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Biomedical subjects

C Brautbar

Publications and source records attributed to C Brautbar.

At least 73 records · Page 4Linked to original sources
PubMed1996

Bone marrow transplantation using unrelated and family related donors: the impact of HLA-C disparity.

The clinical outcomes of unrelated and of family related allogeneic bone marrow transplantation (BMT) were correlated with HLA disparity in a study in which molecular phenotyping of HLA-C was performed for unrelated donor-recipient pairs. The study included 30 patients who underwent BMT from unrelated donors and 43 patients who underwent BMT from family related donors. The unrelated group included 14 full match pairs, 12 class-I-C (molecular HLA-C) mismatched pairs, and 4 haploidentical pairs. The family related group included 9 full match pairs, 19 class-I mismatched pairs, and 15 haploidentical pairs. In the unrelated BMT group, the transplant-related complications of mortality, graft-versus-host disease (GVHD), and graft rejection, were significantly higher in molecular HLA-C mismatched than matched patients (67% vs 14%, P < 0.02; 50% vs 7%, P < 0.02; 42% vs 0, P < 0.02). The actuarial survival and the disease free survival (DFS) at 18 months was better for molecular HLA-C matched than for HLA-C mismatched unrelated transplants: 33% vs 18% (P = 0.065, NS), and 29% vs 16%, respectively. For the family related BMT group, the actuarial survival at 18 months was significantly higher for patients who were fully matched compared to those who were class-I mismatched, or those who were haploidentical pairs: 67%, 37%, and 13% respectively (P < 0.02). The actuarial DFS at 18 months of patients who were fully matched and of those who were class-I mismatched was similar, and better than that of haploidentical patients 45%, 37% (NS) and 13% respectively (P < 0.045). A lower incidence of transplant-related mortality occurred in class-I mismatched, family related (37%) than in locus-C mismatched unrelated patients (67%), and no difference was observed in the fully matched family related and unrelated patients. We conclude that a mismatch in locus C may be detrimental to BMT outcome and should therefore be included as a risk factor in the routine pre-BMT HLA phenotyping.

Adolescent↗
PubMed1995

Local suppression of Epstein-Barr virus (EBV)-specific cytotoxicity in biopsies of EBV-positive Hodgkin's disease.

Epstein-Barr virus (EBV)-positive Hodgkin's and Reed-Sternberg (HRS) cells express the virus-encoded latent membrane proteins LMP1 and LMP2 that could serve as rejection targets in Hodgkin's disease (HD). To examine whether EBV-triggered reactivities can be detected in the tumor, we have compared cytokine mRNA expression, cell phenotype, and cytotoxic activity in biopsies from 8 EBV-carrying and 6 EBV-HD patients. Neither the pattern of lymphokine production nor the cell phenotype of the in vivo-activated interleukin-2-responding populations provided a clear discrimination between EBV+ and EBV- cases. HLA class I-restricted EBV-specific cytotoxicity was shown in interleukin-2-dependent cultures from 3 of 3 EBV- tumors, whereas cultures from 6 of 6 EBV+ tumors were either noncytotoxic or exerted LAK-type cytotoxicity. EBV-specific cytotoxic T lymphocyte precursors were present in the blood of 1 patient carrying an EBV+ tumor. The results suggest that a tumor-associated suppression of EBV-specific T-cell responses may play an important role in the pathogenesis of EBV+ HD.

Adult↗
PubMed1995

Detection of two Epstein-Barr-virus (EBV)-carrying leukemic cell clones in a patient with chronic lymphocytic leukemia (CLL).

The leukemic-cell population of one CLL patient, PG, was found to contain a sub-set of EBV-genome-carrying cells. It was detected directly by the expression of EBNA (EBV-encoded nuclear antigen) and by its capacity to grow in vitro. The proportion of EBNA-positive cells (0.1%) was maintained constantly during the period of this study, the final 3 years of the patient's life. EBV-carrying clonal sibling B-cell lines were established on 5 occasions. They had identically rearranged JH bands and chromosomal markers corresponding to the ex vivo CLL cells. Analysis of the viral episomes in the lines proved that they were the descendants of one cell. On the last occasion of blood sampling, 8 B-cell lines were established; 4 of these contained the same clonal markers as the previous lines, while 4 other lines belonged to another clone with identical JH rearrangement. Their abnormal karyotypes were different from the first clone. The chromosomal markers were only partly identical, suggesting secondary diversifications. The EBV sub-strain carried by this group of lines was different from the sub-strain of the first clone, as judged by the EBNA size distributions (EBNOtype) and EBV-DNA analysis. Analysis of the terminal repeat in the viral episomes also showed that the first and the second set of clones represented 2 independent EBV-infection events in vivo.

