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T Sasazuki

Publications and source records attributed to T Sasazuki.

At least 55 records · Page 3Linked to original sources
PubMed1999

MHC class II-dependent NK1.1+ gammadelta T cells are induced in mice by Salmonella infection.

We observed the emergence of a novel population of gammadelta T cells expressing NK1.1 Ag in the peritoneal cavity of mice infected with Salmonella choleraesuis. The NK1.1+gammadelta T cells accounted for approximately 20% of all gammadelta T cells emerging in the peritoneal cavity of C57BL/6 mice and expressed preferentially rearranged Vgamma4-Jgamma1 and Vdelta6.3-Ddelta1-Ddelta2-Jdelta1 genes with N diversity. The gammadelta T cells proliferated vigorously in response to PHA-treated spleen cells and produced IFN-gamma in the culture supernatant. However, spleen cells from Abetab-deficient mice were unable to stimulate the gammadelta T cells. Furthermore, the NK1.1+gammadelta T cells were stimulated not only by Chinese hamster ovary (CHO) cells expressing wild-type IAb but also by those expressing IAb/Ealpha52-68 or IAb/pigeon cytochrome c-derived analogue peptide complex. These proliferation activities were inhibited by mAb specific for IAb chain. Consistent with these findings, the emergence of NK1.1+gammadelta T cells was reduced in the peritoneal cavity of Abetab-deficient mice after Salmonella infection, whereas NK1.1+gammadelta T cells were rather abundant in the peritoneal cavity of Salmonella-infected beta2m-deficient mice. Moreover, the NK1.1+gammadelta T cells were easily identified in the thymus of beta2m-deficient but not Abetab-deficient mice. Our results indicated that MHC class II expression is essential for development and activation of NK1. 1+gammadelta T cells in the thymus and the periphery.

Animals↗
PubMed1999

Spontaneous clustering of Thy-1 antigens on CD4+ CD8+ thymocytes lacking TCR engagement by MHC/peptide complexes.

While much is known concerning CD4+ CD8+ thymocytes positively or negatively selected through interaction of their TCR with self peptides bound to self-MHC molecules, little is known of the majority of CD4+ CD8+ thymocytes lacking this interaction. We developed a monoclonal antibody (mAb) 1D11, the ligand of which (1D11-L) is expressed on 60-70% of CD4+ CD8+ thymocytes but not on other subsets of thymocytes and peripheral T cells. 1D11-L expression on CD4+ CD8+ thymocytes reversely correlates with their TCR engagement, in vitro and in vivo. In addition, 1D11-L+ CD4+ CD8+ thymocytes were more susceptible than 1D11-L- CD4+ CD8- thymocytes to apoptosis. We also found that T lineage cells other than CD4+ CD8+ thymocytes and a Thy-1-expressing fibroblast cell line became positive for 1D11-L by cross-linking their Thy-1 antigens with anti-Thy-1 mAb but not with their Fab fragment, suggesting that 1D11 recognizes multimerized Thy-1 antigens. Confocal laser scanning microscopy revealed that Thy-1 antigens as well as 1D11-L are clustered on some CD4+ CD8+ thymocytes but not on the other subsets of thymocytes. Taken together, we suggest that clustering of Thy-1 antigens spontaneously and specifically occurs on CD4+ CD8+ thymocytes lacking TCR engagement by MHC/peptide complexes.

Animals↗
PubMed1999

Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5'-flanking region of the TNFalpha gene and HLA genes.

