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C Irlé

Publications and source records attributed to C Irlé.

At least 19 recordsLinked to original sources
PubMed1994

An HLA-DRB alpha-helix motif shared by DR11 and DR8 alleles is implicated in the pluriallelic restriction of peptide-specific T-cell lines.

The T-cell recognition of HLA-DR-peptide complexes is generally restricted by the polymorphism of the DRB molecules but pluriallelic restriction has been described. The molecular basis of restriction and promiscuity of such peptide-specific responses is poorly understood. We isolated a panel of T-cell lines specific for the tetanus toxin peptide p2 (TT830-843) exhibiting pluriallelic restriction by DR11 and DR8 alleles. Fine restriction specificity of the T-cell lines was examined in functional assays against DR oligotyped APCs expressing different variants of DR11 and DR8 alleles. Our results show that (a) polymorphisms between serologically related alleles are relevant in terms of restriction of the peptide-specific T-cell response; in some instances, a single amino acid substitution can determine the restriction of a T-cell line; (b) different patterns of restriction are not the result of specific differences in DR-p2 binding as p2 peptide binds to all DR11 and DR8 alleles tested (DRB1* 1101, -1102, -1103, -1104, 110X, -0801, -0802, -0803, and -0806); and (c) pluriallelic restriction of the peptide-specific T-cell response correlates with the presence of a DRB1 alpha-helix motif (67-71-86) shared by some DR11 and DR8 alleles. Possible implications of pluriallelic restriction of peptide-specific T-cell response in autoimmune disorders associated with DR11 and DR8 are discussed.

Alleles↗
PubMed1993

Functional dissection of the serological DR LYGUE and genotypic DRB1*1303 specificities using a tetanus toxin-specific T-cell clone.

The DRB1 sequence of the homozygous cell line HAG (DR13-DwHAG-DQ7) represents a new DRB allele assigned DRB1*1103, whereas its DRB3 sequence corresponds to the previously described DRB3*0101 (DR52a) allele. The DRB1*1303 gene product is undetectable by current sera used in routine serology typing. We report here direct evidence that the MHC molecule encoded by the DRB1*1303 gene is functional in antigen presentation and in T-cell restriction. We describe a T-cell clone specific for tetanus toxin whose restriction pattern strictly follows the DRB1*1303 allele, as defined by oligonucleotide typing. It also follows the serologic reactivity with the serum LYGUE and also the DwHAG MLC-defined specificity pattern, with one exception. The potential functional sites for the DRB1*1303 gene product involved in T-cell restriction were deduced from sequence comparisons between DRB1*1303 and closely related DRB1 alleles. The relevant as substitutions were located within close proximity to each other on the HLA class II structural model. Our results demonstrate that 1) DRB1*1303 is functional in antigen presentation and T-cell restriction 2) the functional region involved in antigen presentation and T-cell restriction by DRB1*1303 can be defined structurally.

Alleles↗
PubMed1990

Bare lymphocyte syndrome--combined immunodeficiency and neutrophil dysfunction.

A 4-year-old girl presented with recurrent infections. Immunoglobulin deficiency (serum and secretory IgA, serum IgG3) neutropenia and neutrophil dysfunction (defective spontaneous migration and chemotaxis) were found. T-lymphocyte counts were normal and they responded to phytohaemagglutinin but were not stimulated by Concanavalin A, pokeweed mitogen and microbial antigens in vitro. Delayed cutaneous hypersensitivity testing to purified protein derivative and candidin was negative. Despite bacille Calmette-Guérm vaccination and candidiasis, near normal beta-2-micro-globulin and human leucocyte antigen (HLA) class I concentrations were detected on mononuclear cells and phytohaemagglutinin-induced lymphoblasts. HLA class II antigens (HLA-DP, -DQ, -DR) were not expressed. These observations indicated a bare lymphocyte syndrome (BLS) type II. This is the first time neutrophil dysfunction has been noted in association with BLS.

Cell Movement↗
PubMed1989

MHC related genetic susceptibility to Hodgkin's disease.

The present report describes 4 Caucasoid families, HLA genotyped, with at least 2 affected siblings suffering from Hodgkin's disease. The affected sibling pairs were identical (2 shared haplotypes) in 2 families and haploidentical (1 shared haplotype) in the 2 others. These results together with the data already published provide evidence for a distortion of the segregation of HLA haplotypes: from a total of 43 pairs of siblings reported, the observed repartition is 22, 15, 6 (2, 1, 0 shared haplotypes respectively) instead of 10.75, 21.5, 10.75 (mendelian repartition). The excess of identical siblings pairs (51% instead of 25%) (p less than 10(-5) confirms the existence of a genetic linkage between the chromosomal HLA region and the susceptibility to the disease.