B-Lymphocytes↗
PubMed1995

[Kidney transplantation from living, related donors].

Kidney transplantation is the best treatment for selected end-stage renal patients. The shortage of cadaveric organs for transplantation has led to the development of a protocol for kidney transplantation from living, related donors. In the past 20 years, 58 living, related kidney transplantations were done in our department. Mean patient age was 30 +/- 10 (SD) years and mean donor age was 36 +/- 10. There were 34 transplantations between brothers or sisters, 15 from parent to child, 4 between cousins, 4 between spouses and 1 from son to father. Mean follow-up time was 4 years. 1 and 5 years after transplantation, patient survival rates were 85% and 80%, respectively, graft survival rates were 85% and 75%. The introduction of cyclosporin-A as an immunosuppressive agent in 1985 led to improvement in graft survival rates: from 77% and 51% after 1 and 5 years, respectively, to 88% and 84%. No correlation between HLA match or patient's age and graft survival rates was found. We conclude that living, related donor transplantation is effective for suitable cases of end-stage renal disease. It should be recommended to patients who have a healthy, interested family member.

Adult↗
PubMed1995

Correlation between gold-induced enterocolitis and the presence of the HLA-DRB1*0404 allele.

OBJECTIVE: In recent years we have treated 4 rheumatoid arthritis (RA) patients who developed gold-induced enterocolitis, a well-recognized, although rare, complication of chrysotherapy. The aim of the present study was to seek any genetic predisposition for this complication. METHODS: HLA DNA typing was done on fresh white blood cells from the 4 patients. RESULTS: Three of the 4 patients (75%) exhibited the DRB1*0404 allele, whereas the prevalence of this allele among the Ashkenazi Jewish population of RA patients without colitis was 9.2% and 10.2% in 2 different studies. CONCLUSION: The results indicate that the DRB1*0404 may be associated with risk for the development of gold-induced enterocolitis in this population and suggest that HLA DNA typing should be considered in Jews who may be undergoing chrysotherapy.

Adult↗
PubMed1995

Binding of peptides of the human acetylcholine receptor alpha-subunit to HLA class II of patients with myasthenia gravis.

MG is an autoimmune disease in which T cells specific to T-cell epitopes of the human acetylcholine receptor play a role. We have identified two peptides, p195-212 and p259-271, of the human acetylcholine receptor alpha-subunit, to which PBLs of MG patients responded by proliferation. Nevertheless, proliferation assays are relatively complicated to perform and might be affected by medications taken by the patients. Therefore, we tested the possibility of using a different assay to determine recognition of these peptides by MG patients. Thus, we performed a direct binding assay using biotinylated peptides and APCs from peripheral blood of MG patients and healthy controls. With this assay we detected the binding of the two peptides to the surface of intact APCs of both MG patients and control donors. Moreover, the presentation of peptide p259-271 by individuals with MG was significantly higher than that observed in healthy subjects. The peptides were specifically bound to HLA class II determinants on the APCs, as shown by inhibition with antibodies to the HLA class II haplotypes of the individuals investigated. Moreover, the binding of these peptides was in correlation with their ability to induce specific proliferative responses of peripheral blood T cells of these patients. The ability to screen for potentially pathogenic epitopes in each patient is of importance for the future design of specific inhibitory analogues that might be used to treat MG.

Amino Acid Sequence↗
PubMed1995

HLA class II analysis in Jewish Israeli narcoleptic patients.

HLA class II was investigated in eight Jewish narcoleptic patients, representing the total of such patients known in Israel at present, and in three patients suffering from sleep disturbances other than narcolepsy. All (11 out of 11) patients carried the serologic specificities DR2, DQ6 (DQ1). At the DNA level, all narcoleptics were found to be DRB1*1501, DQA1*0102, DQB1*0602 which indicates that the susceptibility gene may be located within the HLA class II region, DR, and/or DQ. As for the nonnarcoleptic patients with idiopathic hypersomnia, they carried different alleles of DR2 and DQ6, namely DRB1*1502, DQA1*0103, DQB1*0601. This study confirms that the incidence of narcolepsy in Israel is extremely low and that HLA class II genes or a gene(s) tightly linked to them are involved in the disease.