OBJECTIVE: To study polymorphisms in the 5'-flanking promoter/enhancer region of the tumor necrosis factor alpha (TNFalpha) gene and in the coding regions of HLA class I and class II genes, in order to better understand the genetic background of juvenile rheumatoid arthritis (JRA). METHODS: One hundred eleven Japanese JRA patients (50 with systemic disease, 29 with pauciarticular disease, and 32 with polyarticular disease) and 575 healthy Japanese subjects were examined for the allele frequencies of the TNFalpha, HLA-A, and HLA class II (DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1) genes, by DNA typing using the polymerase chain reaction-sequence-specific oligonucleotide probe method. RESULTS: The frequencies of the polymorphic allele at positions -1,031 (T to C substitution, termed -1,031C), -863 (C to A, termed -863A), and -857 (C to T, termed -857T) of the TNFalpha gene in patients with systemic JRA, but not in those with polyarticular or pauciarticular JRA, were significantly higher than in the healthy controls. The allele frequencies of DRB1*0405 and DQB1*0401 in systemic JRA, but not in the other JRA types, were significantly higher than in controls. Linkage analysis showed that the presence of both the TNFalpha -857T allele and DRB1*0405 yielded a significantly increased odds ratio (3.84), while the presence of only 1 of them did not yield a high odds ratio (0.87 and 1.58). CONCLUSION: The -1,031C/-863A allele and the -857T allele of the TNFalpha gene, both of which are related to high production of tumor necrosis factor alpha, are associated with systemic JRA. The -857T allele may enhance the effect of the DRB1*0405/DQB1*0401 haplotype in predisposing to development of systemic JRA.

Arthritis, Juvenile↗
PubMed1999

HLA class II alleles in Japanese patients with inflammatory bowel disease.

The association of various HLA class II loci with Crohn's disease (CD) and ulcerative colitis (UC) has yet to be fully elucidated. To determine whether there is an association of HLA class II genes (DR, DQ and DP alleles) with inflammatory bowel disease (IBD), HLA class II genes for polymorphisms were analyzed at the DNA level in 111 patients with CD, 81 with UC and 525 healthy controls by the polymerase chain reaction-sequence specific oligonucleotide probe method. Allele and haplotype frequencies were compared between these populations. Results were as follows: 1) the presence of DQB1*0402 (RR=3.90, Pc=0.0001) was positively associated with CD; 2) the presence of DRB1*1502 (RR=4.51, P<1X10(-8)), DRB5*0102 (RR=4.70, Pc<1x10(-8)), DQA1*0103 (RR=3.72, Pc=1x10(-5)), DQB1*06011 (RR=3.78, PC=1x10(-5)), DPA1*0201 (RR=3.23, Pc=0.0001) and DPB1*0901 (RR=4.83, PC<1x10(8)) was positively associated and that of DRB4*0101 (RR=0.20, Pc<1X10(-8)) and DQA1*0302 (RR=0.34, Pc=0.001) negatively associated with UC; 3) haplotype analysis showed a positive association between the presence of DRB1*0410-DQA1*0302-DQB1*0402 and DRB1*0802-DQA1*0401-DQB1*0402 with CD, and a negative association between the presence of DRB1*1502-DQA1*0103-DQB1*06011 and CD, there was no association of DRB1*08032-DQA1*0103-DQB1*06011 with CD; and 4) in UC, a positive association with the presence of DRB1*1502-DQA1*0103-DQB1*06011 was found, but DRB1*08032-DQA1*0103-DQB1*06011 was not associated with it. In conclusion, in CD in the Japanese population, HLA-linked disease susceptibility alleles appear to be DQB1*0402 and DRB1*1502, a disease resistance allele. In UC, DRB1*1502 appears to be a disease susceptibility allele.

Adolescent↗
PubMed1999

Human platelet alloantigen (HPA)-5a/b mismatch decreases disease-free survival in unrelated bone marrow transplantation.

Matching of human platelet alloantigen (HPA) systems 2-6 was retrospectively investigated in 715 unrelated bone marrow transplantations. Of the five HPA systems studied, HPA-5 mismatching was found to have a significant effect on the disease-free survival rate of recipients following transplantation in the HLA-A, -B, -C, and -DR allele-matched donor-recipient pairs. The effect of the HPA-5 mismatch was most significant in the recipient group possessing the HLA haplotype A*2402-B*5201, which is a highly frequent haplotype among the Japanese population. However, the probability of development of acute graft-versus-host disease (GVHD) was not increased significantly by the HPA-5 mismatching. These findings suggest that the HPA-5 mismatching decreases the recipient's survival by a mechanism different from that in the case of mismatching of minor antigens found often in transplant recipients developing GVHD.

Antigens, Human Platelet↗
PubMed1999

DNA typing of HLA class II genes (HLA-DR, -DQ and -DP) in Japanese patients with histiocytic necrotizing lymphadenitis (Kikuchi's disease).