Adolescent↗
PubMed1988

[Super intensive treatment followed by bone marrow autograft in cases of hematologic neoplasms and solid tumors].

Thirty-one patients underwent autologous bone marrow transplantation (ABMT) after intensive radio and/or chemotherapy. On 18 occasions, bone marrows were treated in vitro with either Asta-Z 7557, Asta-Z 7654 or the rat monoclonal antibody Campath-1M and complement. Sixteen patients were transplanted for acute leukemia: 6 patients were in first complete remission (CR), 5 in CR greater than 1 and 5 in relapse. Twelve out of fourteen evaluable patients have relapsed. Two patients transplanted in CR 2 and CR 1 remain in CR after 9.5 and 12 months respectively. Nine patients were transplanted for aggressive lymphoma: four patients were in CR 1, 2 in CR greater than 1, 1 in first relapse and 2 refractory to best available second line chemotherapy. All 3 achieved CR after ABMT. Nine patients are evaluable: 4 relapsed and 5 remain in CR at 5, 6.5, 21, 25 and 39 months, this last patient transplanted in a refractory state, the others in CR 1. Four patients were transplanted for refractory Hodgkin's disease: 3 patients are evaluable. One patient achieved complete remission which lasted 9 months. Two patients were transplanted for relapsed solid tumors and achieved a partial response. In conclusion, the response rate is encouraging for patients transplanted during active and sometimes refractory phases of the diseases (8/13 evaluable patients achieved CR). However, for the whole group of patients, including those transplanted for acute leukemia in CR 1, the relapse rate was high. Durable remissions were achieved for patients with aggressive lymphoma who were transplanted early in the disease.

Acute Disease↗
PubMed1988

Functional polymorphism of each of the two HLA-DR beta chain loci demonstrated with antigen-specific DR3- and DRw52-restricted T cell clones.

HLA-DR3- and HLA-DRw52-associated functional polymorphism was investigated with selected tetanus toxoid (TT)-specific T cell clones. We have shown earlier that HLA-DR antigens are encoded by two distinct loci, DR beta I and DR beta III. The alloantigenic determinant(s) defined by the serological HLA-DR3 specificity map to the former, while the supratypic HLA-DRw52 determinants map to DR beta III. Furthermore, we have recently recognized by DNA sequencing three alleles of HLA-DRw52 at locus DR beta III, referred to as 52 a, b, and c. Our objective was to correlate the pattern of T cell restriction with the gene products of individual DR beta chain loci and with the three newly described alleles of locus DR beta III. Among the selected T cell clones, 5 reacted exclusively when TT was presented by HLA-DR3+ APCs (TT-DR3-APC). In contrast, two T cell clones were stimulated by TT-DRw52-APC. More specifically, these two T cell clones (Clones 10 and 16) were stimulated by different subsets of TT-DRw52-APC. Clone 16 responded to some DR3 and TT-DRw6-APC, while clone 10 was stimulated by other TT-DR3 and TT-DRw6, and all TT-DR5-APC. This same pattern of DRw52 restriction was found in panel, as well as in family studies. Because this suggested a correlation with the pattern of DRw52 polymorphism observed earlier by DNA sequencing and oligonucleotide hybridization, the APC used in these experiments were typed for the 52 a, b, and c alleles of locus DR beta III by allele-specific oligonucleotide probes. This distribution overlapped exactly with the stimulation pattern defined by the T cell clones. Clone 16 responded to TT-52a-APC, clone 10 to TT-52b-APC, and both clones to a TT-52c-APC. The response of the T cell clones was inhibited differentially by mAbs to DR. Raising TT concentration, or increasing HLA-class II expression with INF-gamma both affected the magnitude of response of the TT-specific clones but did not modify their specificities. These results demonstrate that a restriction specificity can be attributed to the DR beta III locus and illustrate the functional relevance of the polymorphism observed at this locus. This is of special interest in view of the striking difference in the pattern of structural diversity among alleles of DR beta I and DR beta III.

Alleles↗
PubMed1988

Effect of factors inhibiting HLA-DR antibodies before transplantation on kidney graft survival.