Alleles↗
PubMed1995

Comparative analysis of HLA polymorphism at the serologic and molecular level in Moroccan and Ashkenazi Jews.

The Jewish people comprise two major groups, one encompassing the Jews of Ashkenazi (Central and Eastern European) origin and the other including those of Sephardic (Middle Eastern and North African) descent. To the latter belong the Jews of Moroccan stock, who form the largest Jewish subgroup among the non-Ashkenazi population living in Israel. As the members of each of these groups differ in physiognomy and life style, it was of interest to investigate whether these differences are also reflected in their respective HLA compositions. To this end, 132 subjects of Ashkenazi and 113 individuals of Moroccan origin residing in Israel were tested and the results compared with data for other populations made available by the 11th International Histocompatibility Workshop. Comparison between their HLA profiles and those of non-Jews revealed that the Jewish groups in some aspects resembled one another but in others showed disparities. The dissimilarities between the various groups are expressed in terms of gene and haplotype frequencies, as well as in HLA-disease associations (as for example rheumatoid arthritis, erosive lichen planus, primary Sjögren's syndrome, pemphigus vulgaris). However, both Jewish groups shared some unique features with respect to HLA class II allelic frequencies, pointing to a common ancestry.

Adolescent↗
PubMed1995

Identical HLA class II alleles predispose to drug-triggered and idiopathic pemphigus vulgaris.

In pemphigus vulgaris, a dermatological autoimmune disease, specific human leukocyte antigen (HLA) class II alleles, DR4 (DRB1*0402) and DRw14 (DRB1*1401, in linkage disequilibrium with DQB1*0503), are thought to be susceptibility genes involved in the onset of the disease. We studied the HLA class II alleles (DQA1, DQB1, DRB1 and DPB1) of 6 patients with pemphigus, in whom the disease was "triggered" by drugs containing sulphydryl or another sulphur-containing group. All patients carried the DRB1*0402 susceptibility allele, and one patient also carried the second susceptibility allele, namely DQB1*0503 (in linkage with DRB1*1401). Bacterial, viral or environmental agents are suspected to trigger the onset of autoimmune diseases. Our study demonstrated the presence in patients with drug-triggered pemphigus vulgaris of the same HLA alleles thought to predispose to idiopathic pemphigus vulgaris. This finding strengthens the notion that these HLA alleles may be true disease susceptibility genes.

Adult↗
PubMed1995

Human umbilical cord blood for hematopoietic progenitor cells transplantation.

Human umbilical cord blood (HUCB) represents a unique source of transplantable hematopoietic progenitor cells. HUCB from a newborn sibling has been used successfully for hematopoietic reconstitution of more than 50 children with congenital and malignant diseases. Moreover, 13 HUCB transplants have been performed from unrelated donors. Bone marrow transplantation (BMT) has rapidly progressed over the last two decades offering cure and prolonged disease free survival in patients with hemato-oncological malignancies, metabolic and genetic disorders. BMT is limited by the paucity of HLA-matched donors and the morbidity and mortality due to graft-versus-host disease (GVHD). HUCB could alleviate some of the problems associated with BMT and establishment of HUCB bank and registries could become an easily available source of suitable stem cells for transplantation. This review focuses on identifying current scientific problems and clinical achievement as well as noting the most recent developments in the field with special attention to the collection, processing, cryopreservation, and banking of HUCB. Progenitor cells from cord blood may provide an excellent vehicle for future gene therapy. As a result of relative immunodeficiency at birth, it is likely that partially matched unrelated cord blood transplants (CBT) would be successful due to a lower risk of GVHD related problems. Therefore, the establishment of large cord blood banks is of the utmost importance, in the future.

Bone Marrow Transplantation↗
PubMed1995

CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens.

Congenital bilateral aplasia of the vas deferens (CBAVD) was suggested to be a mild form of cystic fibrosis (CF). Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in males with CBAVD revealed that in some males CBAVD is caused by two defective CFTR alleles. The genetic basis of CBAVD in the other males and its association with CF remained unclear. We undertook this study to test the hypothesis of commonality of CBAVD and CF by haplotype analysis, in the CFTR locus, of males suffering from CBAVD and of their families. According to the hypothesis of commonality of CBAVD and CF, two brothers with CBAVD are expected to carry the same two CFTR alleles, while their fertile brothers are expected to carry at least one different allele. Eleven families were studied, of which two families, with unidentified CFTR mutations, did not support this hypothesis. In these families two brothers with CBAVD inherited different CFTR alleles. Their fertile brothers inherited the same CFTR alleles as their brothers with CBAVD. These results provide evidence for genetic heterogeneity in CBAVD. Though in some families CBAVD is associated with two CFTR mutations, we suggest that in others it is caused by other mechanisms, such as mutations at other loci or homozygosity or heterozygosity for partially penetrant CFTR mutations.