The pathogenesis of histiocytic necrotizing lymphadenitis (HNL), which was reported first by Kikuchi et al. and Fujimoto et al. in 1972, is as yet unknown. HNL is frequently reported in Asian countries including Japan, however it is rare in Europe and North America. To elucidate whether the human leukocyte antigen (HLA) alleles and haplotypes are associated with HNL, we performed DNA typing of HLA class II genes (HLA-DR, -DQ, and -DP) in 86 patients with HNL and 525 unrelated healthy Japanese controls with polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP). In this study, we found DPA1*01 and DPB1*0202 allele frequencies in HLA class II genes are significantly higher in HNL patients than in normal controls. It is known that the frequency of DPB1*0202 alleles is extremely low or absent in Caucasians (e.g., French 0.4%, Italian 0.8%) and Negroid (e.g., South African 0%, Hottentot 0%), but relatively frequent in Asians (e.g., Korean 9.9%, Japanese 4.5%). Previous reports have said the incidence of HNL is frequent in Asians but rare in other races. In light of this background, HLA class II genes of HNL and the incidence of HNL in Asian countries, including Japan, might have a positive relationship to DPA1*01 and DPB1*0202 allele.

Adolescent↗
PubMed1999

A new predictive model for insulin-dependent diabetes mellitus susceptibility based on combinations of molecular HLA-DRB1 and HLA-DQB1 pockets.

With a view to establishing an accurate evaluation of the genetic predisposition to insulin-dependent type I diabetes (IDDM), we have built a model based on the characteristics of the relevant pockets of HLA-DR and -DQ molecules. Three independent populations were investigated. Group I and group II were Caucasoids, while group III was Japanese, including a total of 1,166 IDDM patients and 2,391 healthy controls. We formulate the hypothesis that suceptibility to IDDM is not only explained by the absence of Aspartate 57 (negative charge) from pocket 9 of DQB1 (P9DQ), but also by the presence of an electric charge (+/- vs. neutral), generated by residues 70, 71 and 74 in pockets 4 of DRB1 (P4DR) and DQB1 (P4DQ) molecules. The respective weight of each pocket, was evaluated in a multivariate analysis based on the logistic regression method. The 4 components (2 loci and 2 pockets) were systematically analysed in the computer model. It was clearly shown that the structural characteristics of pockets P9DQ-P4DR and, to a lesser degree that of P4DQ, account for IDDM predisposition. On applying the model to the whole international series, it appears that the highest risk concerns individuals with P9DQ non-Asp 57 and both the charged P4 of DRB1 and P4 of DQB1, conferring a 80% prediction of susceptibility. Conversely, P9DQ Asp and neutral P4DR and P4DQ give the lowest risk with a predictive value of 5%. This model of risk susceptibility prediction fits remarkably well with the observed distribution in a worldwide study. It allows a better evaluation of the respective role of HLA-DR and -DQ molecules as a major component of susceptibility to IDDM.

Alleles↗
PubMed1999

Targeted disruption of the K-ras oncogene in an invasive colon cancer cell line down-regulates urokinase receptor expression and plasminogen-dependent proteolysis.

The urokinase receptor, overexpressed in invasive colon cancer, promotes tumour cell invasion. Since K-Ras is activated in many colon cancers, we determined if urokinase receptor overexpression is a consequence of this activated oncogene. Accordingly, urokinase receptor expression was compared in HCT 116 colon cancer cells containing either a mutation-activated K-Ras or disrupted for this oncogene (by homologous recombination). HCT 116 cells containing the disrupted K-Ras oncogene expressed between 50 and 85% less urokinase receptor protein compared with the parental HCT 116 cells. Reduced urokinase receptor expression in cells containing the disrupted mutated K-Ras was not due to a physical impairment of the urokinase receptor gene since phorbol ester treatment was inductive for its expression. Constitutive urokinase receptor expression in HCT 116 cells required an intact AP-1 motif in the promoter (at -184) and electrophoretic mobility shifting assays indicated less c-Jun, JunD, c-Fos and Fra-1 bound to this motif in the K-Ras-disrupted cells. Since the urokinase receptor accelerates proteolysis, laminin degradation was compared in cells containing the mutation-activated and disrupted K-Ras oncogene. The latter cells displaying fewer urokinase receptors, degraded 80% less laminin. This is the first study to demonstrate a role for K-Ras as a regulator of the constitutive expression of the urokinase receptor.