Blood transfusions administered before renal allografts are known to enhance graft survival. Among alternative hypotheses proposed to explain this effect, one of the most attractive is the possible induction of antiidiotypic antibodies directed against the specific antigen-binding site of donor-specific antibodies. In order to determine if such blocking antibodies are generated after blood transfusions, serial serum samples obtained before transplantation from 44 kidney recipients were analyzed for the development of HLA-DR alloantisera inhibitory activity by a microcytotoxicity inhibition assay. A significant correlation was found between the presence of inhibitory factors before transplantation and prolonged graft survival. However a clear relation between the development of inhibitory factors and the administration of transfusions could not be established. In addition the sera of 36 patients were studied for the presence of circulating immune complexes (CIC) before grafting. The presence of CIC was clearly associated with that of inhibitory factors, and with a prolonged graft survival. Thus these studies provide support for the development of blocking (possibly antiidiotypic) antibodies to anti-MHC in human renal graft recipients.

Adult↗
PubMed1987

[Quantitative detection and elimination of neuroblastoma cells in vitro. Comparative study of the efficacy of an immunomagnetic method and lymphokine-activated killer cells].

Much effort is devoted to eliminating residual tumor cells - which escape detection by conventional methods - from remission bone marrow harvested for autologous transplantation. The quantitative determination of the efficacy of these purging methods is generally difficult. This report describes an in vitro reproducible tumor model. Normal mononuclear blood cells were deliberately contaminated with cells from the human neuroblastoma cell line SK-N-AS. The frequency of clonogenic SK-N-AS cells was determined in limiting dilution culture before and after treatment. Two methods of purging these tumor cells from the mixed cell suspension were compared, 1) an immunomagnetic method taking advantage of the existence of a monoclonal antibody (mAb) specific for 90-95% of the tumor cells, and 2) a method based on cell mediated cytotoxicity testing the activity of previously lymphokine activated killer (LAK) cells. Immunomagnetic purging eliminated 90% (1 log) of all SK-N-AS cells and 99% (2 log) of the mAb-binding clonogenic tumor cells. In contrast, LAK cell treatment removed only between 0.1 to 0.3 log (23-50%) of the clonogenic SK-N-AS cells.

Antibodies, Monoclonal↗
PubMed1987

Constitutive and induced expression of the individual HLA-DR beta and alpha chain loci in different cell types.

The HLA-DR subregion of the human major histocompatibility complex encodes molecules involved in the regulation of the immune response. These HLA class II molecules are transmembrane heterodimers composed of an alpha and a beta chain. The polymorphic beta chains are encoded by multiple, highly homologous loci, whereas the alpha chain is encoded by a single, nonpolymorphic locus. HLA-DR is expressed constitutively on B lymphocytes and on activated T lymphocytes. It can also be induced by interferon-gamma on most nonlymphoid cells. In a quantitative study of the expression of the individual DR beta chain loci, we have investigated: the levels of mRNA transcripts of the two functional DR beta loci (beta I and beta III) in B cells of various haplotypes; whether both beta chain loci are expressed in activated T cells and, if so, the level of expression of each; whether both loci are expressed in interferon-gamma-induced nonlymphoid cells. This analysis relied on locus-specific DR beta chain oligonucleotide probes. Expression of both the beta I and the beta III loci was observed in all cell types and in all haplotypes tested. In every case the amount of beta I mRNA was about 5 times higher than that of beta III mRNA. This indicates a controlled and coordinated regulation of the mRNA levels of these two HLA-DR loci under all conditions of major histocompatibility complex class II gene expression.

B-Lymphocytes↗
PubMed1987

Quantity and nature of residual bone marrow T cells after treatment of the marrow with Campath-1.

Precise characterization of T-cell depletion in marrows used for transplantation is necessary for the evaluation of their potential contribution to engraftment and to graft-versus-host disease. A limiting dilution culture method that allows the determination of small numbers of bone marrow T cells is described. It can detect less than one T cell in 10(4) cells. Bone marrow T-cell depletion with the rat monoclonal antibody Campath-1 and fresh human complement results in a median decrease of 1.7 log (range, 1.6-2.1 log) of marrow T cells. A 2.7 to 3.3-log reduction is obtained when peripheral blood T cells are treated. A second incubation with fresh complement removes additional T cells from peripheral blood and from marrow samples, indicating the importance of bystander marrow cells to complement activity. The assay system described also allows the phenotypic study of responding cells growing in culture. These studies demonstrate that, after treatment with Campath-1 plus complement, no T-subset imbalance occurs. Furthermore, the T cells in these cultures are derived from mature T cells contained in the samples.

Antibodies, Monoclonal↗
PubMed1986

[Effect of T-cell depletion of the graft on graft survival and graft vs host disease].