Congenital Abnormalities↗
PubMed1995

The putative role of HLA-C recognition in graft versus host disease (GVHD) and graft rejection after unrelated bone marrow transplantation (BMT).

We assessed cytotoxic activity of large granular lymphocytes (LGLs) derived from 10 patients transplanted from molecular HLA-C mismatched (5) and matched (5) unrelated donors and compared it to the cytotoxic activity of 10 patients transplanted from HLA-identical siblings. In addition, we correlated clinical outcome with the level of molecular HLA-C disparity in a cohort of 22 patients who underwent unrelated BMT. Cells obtained from patients transplanted (related or unrelated) from fully matched donors did not generate allospecific lysis of patient (pre-BMT) or donor PHA blasts. Five of nine patients who received BMT from HLA-C mismatched unrelated donors developed > grade II graft-vs.-host disease (GVHD), and four developed graft rejection. Cells derived from three of three patients with GVHD lysed patients' pre-BMT PHA blasts. In the patients with GVHD grade III-IV, cytotoxicity was higher (60-70%) than in the patient with grade II GVHD (20%) (p < 0.05). Cytotoxic cells derived from one patient who rejected his graft lysed donor PHA blasts. In one remaining patient who had graft rejection followed by autologous rescue, no in vitro allospecificity was observed. In summary, cytotoxic cells from patients transplanted with marrow mismatched at locus C demonstrated in vitro cytolysis of PHA blasts, and this phenomenon showed positive correlation with the clinical outcome of the BMT. These findings may indicate specific allorecognition. A mismatch at locus C leading to alloreactivity should be considered a risk factor in determining an appropriate match for allogeneic BMT, especially when the donor is unrelated.

Adolescent↗
PubMed1994

Prediction by a modified mixed leukocyte reaction assay of graft-versus-host disease and graft rejection after allogeneic bone marrow transplantation.

In this report we describe a modified, sensitive MLR test that appears to detect fine antigenic disparities between HLA-identical siblings confirmed as such by serology and the standard MLR test. In a group of 40 consecutive allogeneic bone marrow transplants, reactivity detected by the modified MLR test correlated with the development of rejection of matched marrow grafts and onset of acute graft vs. host disease (aGVHD). Thus, 13/15 positively reacting patient/donor pairs developed one of these complications (P < 0.001), while only 2/25 developed aGVHD in the negatively reacting group. This test may be useful for selecting the most compatible donor when several potential donors are available.

Acute Disease↗
PubMed1994

Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity and promiscuity.

Copolymer 1 (Cop 1) is a synthetic basic random copolymer of amino acids that has been shown to be effective in suppression of experimental allergic encephalomyelitis and is being tested as a candidate drug for multiple sclerosis. It has been previously demonstrated that Cop 1 is immunologically cross-reactive with the autoantigen myelin basic protein (BP) and competitively inhibits the response to BP of T-cell lines and clones of different major histocompatibility complex (MHC) restrictions, of both mouse and human origin. In the present study we demonstrated the direct binding of Cop 1, using its biotinylated derivative, to MHC molecules on living antigen-presenting cells. Binding of biotinylated BP and peptide p84-102 (an immunodominant epitope of BP) was also demonstrated. Cop 1 and BP bound in a promiscuous manner to different types of antigen-presenting cells of various H-2 and HLA haplotypes. The specificity of the binding was confirmed by its inhibition with either the relevant anti-MHC class II antibodies or unlabeled analogs. Cop 1 exhibited the most extensive and fast binding to antigen-presenting cells. In addition, Cop 1 inhibited the binding of biotinylated derivatives of BP and of p84-102 to the MHC class II molecules and even displaced these antigens when already bound. Thus, these results suggest that Cop 1 indeed competes with BP for MHC binding and, thereby, inhibits T-cell responses to BP. The binding of Cop 1 to different DR alleles, probably because of its multiple MHC binding motifs, may indicate its potential as a broad-spectrum drug for multiple sclerosis.

Amino Acid Sequence↗