Evolution of the major histocompatibility complex: a current overview.
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Biomedical subjects
Publications and source records attributed to T Natori.
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The characteristic features of OLETF rats are: (1) late onset of hyperglycemia (after 18 weeks of age); (2) a chronic course of disease; (3) mild obesity; (4) clinical onset of diabetes mellitus (DM) mostly in males; (5) hereditary trait: (a) multiple recessive genes are involved in the induction of DM; (b) rat MHC, RT1 has no diabetogenic effect; (c) control strain, LETO appears to share some of diabetogenic genes with OLETF rats; (d) female OLETF rats also carry diabetogenic genes; and (e) one of the diabetogenic genes, designated as odb-1, is transmitted linked with the X-chromosome of OLETF rats, however testosterone is an important factor involved in developing diabetes; (6) the changes of pancreatic islets can be classified into three stages: (1) an early stage (at less than 9 weeks of age) mild lymphocyte infiltration; (2) a hyperplastic stage (10-40 weeks of age); hyperplastic change and fibrosis in or around islets; (3) a final stage (at more than 40 weeks of age) showing atrophy of islets; (7) diabetic nephropathy; (a) diffuse glomerulosclerosis; (b) nodular lesion (thickening of basement membranes, mesangial proliferation, fibrin cap). These clinical and pathologic features of disease in OLETF rats resemble those of human NIDDM.
We conducted the establishment of erythropoietin (Epo) producing human renal cell carcinoma heterotransplanted in nude mice (JRC 901) and analysed its histopathological and biological characteristics. Regarding to histopathological analysis, JRC 901 showed renal cell carcinoma with granular cell subtype, alveolar pattern and grade II malignancy. In an effort to the electron microscopic analysis, JRC 901 showed renal cell carcinoma with microvilli, rich lipid droplets and mitochondria. As to the tumour doubling time, the JRC 901 showed 14.81 days in a logarithmic phase. As to the karyotype, the JRC 901 showed human, 46, XY, -11, 8p+, 17q-, +mar. After tumour inoculation to the nude mice, the blood level of Epo increased at 5 weeks, and its level reached at 485.2 mU/ml at 12 weeks after tumour inoculation. Furthermore, immunohistochemical staining using anti-Epo showed positive staining within cytoplasm of JRC 901. Moreover, the production of Epo was observed in the level of mRNA (264 bp) using RT-PCR method. We conclude that the JRC 901 is a human renal cell carcinoma heterotransplantable to nude mice and this tumour produce the Epo after tumour inoculation to nude mice.
Interleukin-5 (IL-5), initially described as possessing eosinophil differentiating and proliferating activity, has now been shown to exert its effects on mature eosinophils. To investigate the ability of recombinant human IL-5 (rhIL-5) to cause the migration of eosinophils in the nasal mucosa in vivo, we compared the eosinophil counts in nasal mucosa without and after the nasal application of rhIL-5. In addition, the percentages of eosinophils in leukocytes within the vascular lumens in the nasal mucosa were counted to determine whether IL-5 recruited eosinophils from the vessels. The total number of eosinophils in both the epithelium and lamina propria, as well as the percentage of eosinophils in leukocytes within the lumens of vessels in the nasal mucosa after the application of IL-5, were higher than those in control nasal mucosa. Conversely, neither the number of neutrophils in the nasal mucosa nor the percentages of neutrophils in vessels differed between the two groups of nasal mucosa. The results strongly suggest that IL-5 preferentially recruits eosinophils from vessels into the lamina propria.
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A spontaneously diabetic rat with polyuria, polydipsia, and mild obesity was discovered in 1984 in an outbred colony of Long-Evans rats, which had been purchased from Charles River Canada (St. Constant, Quebec, Canada) in 1982. A strain of rats developed from this rat by selective breeding has since been maintained at the Tokushima Research Institute (Otsuka Pharmaceutical, Tokushima, Japan) and named OLETF. The characteristic features of OLETF rats are 1) late onset of hyperglycemia (after 18 wk of age); 2) a chronic course of disease; 3) mild obesity; 4) inheritance by males; 5) hyperplastic foci of pancreatic islets; and 6) renal complication (nodular lesions). Histologically, the changes of pancreatic islets can be classified into three stages: 1) an early stage (6-20 wk of age) of cellular infiltration and degeneration; 2) a hyperplastic stage (20-40 wk of age); and 3) a final stage (at > 40 wk of age). These clinical and pathological features of disease in OLETF rats resemble those of human NIDDM.