Cell Nucleus↗
PubMed1999

Analysis of 500 bone marrow transplants from unrelated donors (UR-BMT) facilitated by the Japan Marrow Donor Program: confirmation of UR-BMT as a standard therapy for patients with leukemia and aplastic anemia.

In December 1991, the Japan Marrow Donor Program (JMDP) was established with the cooperation of the Japanese Red Cross and Japan Marrow Donor Foundation under the auspices of the Ministry of Health and Welfare in Japan. By December 1998, 122365 HLA-A,B typed volunteer marrow donors and 7207 patients had been cumulatively registered in the JMDP. The results of HLA-matching between donors and patients revealed that 5684 out of 7207 (78.9%) patients could have at least one HLA-A,B,DR serologically matched donor. Among these matched pairs, 1829 unrelated bone marrow transplants (UR-BMT) were performed. The initial 500 UR-BMT transplanted from January 1993 to October 1995 were analyzed as of July 1998. Engraftment was achieved in 95% of cases. Probability of the occurrence of grade III and IV acute GVHD was 18.4%. The rate of disease-free survival (DFS) of the patients who had standard-risk leukemia and did not suffer from grade III or IV acute GVHD (n = 154) was 60-71% and the rate of survival of patients with aplastic anemia was 56%. It can be stated that UR-BMT is a modality of treatment which is as effective as related BMT if the occurrence of grade III or IV acute GVHD is predicted and prevented.

Acute Disease↗
PubMed1999

Contribution of major histocompatibility complex genes to susceptibility and resistance in Helicobacter pylori related diseases.

BACKGROUND/AIM: Although there have been numerous reports concerning the virulence factors of isolates for investigating the pathogenesis of Helicobacter pylori infection, few studies have been carried out regarding the association of HLA class II genes of the host with H. pylori related diseases. Two published studies have only analysed the HLA DQ locus alone. The aim of this study was thus to determine the association of HLA class II genes (DR, DQ and DP) with H. pylori related diseases using the DNA typing method. METHODS: Fifty-eight patients with H. pylori positive gastric ulcers, 44 patients with H. pylori positive duodenal ulcers, 45 patients with H. pylori positive gastritis and 34 healthy subjects without H. pylori infection were typed for HLA class II genes by means of DNA typing with the polymerase chain reaction-sequence specific oligonucleotide probes method. RESULTS: A negative association with DRB1*1501, DQA1*01021 and DQB1*0602 alleles was noted in all three of the patient groups studied. Compared with the healthy controls, a positive association with DPA1*0201 (P= 0.032) and DPB1*0901 (P=0.005) in gastric ulcers, a positive association with DRB1*0405 (P=0.022) and DQB1*0401 (P=0.044) in duodenal ulcers, and a positive association with DPB1*0901 (P=0.016) in gastritis were observed. A haplotype analysis showed that the association of alleles with H. pylori related disease was with the haplotype rather than with either of the alleles individually. After correction for multiple comparisons, all the significant associations obtained between H. pylori related diseases and HLA class II genes disappeared. CONCLUSIONS: The interplay between host immunogenetic factors, bacterial virulence factors and environmental conditions may thus play a more important role in the outcome of H. pylori infection than immunogenetic factors alone.

Adult↗
PubMed1999

Use of BONSAI decision trees for the identification of potential MHC class I peptide epitope motifs.

Recognition of short peptides of 8 to 10 mer bound to MHC class I molecules by cytotoxic T lymphocytes forms the basis of cellular immunity. While the sequence motifs necessary for binding of intracellular peptides to MHC have been well studied, little is known about sequence motifs that may cause preferential affinity to the T cell receptor and/or preferential recognition and response by T cells. Here we demonstrate that computational learning systems can be useful to elucidate sequence motifs that affect T cell activation. Knowledge of T cell activation motifs could be useful for targeted vaccine design or immunotherapy. With the BONSAI computational learning algorithm, using a database of previously reported MHC bound peptides that had positive or negative T cell responses, we were able to identify sequence motif rules that explain 70% of positive T cell responses and 84% of negative T cell responses.

