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Biomedical subjects

S Caillat-Zucman

Publications and source records attributed to S Caillat-Zucman.

At least 37 records · Page 2Linked to original sources
PubMed2001

[T-cell-depleted HLA non-identical bone marrow transplantation in the child: prevention of graft-versus-host reaction by administration of donor T lymphocytes alloreactive against the recipient].

The success of HSCT from HLA partially disparate donors depends on the development of new strategies able to efficiently prevent GVHD and to protect patients from infections and relapse. Using an immunotoxin (IT) directed against the alpha-chain (p55) of the human IL-2r (RFT5-SMPT-dgA), we have previously shown that it is possible to kill mature T cells activated towards a specific HLA complex by a one-way MLR. We designed a clinical trial assessing the effect of infusing increasing doses of T lymphocytes in the setting of children recipients of non HLA genetically identical HSCT. Thirteen patients have been enrolled from September 1998 to April 2000 and fourteen HSCT have been realized in 13 patients (pts). Donors were MUD in 3 cases and familial HLA partially disparate in the remaining cases. Allodepleted donor T cells were injected between day +14 and day +30 provided that ATG was undetectable in the serum and blood PMN counts was > 500/microliter. The mean age of these patients was 17 months (range 1 to 42). Diagnosis included immune deficient and malignant hemopathies. Three patients received 1 x 10(5) allodepleted T cell/kg, 7 patients received 4 x 10(5)/kg and 4 patients received 6 x 10(5)/kg allodepleted T cells. Full inhibition of MLR was achieved in 12 out of 14 cases. In two cases, a residual T cell reactivity to the recipient was observed (4 to 5%) and patients developed grade II aGVHD. aGVHD occurred in 4 out of 11 grafted patients (all grade II). No chronic GVHD has developed, so far. Three patients died from severe VOD or PHT at day +34, day 51 and day +166, while one infected patient by VZV, CMV and EBV before HSCT died 6 months after transplantation from meningoencephalitis and another patient died from relapse at day +291. The patient for which there was no engraftment died at day +48 from staphylococcus infection. Overall survival is 54%, with a median follow up of 8 months; the mean time to reach a blood lymphocyte count > 500 was 41 days, to reach a CD3 count > 300 microliters 63 days (20-111), CD4 > 200 microliters 97 days and positive mitogen-induced proliferation 90 days. In three patients, a tetanus-toxoid positive proliferation was detected before immunization. From this intermediate analysis, we conclude that 1) specific allodepletion is an effective approach to prevent aGVHD in a haploincompatible setting, 2) data on immunological reconstitution suggest that infused T cells do survive and expand. A higher number of patients must be enrolled to determine the optimal number of T cells to infuse.

Acute Disease↗
PubMed2000

Structural analysis of two HLA-DR-presented autoantigenic epitopes: crucial role of peripheral but not central peptide residues for T-cell receptor recognition.

Specific and major histocompatibility complex (MHC)-restricted T-cell recognition of antigenic peptides is based on interactions of the T-cell receptor (TCR) with the MHC alpha helices and solvent exposed peptide residues termed TCR contacts. In the case of MHC class II-presented peptides, the latter are located in the positions p2/3, p5 and p7/8 between MHC anchor residues. For numerous epitopes, peptide substitution studies have identified the central residue p5 as primary TCR contact characterized by very low permissiveness for peptide substitution, while the more peripheral positions generally represent auxiliary TCR contacts. In structural studies of TCR/peptide/MHC complexes, this has been shown to be due to intimate contact between the TCR complementarity determining region (CDR) three loops and the central peptide residue. We asked whether this model also applied to two HLA-DR presented epitopes derived from an antigen targeted in type 1 diabetes. Large panels of epitope variants with mainly conservative single substitutions were tested for human leukocyte antigen (HLA) class II binding affinity and T cell stimulation. Both epitopes bind with high affinity to the presenting HLA-DR molecules. However, in striking contrast to the standard distribution of TCR contacts, recognition of the central p5 residue displayed high permissiveness even for non-conservative substitutions, while the more peripheral p2 and p8 TCR contacts showed very low permissiveness for substitution. This suggests that intimate TCR interaction with the central peptide residue is not always required for specific antigen recognition and can be compensated by interactions with positions normally acting as auxiliary contacts.