A limiting dilution culture method has been developed which allows the detection of small numbers of residual marrow T cells following their depletion with the monoclonal antibody Campath-I and autologous complement. In seven consecutive patients the degree of T cell depletion obtained was 1.82 (1.27-2.82) log. The number of nucleated cells per kg decreased by 50% and the number of CFU-GM per kg decreased by 60%. In all except one case marrow cellularity was found to be satisfactory 3 weeks after the transplant. Peripheral engraftment of granulocytes (greater than 500/mm3 on day 20, greater than 1000/mm3 on day 27), lymphocytes (greater than 500 on day 39, greater than 1000 on day 66), platelets (greater than 20,000 and self-sustained after day 24) and red blood cells (day to last infusion = 19) indicated a delay in recovery of lymphocytes and possibly granulocytes, but not platelets or red blood cells, compared to the engraftment seen in non-T depleted patients. No correlation between nucleated cells infused, GFU-GM and engraftment was found. However, the extent of T cell depletion apparently affects lymphocyte, and possibly granulocyte, recovery. The delay in lymphoid engraftment is also reflected by nonresponsiveness to alloantigens during the first 6-9 months following marrow grafting in the absence of graft vs. host disease.

Graft Survival↗
PubMed1986

[In vivo detection of alloreactive T cells of the donor in graft versus host disease].

A male patient with severe aplastic anemia who had rejected a first T cell depleted graft from his HLA-identical sister was retransplanted from the same donor without T cell depletion and using an intensified conditioning regimen. After 8 weeks acute graft versus host disease (GVHD) developed and peripheral blood mononuclear cells (PBMC) were obtained. After in vitro restimulation and following limiting dilution cloning, 15 proliferative (PLT) and 25 cytolytic (CTL) T cell lines specific for host PBMC but unreactive to donor PBMC were isolated. Only 1 of 10 clones which could be expanded sufficiently for testing recognized a target cell (haploidentical sister), and in only 4 instances could a restriction element be found in a panel study (3 times HLA-A2; once HLA-BW49) of 13 unrelated stimulators. Of the 8 CTL clones testable after expansion, none showed a clear restriction and none recognized any of the family cells. Our data demonstrate that anti-patient reactive PLT and CTL lines can be found in PBMC. In no instance was segregation with HLA found. Only HLA-class I restriction was detectable.

Anemia, Aplastic↗
PubMed1986

[Transplantation of allogeneic bone marrow treated in vitro with Campath-1 monoclonal antibody].

Out of 14 bone marrow transplants, 12 patients received transplantations with allogeneic bone marrow after in vitro T-cell depletion with monoclonal Campath 1. The patients also received short term cyclosporin. This small series is in agreement with the results of larger series using T-depleted marrow as far as the prevention of graft versus host disease is concerned, and with respect to mixed chimerism, slow take, late rejection and, possibly, increased risk of recurrence.

Aged↗
PubMed1985

[Quantitative determination of human bone marrow T cells following in vitro depletion by Campath-1 monoclonal antibody].

Bone marrow T cell depletion is an effective graft vs host disease prophylaxis in allogeneic bone marrow transplantation. Standard methods of identifying T cells are not sensitive enough to determine small numbers of residual T cells following T cell depletion. A rapid and sensitive method, using limiting dilution culture technology and radionucleotide labelling and allowing the detection of 1/10(4)-1/10(5) residual T cells, has been developed. Its usefulness in the evaluation of the number of T cells after monoclonal antibody (Campath-1) + autologous complement marrow treatment is demonstrated.

Antibodies, Monoclonal↗
PubMed1985

[Transplantation of allogeneic bone marrow treated in vitro with Campath-1 monoclonal antibody].

5 patients underwent bone marrow transplantation for severe aplastic anemia (2) and acute leukemia (ALL) in first remission (3). Graft versus host disease prophylaxis was performed by depleting T lymphocytes in the donor bone marrow with the rat monoclonal Campath-1 and autologous complement. In addition, patients received cyclosporin A. Engraftment occurred normally in all 5 patients but 1 patient (SAA) had a late graft failure. Two patients suffered mild degrees of GvHD. All patients are currently in complete remission, one having undergone a second transplantation.

Adult↗
PubMed1985

[In vivo detection of alloreactive T cells of host origin after rejection of HLA-identical allogeneic bone marrow transplant].

Rejection and graft vs host disease after HLA-identical allogeneic bone marrow transplantation are probably due to in-vivo T-cell reactivity against non-MHC antigens. Peripheral blood lymphocytes from a patient transplanted for aplastic anemia have been obtained during graft failure and tested for their alloreactivity towards unrelated and marrow donor lymphocytes. Their caryotype was determined. Our results demonstrate (1) alloreactive T cells of host origin and (2) the presence of donor-specific host cells in vivo, providing evidence for rejection following in vivo sensitization to non-MHC antigens.

Anemia, Aplastic↗