Algorithms↗
PubMed1999

The role of HLA matching in hematopoietic cell transplantation.

Hematopoietic cell transplantation (HCT) can be a life-saving therapy for patients with genetic and acquired hematologic diseases. Despite major advances in supportive care during HCT, immunological complications of the alloimmune response, including graft rejection and graft-versus-host disease (GVHD), remain major impediments to successful clinical outcomes. Although graft rejection mediated by host immune cells and GVHD mediated by donor immune cells can be prevented or mediated by immune suppression therapy, genetic HLA matching remains essential for successful strategies designed to minimize the risks of transplantation. The most favorable HCT results are seen in patients with a genotypically HLA-identical sibling donor, but the limited availability of matched related donors has severely restricted the clinical application of this therapy. Fortunately, the establishment of large unrelated volunteer donor registries now provides the opportunity to identify HLA matches for many patients who lack a family donor. The criteria for unrelated donor matching, however, are poorly defined. Until recently, an analysis of matching beyond HLA-identical siblings has been limited by typing technology. The introduction within the past few years of new methods for high resolution typing and definition of HLA alleles has had a profound impact on our ability to identify and interpret the multiple nucleotide sequence polymorphisms that encode HLA antigens. Preliminary studies clearly demonstrate the importance of precise matching at the allele level for successful transplantation. There remain, however, important unanswered questions about the relative importance of different HLA loci in matching strategies, as well as incomplete information about permissible limits of mismatching in different patient populations.

HLA Antigens↗
PubMed1998

Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program.

BACKGROUND: The requirements with respect to HLA compatibility and the relative importance of matching for individual class I and class II HLA alleles in the transplantation of hematopoietic stem cells from unrelated donors have not yet been established. METHODS: We performed retrospective DNA typing of alleles at 11 polymorphic loci of HLA genes in 440 recipients of hematopoietic stem cells from unrelated donors who were serologically identical with their respective recipients for HLA-A, B, and DR antigens. Of these recipients, 80 percent had leukemia; the rest had lymphoma, marrow failure, or a congenital disorder. RESULTS: Multivariate analysis showed that incompatibility for HLA-A alleles and incompatibility for HLA-C alleles were independent risk factors for severe acute graft-versus-host disease (GVHD) (HLA-A, P=0.006; HLA-C, P=0.001). Mismatching of HLA-A, but not of HLA-C, alleles was an independent risk factor for death (P<0.001). Matching [corrected] of HLA-C alleles was a significant risk factor for relapse of leukemia (P=0.035). HLA-B disparity was a significant risk factor for both GVHD and death in the univariate analysis, but not in multivariate analysis. Disparities in class II HLA alleles of the DRB1, DQA1, DQB1, DPA1, and DPB1 loci were not identified as significant risk factors for acute GVHD or death in the multivariate analysis. CONCLUSIONS: Genomic typing of class I HLA alleles adds substantially to the success of transplantation of hematopoietic stem cells from unrelated donors, even if the donors are serologically identical to their recipients with respect to HLA-A, B, and DR antigens.

Adolescent↗
PubMed1998

Highly restricted T cell repertoire shaped by a single major histocompatibility complex-peptide ligand in the presence of a single rearranged T cell receptor beta chain.

The T cell repertoire is shaped by positive and negative selection of thymocytes through the interaction of alpha/beta-T cell receptors (TCR) with self-peptides bound to self-major histocompatibility complex (MHC) molecules. However, the involvement of specific TCR-peptide contacts in positive selection remains unclear. By fixing TCR-beta chains with a single rearranged TCR-beta irrelevant to the selecting ligand, we show here that T cells selected to mature on a single MHC-peptide complex express highly restricted TCR-alpha chains in terms of Valpha usage and amino acid residue of their CDR3 loops, whereas such restriction was not observed with those selected by the same MHC with diverse sets of self-peptides including this peptide. Thus, we visualized the TCR structure required to survive positive selection directed by this single ligand. Our findings provide definitive evidence that specific recognition of self-peptides by TCR could be involved in positive selection of thymocytes.

Amino Acid Sequence↗