DMA, DMB, and LMP2 gene polymorphisms on kidney graft outcome.

We previously studied the relationship between TAP1 and TAP2 gene polymorphism and compatibility in kidney graft outcome and reported that the currently described TAP1 and TAP2 gene polymorphisms did not influence the incidence of acute rejection episodes. In this study, we report on the effect of polymorphism and matching of HLA-DMA, -DMB, and LMP2 genes on kidney graft outcome. This study was performed on 102 selected kidney recipients who experienced two or more acute rejection episodes (rejection group) during follow up and who were compared to a group of 150 patients who never had rejection (non rejection group). Although a significant effect of HLA-DR matching was observed between these two groups, our data suggest that matching for all the new genes located in the HLA class II region (TAP1, TAP2, LMP2, HLA-DMA and -DMB) does not influence the kidney graft outcome. However, a significant increase (pc < 0.05) of DMA*0102 allele was observed in the recipients of the rejection group as compared to those of the non rejection group. This effect was not due to a linkage disequilibrium between DMA and HLA-DR loci and suggests that this specific HLA-DMA allele could play a role in the indirect pathway of class II presentation of donor antigens.

Adult↗
PubMed1997

[Which cross-match before organ transplantation in 1997?].

GOALS: The objective of pre-transplantation cross-matching is to detect in the recipient's serum solely those anti-donor antibodies which could have a deleterious effect on the grafted organ. It is important to avoid refusing organs on the basis of recipient antibodies which do not imply a risk of rejection. SEVERAL METHODS: In most laboratories cross-matching or compatibility tests made before organ transplantation are based on a complement-dependent microlymphocytotoxicity technique, sometimes sensitized with anti-human globulin serum, reactive against target T-cells. A positive results is reported if the reactions are week, but other methods are available. CHOICE OF SERA FOR CMX: This is essential. Several sera must be used: the most positive sera, the last serum and the current sera if the patient has been transfused between the date of the last serum harvested and the CMX. IMMUNOLOGICAL STATUS: There is wide agreement on the requirement for quality surveillance of the recipient's immunological status. This policy is the only way to effectively select sera to cross-match before transplantation, whatever the technique used, and thus improve transplantation outcome and reduce the number of rejections. CASE BY CASE: These prerequisites hold for all organs, but especially so for renal (and/or pancreas) grafts. For heart or heart-lung transplantations, emergency procedures may be needed.

Graft Rejection↗
PubMed1997

Idiopathic and secondary membranous nephropathy and polymorphism at TAP1 and HLA-DMA loci.

In a previous study on the effects of TAP1 and TAP2 gene polymorphism in kidney allograft recipients, we found no association between graft outcome and recipient/donor TAP1 and TAP2 allele polymorphism or compatibility, but we observed a surprising increased frequency of the TAP1*0201 allele among kidney recipients. This increase was restricted to patients with glomerulopathy. We now report on a larger cohort of 178 patients with membranous nephropathy who were typed for their HLA-DPB1, -DRB1, -DMA, -DMB, LMP2, LMP, TAP1 and TAP2 genes compared with 100 random ethnically matched and healthy unrelated individuals used as controls. The results show a significant increased frequency of two markers in membranous nephropathy patients as compared with controls: firstly the previously recognized increase in HLA-DR3 (59% vs 18%: Pc < 1 x 10(-9), RR = 6.6), secondly a new association with two TAP1 amino acid variants displaying respectively a valine in amino acid position 333 (TAP1-Val-333) and consequently a glycine in position 637 (TAP1Gly-637) due to its strong linkage disequilibrium with Val-333. No linkage disequilibrium was found between TAP1-Val-333 and HLA-DR3. Moreover, we also noticed a decrease of the DMA*0102 phenotype in membranous nephropathy patients. The other HLA-DPB, -DMB, LMP2, LMP7 and TAP2 phenotype frequencies were roughly similar between patients and controls. These results show that the TAP1-Val-333 like HLA-DR3 phenotype is positively associated with membranous nephropathy and that these two risk factors are not cumulative in membranous nephropathy pathophysiology.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

An exceptional genealogy for hereditary chronic pancreatitis.