Antigen Presentation↗
PubMed2000

Focal segmental glomerulosclerosis associated with mitochondrial cytopathy.

BACKGROUND: The nonspecific lesion of focal segmental glomerulosclerosis (FSGS) can occur as a primary disease or in a variety of secondary settings. In mitochondrial cytopathies (MCs), the phenotypic expression of the disease depends on the degree of cellular dysfunction, and this correlates with the proportion of abnormal mitochondrial DNA in the cells and the dependence of tissues on oxidative metabolism. The most common renal manifestation in MCs is tubular dysfunction; little has been reported about glomerular diseases. METHODS: Cases of four adult patients with FSGS and MC are reported. Routine histology and mitochondrial DNA analysis were carried out on renal biopsies. RESULTS: Family history and clinical manifestations in the four patients with FSGS suggested a diagnosis of MC. An A3243G transition in the mitochondrial DNA tRNA(leu(UUR)) was found in lymphocytes and kidney. Glomerular lesions of FSGS were associated with unusual hyaline lesions, which appeared to represent individual myocyte necrosis in afferent arterioles and small arteries. CONCLUSION: FSGS is a renal manifestation of MCs. The renal lesion can precede other manifestations of the genetic disease by many years. The striking arteriolar lesions in these cases may have resulted in glomerular hypertension and hyperperfusion, leading to secondary epithelial cell abnormalities and, ultimately, FSGS. However, primary epithelial cell dysfunction caused by mitochondrial defects could not be ruled out on morphological grounds. MCs should be considered in cases of so-called primary FSGS, particularly if there is a familial history of diabetes, neuromuscular disorders, or deafness.

Adolescent↗
PubMed2000

Clinical characteristics of type 2 diabetes in patients with mutations of HFE.

Genetic hemochromatosis (GH) is associated with two mutations of the HFE gene (Cys282Tyr and His63Asp). Heterozygosity for GH is associated with a mild increase in iron metabolism parameters, and increased iron stores are associated with abnormal glucose tolerance and decreased insulin sensitivity in the general population. We have previously shown that the frequency of the two HFE mutations is not increased in patients with type 2 diabetes. However, to assess whether the presence of HFE mutations modulates the clinical presentation of type 2 diabetes, we studied the clinical characteristics and iron metabolism indexes according to the presence of the two mutations in 266 patients with type 2 diabetes. The Cys282Tyr mutation and the His63Asp mutation were present in 9. 8% and 26% of the patients, respectively. Serum iron, transferrin saturation and ferritin concentrations were significantly increased in patients expressing either HFE mutations, compared to those without any mutation. There was no difference in the clinical characteristics in the two groups except that obesity was significantly less frequent in the patients with at least one mutation than in those without any mutation (27.6% vs 42.8%, p=0.02). This finding suggests that, in the absence of obesity, HFE mutations, through the insulin resistance associated with the increase in iron stores, may contribute to the onset of type 2 diabetes.

Amino Acid Substitution↗
PubMed1999

Tapasin enhances assembly of transporters associated with antigen processing-dependent and -independent peptides with HLA-A2 and HLA-B27 expressed in insect cells.

Assembly of HLA class I-peptide complexes is assisted by multiple proteins that associate with HLA molecules in loading complexes. These include the housekeeping chaperones calnexin and calreticulin and two essential proteins, the transporters associated with antigen processing (TAP) for peptide supply, and the protein tapasin which is thought to act as a specialized chaperone. We dissected functional effects of processing cofactors by co-expressing in insect cells various combinations of the human proteins HLA-A2, HLA-B27, beta(2)-microglobulin, TAP, calnexin, calreticulin, and tapasin. Stability at 37 degrees C and surface expression of class I dimers correlated closely in baculovirus-infected Sf9 cells, suggesting that these cells retain empty dimers in the endoplasmic reticulum. Both HLA molecules form substantial quantities of stable complexes with insect cell-produced peptide pools. These pools are TAP-selected cytosolic peptides for HLA-B27 but endoplasmic reticulum-derived, i.e. TAP-independent peptides for HLA-A2. This discrepancy may be due to peptide selection by human TAP which is much better adapted to the HLA-B27 than to the HLA-A2 ligand preferences. HLA class I assembly with peptides from TAP-dependent and -independent pools was enhanced strongly by tapasin. Thus, tapasin acts as a chaperone and/or peptide editor that facilitates assembly of peptides with HLA class I molecules independently of mediating their interaction with TAP and/or retention in the endoplasmic reticulum.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS.