Nearly one hundred families affected with hereditary chronic pancreatitis (HCP) have been reported in the literature. However, the fact that the disease involved only a few members of each family limits the informativeness of these reports and accounts for the infrequency and disappointing results of pathogenetic and genetic research. Our study concerned an exceptional HCP genealogy which would seem to provide an ideal model for the detection of a genetic anomaly linked to the expression of the disease. We studied 249 members of a family (214 still alive), covering eight generations born between 1800 and 1993. According to the customary criteria, 63 had definite and 17 probable HCP. Fifty-eight members under 18 years of age were still susceptible to developing the disease. This series confirms the mode of autosomal dominant heredity with variable penetrance. The clinical features and disease course were typical, except that symptoms tended to appear earlier. The series represents the most extensive HCP genealogy compiled and is one of the largest families studied in the field of genetic disease, regardless of etiology. Blood samples were taken from 146 subjects to facilitate pathogenetic and genetic research.

Chronic Disease↗
PubMed1996

The hereditary pancreatitis gene maps to long arm of chromosome 7.

Hereditary pancreatitis (HP) is an autosomal dominant disorder with incomplete penetrance characterized by recurring episodes of severe abdominal pain often presenting in childhood. Although this disorder has only been recently described, about 100 families have been documented worldwide. The pathophysiology of this disorder is unknown. Here, a large French family of 147 individuals (47 of whom were affected) from a four-generation kindred with HP has been examined and a genome segregation analysis of highly informative microsatellite markers has been performed. Linkage has been found between HP and six chromosome 7q markers. Maximal two point lod scores between HP and D7S 640, D7S 495, D7S 684, D7S 661, D7S 676 and D7S 688 were 4.00 (theta = 0.143), 5.85 (theta = 0.143), 4.91 (theta = 0.156), 8.58 (theta = 0.077), 8.28 (theta = 0.060), 4.40 (theta = 0.169), respectively. Multipoint linkage data combined with recombinant haplotype analysis indicated that the most likely order is: D7S 640-D7S 495-D7S 684-D7S 661-D7S 676-D7S 688, with the HP gene situated in the underlined region. As in all families reported in the literature, the clinical presentation of the disease is identical to the presentation of sporadic cases, one could expect that the knowledge of the HP gene could be a clue to pancreatitis in general. Based on its map position, this is the first step towards the positional cloning of the Hereditary Pancreatitis Gene (HPG).

Chromosome Mapping↗
PubMed1995

Late acute failure of well-HLA-matched renal allografts with capillary congestion and arteriolar thrombi.

Seventeen cases of a histologically and clinically unusual renal acute dysfunction in kidney recipients, individualized among a population of 1378, are reported. The basic histological lesion was a huge capillary congestion, associated with capillary and arteriolar thromboses or parenchymal necrosis in most patients, and contrasting with the absence of the classical features of acute cellular rejection, i.e., tubulitis, glomerulitis, edema, and infiltrate. The corresponding clinical history was characterized by its early timing in the course of transplantation (< 3 months), its sudden occurrence in patients usually having good transplant function, leading to end-stage renal failure in a few days, and its resolution under rejection treatment. The occurrence of this syndrome was significantly linked with a good HLA matching: 13 of the 17 recipients were HLA-DR matched (P < 0.0001). The etiology of this syndrome remains unknown. There was no evidence for graft vessel thrombosis. Because of some histological similarities, the usual causes of the hemolytic uremic syndrome, including bacterial and viral infections or cyclosporine arteriolopathy, were discussed. Acute vascular rejection was suspected, but the cross-match was negative on T lymphocytes in all cases and anti-HLA class I and II antibodies were not found to develop at the time of transplant dysfunction, except in 1 patient, in whom the detected anti-DR antibodies were not directed at the kidney donor. Anti-human umbilical vein endothelial cell antibodies, detected in an antibody-dependent cellular cytotoxicity assay, were present in 6 patients (of the 14 tested) at the onset of renal failure, but they were either absent (n = 3) or already present at the time of transplantation (n = 5) in the other 8 patients. Therefore, reliable arguments are lacking to conclude that this acute transplant dysfunction is an acute vascular rejection and its strong association with HLA matching has, as yet, no satisfactory explanation.