The genetics of resistance to infection by HIV-1 cohort consists of 200 slow and 75 rapid progressors to AIDS corresponding to the extremes of HIV disease outcome of 20,000 Caucasians of European descent. A comprehensive analysis of HLA class I and class II genes in this highly informative cohort has identified HLA alleles associated with fast or slow progression, including several not described previously. A quantitative analysis shows an overall HLA influence independent of and equal in magnitude (for the protective effect) to the effect of the CCR5-Delta32 mutation. Among HLA class I genes, A29 (p = 0.001) and B22 (p < 0.0001) are significantly associated with rapid progression, whereas B14 (p = 0.001) and C8 (p = 0.004) are significantly associated with nonprogression. The class I alleles B27, B57, C14 (protective), and C16, as well as B35 (susceptible), are also influential, but their effects are less robust. Influence of class II alleles was only observed for DR11. These results confirm the influence of the immune system on disease progression and may have implications on peptide-based vaccine development.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group.

OBJECTIVE: To evaluate the prevalence of macular pattern dystrophy (MPD) in maternally inherited diabetes and deafness (MIDD), a new subtype of diabetes mellitus that cosegregates with a mutation of mitochondrial DNA (i.e., the substitution of guanine for adenine at position 3243 of leucine transfer RNA) and to report the clinical characteristics of MPD. DESIGN: Prospective cohort study. PARTICIPANTS: Forty-six patients from 29 families with an adenine-to-guanine mutation of mitochondrial DNA were recruited from a French collaborative multicenter study. Thirty-five patients had MIDD, 8 were asymptomatic children of MIDD patients, and 3 had MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). The 33 MIDD patients with diabetes were matched for diabetes duration and gender with 33 patients with "common" type-2 diabetes to compare the prevalence of diabetic retinopathy (DR) in both series. METHODS: All patients had a full ophthalmologic examination and fundus photographs. MAIN OUTCOME MEASURES: The presence and severity of MPD and DR were assessed in each patient. RESULTS: Thirty MIDD patients (85.7%) of 35 exhibited bilateral MPD characterized by linear pigmentation surrounding the macula and optic disc. In 24 of these 30 patients, visual acuity was 20/25 or more in both eyes. The prevalence of DR was 6% in MIDD patients with diabetes versus 15% for patients with common type-2 diabetes (a difference that was not significant, P = 0.23). The fundus of each of the eight asymptomatic children was normal. MPD was present in one of the three cases of MELAS. CONCLUSION: The prevalence of MPD in MIDD is high. Its detection may be helpful for the diagnosis of this new subtype of diabetes, for which specific treatments may be proposed.

Adult↗
PubMed1999

Linkage and association study of the CTLA-4 region in coeliac disease for Italian and Tunisian populations.

Coeliac disease (CD) is a multifactorial disease for which there is an intensive search for genetic risk factors. Some authors found an association between the CTLA-4 region and CD. In the present work, we investigate the possible implication of the CTLA-4 region as a genetic risk factor for CD, through two statistical approaches: the maximum likelihood score (MLS) test in a large Italian sample of affected sib-pairs using polymorphic genetic markers on chromosome 2, and the transmission disequilibrium test (TDT) in continental Italian and Tunisian families using the CTLA-4 exon 1 49 A/G polymorphism. None of these approaches provides evidence for linkage or association between the CTLA-4 region and CD. This might result from a difference in the CTLA-4 region from population to population, either in its involvement as a risk factor or in the strength of linkage disequilibrium.