Acute Disease↗
PubMed1995

Effects of MHC-encoded TAP1 and TAP2 gene polymorphism and matching on kidney graft rejection.

The products of TAP1 and TAP2 genes, recently mapped within the MHC class II region, are involved in antigen presentation by MHC class I molecules, especially in the transport of endogenous peptides. As for most MHC genes, a polymorphism has been described and the possibility that it could influence the recipient immune response by modulating antigen presentation in kidney transplantation has been tested. The aim of our study was to compare TAP1 and TAP2 gene polymorphism and matching in 53 couples of kidney donors and recipients without any rejection episodes and in 55 other couples who had experienced at least 2 acute cellular rejection episodes; 70 healthy individuals served as controls. Our results showed that allelic variant frequencies of TAP1 alleles (1A to 1C) and TAP2 alleles (2A to 2E), as assessed by amplification refractory mutation system-polymerase chain reaction, were similar among "rejection" and "no rejection" populations. Furthermore, there were no differences of TAP1 and/or TAP2 matching between donors and recipients in the 2 groups. In contrast, we showed that the recipients of the no rejection group were better matched with their corresponding donors for the HLA-DR genes than those of the rejection group. These results suggest that the currently described polymorphism in the limited coding region of TAP1 and TAP2 genes does not influence the incidence of kidney allograft rejection episodes and seems not to be a strong link to the adjacent DR/DQ subregion. Moreover, the observed increase frequency of TAP1B allele in the whole recipient's group as compared with controls (16.2% vs. 7.1% in the healthy individuals; P < 0.02) was not linked to the rejection occurrence but to the presence of glomerulonephritis as initial disease. Our study suggests that, in the clinical conditions tested, neither TAP polymorphism nor TAP matching influences the renal graft outcome.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Susceptibility to alloimmunization to platelet HPA-1a antigen involves TAP1 polymorphism.

The alloimmunization against platelet HPA-1a antigen in mothers of thrombocytopenic neonates is strongly associated with HLA class II structures (DR3 and DR13) and especially with HLA-DR52a antigen (98% of the cases reported here). Because new genes have recently been mapped within the MHC class II region, we typed TAP1 and TAP2 gene polymorphisms by ARMS-PCR in order to characterize more effectively MHC genes involved in this alloimmunization. Our results showed that TAP1*0102 allele was significantly associated with NAIT only in the population of HLA-DR 13-DR52a-immunized women (50%) versus HLA-DR 13-DR52a controls (20%) (p < 0.05), and not in HLA-DR3-DR52a-immunized women versus HLA-DR3-DR52a controls. There is no linkage disequilibrium between TAP1*0102 and DRB1*13 alleles (delta = -0.0063) that could account for this result. The higher frequency of TAP1*0102 allele among HLA-DR 13-DR52a-immunized women suggests that HPA-1a antigen presentation and recognition may be influenced by nonclassic HLA class II gene polymorphisms, or that other linked but yet unknown genes could interfere.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Recognition of shared melanoma antigen by HLA-A2-restricted cytolytic T cell clones derived from human tumor-infiltrating lymphocytes.

Three melanoma-specific cytotoxic T lymphocytes (CTL) clones were derived from the tumor-infiltrating lymphocyte (TIL) of human melanoma M17, and were used to study the expression of immunogenic melanoma peptides on allogeneic tumors. Antibody inhibition studies showed that two of these TIL clones were restricted by an HLA-A2 molecule which was identified as A2.1 by gene sequencing. The third CTL clone was not restricted by HLA-A2, but by a B or C HLA antigen. HLA-A2-restricted CTL clones M17-1 and M17-2 lysed 5 and 12 out of 15 HLA-A2+ allogeneic melanomas, respectively. Since they did not lyse autologous Epstein-Barr virus B cells, HLA-A2.1-transfected P815 cells, 13 HLA-A2+ non-melanoma tumor cell lines and 10 HLA-A2- melanomas, these clones appeared specific for melanoma-restricted epitopes presented by the HLA-A2.1 molecule. We then tried to determine why a few HLA-A2+ melanomas were refractory to TIL lysis. By using a combination of flow cytometry analysis, partial cloning and sequencing of their HLA-A2 genes, we show that failure to lyse did not result from low expression or polymorphism of the HLA-A2 molecule, or from deficient expression of the adhesion molecules ICAM-1 and LFA-3 by these melanomas. Taken together, our data confirm at the clonal level the existence of shared melanoma antigens recognized by TIL in the HLA-A2.1 context. They further show that individual peptides derived from these antigens are expressed by a large majority of HLA-A2+ melanomas. Identification of such peptides appears crucial for the future of vaccination therapies.

Antigens, Neoplasm↗
PubMed1993

Lack of binding of peptides carrying the human platelet antigen 1 (HPA-1) dimorphism to purified HLA-DRw52a molecules.

The strong association between anti-HPA-1a alloimmunization and DR3, DRw52a phenotype in HPA-1b homozygous women suggests that these class II molecules play a crucial role in the immune response against HPA-1a. The diallelic system HPA-1 results in a single amino acid polymorphism at the residue 33 of the glycoprotein IIIa. So, we tested the binding of peptides from the 25-42 region of the GPIIIa to purified HLA-DR3 and -DRw52a molecules, using a solid phase assay and a liquid phase peptide binding assay. No binding was demonstrated, indicating that either the crucial region for binding to class II molecules is not the 25-42 region, or that other events only occurring "in vivo" are required for binding. These results may also suggest an indirect role of the residue 33 for T-cell stimulation.

Amino Acid Sequence↗
PubMed1993

[Kidney transplantation and HLA-DR compatibility evaluated by genomic analysis: one center study].

The actual effect of HLA-DR matching in renal transplantation remains controversial. Since DNA analysis has been shown to be more reliable than serological typing, a re-evaluation of the impact of DR-matching on graft prognosis is required. In this study, 224 cadaver kidney transplantations performed in our center were retrospectively matched according to Restriction Fragment Length Polymorphism DR incompatibilities and compared to prospective serological DR-matching. Transplant outcome was evaluated using graft survival, first rejection onset and rejection frequency. In 18.8% individuals, a discrepancy between serology and DNA typing for at least one antigen was noted. Serology particularly failed to type recipients (21.7%) and 43.2% of the total missed antigens were serologically "blank" or unidentified ("X") alleles. A graft survival rate of 100% after one year was observed for transplantations with no DNA DR mismatch (n = 31). Furthermore, there was a definite correlation between DNA matching and (i), the percentage of individuals with one or more than one acute rejection episode (18% and 41.8% at one year for O incompatibility and pooled 1 and 2 incompatibilities respectively, p < 0.05); (ii), the mean of acute rejection per individual (p < 0.001); and (iii), the rejection onset time (p < 0.01). No correlation between serological matching and the acute rejection episodes parameters was noted. Since HLA typing could be performed in less than 2 hrs using new molecular biology techniques, we conclude that prospective DNA typing should improve kidney transplantation outcome in the near future.

Graft Rejection↗
PubMed1993

DNA HLA-DR typing results of 4000 kidney transplants.

Recipients (4076) and donors (3325) of kidney transplants performed at 110 transplant centers were typed for HLA-DRB by the DNA RFLP method. The discrepancy rate of replicate samples distributed among 8 participating laboratories was a low 2.6%. The discrepancy rate between RFLP-DRB and serological HLA-DR typings was 25.0% for organ donors and 27.6% for kidney recipients. Discrepancy rates at the different transplant centers ranged from 9.7% to 86.7%. The discrepancies consisted of antigens being incorrectly interpreted by serology (16.8%), and of serological "blanks" turning out to be definable alleles by the DNA method (10.8%). The alleles that were mainly affected by discrepancies were DR1, DR8, DR10, DR12, DR13, DR14, DR16, DR17.2, and DR18.

Alleles↗