Abatacept↗
PubMed1999

Identification of peptides from autoantigens GAD65 and IA-2 that bind to HLA class II molecules predisposing to or protecting from type 1 diabetes.

Type 1 diabetes is a T-cell-mediated disease in which presentation of autoantigens to CD4+ T-cells is thought to play a crucial role. Polymorphism of HLA class II genes accounts for 50% of the genetic risk of contracting type 1 diabetes. HLA-DQ and -DR molecules predisposing to or protecting from type 1 diabetes have been identified, but the molecular basis controlling these associations is as yet undefined. Apart from distinct thymic selection of autoreactive T-cells by susceptible and protective HLA molecules, exclusive presentation of autoantigenic peptides by type 1 diabetes-predisposing HLA molecules or, alternatively, induction of regulatory T-cells by protective alleles are potential mechanisms for modification of type 1 diabetes risk by HLA polymorphism. As a first step in exploring the role of HLA molecules in autoantigen-specific cellular responses in type 1 diabetes, we have screened peptides covering the sequence of two major autoantigens targeted by humoral and cellular immune responses, GAD65 and islet associated-2 (IA-2), for binding to class II molecules. We developed a sensitive novel competition binding assay allowing us to measure peptide binding on intact cells to 10 HLA-DR and 4 HLA-DQ molecules. For all tested alleles, multiple peptides binding with high affinity were identified. We report clustering of binding peptides in the COOH-terminal regions of GAD65 and IA-2, as well as highly promiscuous binding patterns of some peptides. Our results demonstrate that most peptides derived from the GAD and IA-2 autoantigens can bind to both type 1 diabetes-predisposing and type 1 diabetes-protective HLA molecules, although some exceptions were observed. The binding inventory presented here for GAD and IA-2 peptides can be useful for mapping natural epitopes and predicting peptide-specific responses induced by preventive immunization.

Alleles↗
PubMed1999

[Recent findings on the genetics of Behçet's disease].

Behçet's disease is a systemic inflammatory disease with a multifactorial genetic and environmental pathogenesis. The main factor of genetic predisposition is located in the HLA region. The disease is significantly linked with the HLA-B51 antigen in different ethnic groups. Recently, a linkage with MICA gene polymophism has been evidenced. This gene, located 46 kb centromerically from the HLA-B gene, codes for a non-classic HLA class I protein induced by stress and probably plays an important role in the destruction of cells targeted by Tgd lymphocytes. The functional significance of this polymorphism in Behçet's disease remains unclear.

Animals↗
PubMed1998

Distinctive effects of CCR5, CCR2, and SDF1 genetic polymorphisms in AIDS progression.

The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represents 200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progressor (Fastprog) HIV-1-infected patients. Using this unique assembly, we performed genetic studies on three recently discovered polymorphisms of CCR5, CCR2, and SDF1, which have been shown to slow the rate of disease progression. The increased prevalence of mutant alleles among Slowprogs from the GRIV cohort was significant for CCR5 (p < .0001) but not for CCR2 (p = .09) or SDF1 (p = . 12), emphasizing the predominant role of CCR5 as the major HIV-1 coreceptor. However, the prevalence of the CCR2 mutant allele (64I) was significantly increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .04). The prevalence of double mutants SDF1-3'A/3'A genotypes was also increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .05). The effects of the CCR2 and SDF1 mutations are overshadowed by the protective effects of the CCR5 deletion. Predictive biologic markers such as CD4 cell counts or viral load in the Slowprog population did not show significant differences between Slowprog groups with wild-type or mutant alleles for the three genes. Thus, our data suggest that the effects of these genes are exerted earlier in infection and no longer evident in the Slowprog of the GRIV cohort whose average duration of HIV infection is 12 years. We conclude that these genes, whose products serve as viral coreceptors or their ligands, may play a role early in infection and delay the onset of disease. However, among Slowprogs, whose duration of infection is >8 years, they are no longer influential for maintenance of their longterm nonprogression status. Other genetic determinants may be responsible for late protective effects.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Relationship between peptide selectivities of human transporters associated with antigen processing and HLA class I molecules.

Efficiency of presentation of a peptide epitope by a MHC class I molecule depends on two parameters: its binding to the MHC molecule and its generation by intracellular Ag processing. In contrast to the former parameter, the mechanisms underlying peptide selection in Ag processing are poorly understood. Peptide translocation by the TAP transporter is required for presentation of most epitopes and may modulate peptide supply to MHC class I molecules. To study the role of human TAP for peptide presentation by individual HLA class I molecules, we generated artificial neural networks capable of predicting the affinity of TAP for random sequence 9-mer peptides. Using neural network-based predictions of TAP affinity, we found that peptides eluted from three different HLA class I molecules had higher TAP affinities than control peptides with equal binding affinities for the same HLA class I molecules, suggesting that human TAP may contribute to epitope selection. In simulated TAP binding experiments with 408 HLA class I binding peptides, HLA class I molecules differed significantly with respect to TAP affinities of their ligands. As a result, some class I molecules, especially HLA-B27, may be particularly efficient in presentation of cytosolic peptides with low concentrations, while most class I molecules may predominantly present abundant cytosolic peptides.

ATP-Binding Cassette Transporters↗
PubMed1998

Substrate selection by transporters associated with antigen processing occurs during peptide binding to TAP.

Presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules depends on translocation of cytosolic peptides into the endoplasmic reticulum (ER) by transporters associated with antigen processing (TAP). Peptide transport by TAP is thought to include at least two steps: initial binding of peptide to TAP, and its subsequent translocation requiring ATP hydrolysis. These events can be monitored in peptide binding and transport assays. Previous studies have shown that the efficiency of peptide transport by human, mouse and rat transporters varies according to the C-terminals of peptide substrates in an allele and species-specific manner. However, it has not been clear during which step of peptide interaction with TAP selection occurs. We used an assay monitoring the peptide binding step to study the binding affinity of a library of 199 peptides for human TAP and the two major allelic rat TAP complexes. We observed a dominant influence of the C-terminus on peptide binding affinity for all transporters, and highly restrictive selection of peptides with aliphatic and aromatic C-terminals by rat TAP1/TAP2u complexes. The selectivity of peptide binding to rat TAP complexes is in full accordance with published data on selective peptide transport and on control of antigen presentation by rat TAP. These results strongly suggest that (i) peptide selection by TAP occurs exclusively in the initial binding step; (ii) all factors involved in peptide selection by TAP are present in insect cells.

Alleles↗
PubMed1998

Major histocompatibility class II genes polymorphism in insulin dependent diabetes mellitus with or without associated thyroid autoimmunity.

Insulin dependent diabetes mellitus (IDDM) is sometimes associated with extrapancreatic organ-specific autoimmune diseases, but whether this phenotype results from a peculiar genetic profile is still unclear. The allelic distribution of the major histocompatibility complex (MHC) class II genes (HLA-DRB1, DQA1, DQB1 and TAP) was analysed in 143 patients with IDDM alone by comparison with 82 IDDM patients with autoimmune thyroid disease (IDDM/AITD). The frequency of the DQB1*0301 IDDM-protective phenotype seemed to be lower in IDDM than in IDDM/AITD patients (16.8% vs 30.5% respectively, p = 0.02). By contrast, the frequency of the DRB1*04-DQB1*0302 IDDM-predisposing phenotype was higher in IDDM than in IDDM/AITD patients (91.3% vs 76.1% of DR4-positive patients respectively, p = 0.007), but these differences were not significant after correcting the p values, except in the case of the DRB1*0405-DQB1*0302 combination (21.3% vs 2.4% of DR4-positive patients, Pc = 0.05). Furthermore, all differences disappeared when patients were matched for age at IDDM-onset. Our data do not long give support for a particular role of MHC class II genes in favouring the occurrence of thyroid autoimmunity in IDDM patients, but rather suggest that some class II alleles or residues might determine the rapidity of progression to IDDM in genetically susceptible individuals. The involvement of non-MHC genes and/or environmental factors remains to be determined.

ATP Binding Cassette Transporter, Subfamily B, Mem↗