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The class II region of major histocompatibility complex of the rat. Rattus norvegicus (RT1) consists of RT1.B, RT1.D, and RT1.H subregions. The gene order around the H subregion was determined as RT1.A--H beta-H alpha--B by RFLP analysis of naturally occurring intra-RT1 recombinant rats with HLA DP probes. A unique recombinant strain, LEJ, was found to have its recombinational site between H beta and H alpha (RT1.AuH beta uH alpha bBbDb). Northern analysis of class II mRNAs showed that transcripts of RT1.D alpha, RT1.D beta, and RT1.B alpha shared identical sizes among various strains of rats, but RT1.B beta mRNA showed allele-specific size heterogeneities. Northern hybridization with HLA DP alpha probes detected possible RT1.H alpha transcripts. On the other hand, no clear signal of H beta was observed. BDIX whose RT1.B products had not been identified was found to transcribe B alpha and B beta mRNAs.
Experimental autoimmune uveitis (EAU) is an organ-specific autoimmune disease and has served as a model of certain ocular inflammatory conditions in man. The present study was aimed at separating the effects of MHC and non-MHC genes on the development of EAU in the rat. EAU-susceptible LEW (RT1l), EAU-resistant WKAH (RT1k), and WKAH.1L (RT1l) MHC congenic strain of WKAH background rats were immunized with retinal soluble antigen (S-Ag) in Freund's complete adjuvant (FCA). LEW rats showed typical EAU, while neither WKAH nor WKAH.1L congenic rats developed EAU. However, when an additional i.v. injection of Bordetella pertussis was given, all rat strains developed EAU. Furthermore, when immunized with peptide M, an 18-mer synthetic peptide, which corresponds to amino acid positions 303-320 of bovine S-Ag, and given an additional i.v. injection of B. pertussis, LEW and WKAH.1L rats developed EAU, whereas WKAH did not. When ACI (RT1avl), BUF (RT1b), LEJ (RT1j), W (RT1k), F344 (RT1lvl), BN (RT1n), NIG-III (RT1q), TO (RT1t), and SDJ (RT1u) rats were immunized with peptide M or S-Ag and then B. pertussis, all strains developed EAU by immunization with S-Ag plus B. pertussis, but only F344 and NIG-III developed EAU by immunization with peptide M. These findings suggest that susceptibility to EAU in rats is controlled by both MHC and non-MHC genes; and that in the absence of B. pertussis adjuvant, the form of disease induced by native S-Ag in FCA is governed by non-MHC gene(s). However, this effect of non-MHC gene(s) could no longer be observed when the rats were also injected with B. pertussis adjuvant at sensitization.
The immunological distribution of tumour-infiltrating lymphocytes (TIL), regional lymph node lymphocytes (RLNL) and peripheral blood lymphocytes (PBL) was evaluated by means of immunohistochemical staining using monoclonal antibodies of each subset of lymphocytes (stored in frozen sections) in a series of 22 patients with renal carcinoma. The immunological effect of IFN (interferon)-gamma on these immunocompetent cells was also investigated. The effect of IFN-gamma on TIL was an increase in CD3 (pan-T cells), especially an increase in CD8 (cytotoxic/suppressor-T cells). When examining these cells according to stage and grade, a marked increase in CD3 was found in low stage and low grade patients. With regard to RLNL, there was a tendency towards a decrease in CD3 and an increase in CD20 (B-cells) following the administration of IFN-gamma. No specific effect on stage and grade was observed apart from a reduction in T cell subset ratios in high grade patients. With regard to PBL, no specific trend was noted except for an increase in CD16 (NK cells) when IFN-gamma was administered.
Spontaneously diabetic rats with remarkable polyuria, polyphagia, and polydipsia were discovered in 1983 in an outbred colony of Long-Evans rats purchased from Charles River Canada in 1982. They have since been maintained at the Tokushima Research Institute (Otsuka Pharmaceutical, Tokushima, Japan). A strain of rats (Long-Evans Tokushima Lean [LETL]) with diabetes was bred from these rats. The characteristic features of the disease in LETL rats are 1) sudden onset of polyuria, polyphagia, hyperglycemia, and weight loss; 2) no sex differences in the rate of onset or severity; 3) lymphocyte infiltration into islets followed by destruction of beta-cells and disappearance of lymphocytes at the onset of diabetes; 4) no significant T lymphopenia; 5) lymphocyte infiltration into the salivary glands and lacrimal glands; and 6) at least two recessive genes involved in the pathogenesis of insulitis, one of which is closely linked with RT1u. These characteristics closely resemble those of human insulin-dependent diabetes mellitus (IDDM). Results suggest that the LETL rat is a useful animal model for analysis of genetic and immunologic factors relating to the pathogenesis of human IDDM.
Genetic background for SHR (SHRSR) and SHRSP and WKY lines were screened by using biochemical genetic markers and class I major histocompatibility complex (RT1) typing. There were many kinds of SHR (SHRSR), SHRSP and WKY inbred lines. The genetic variabilities within SHR (SHRSR) or SHRSP strains were small, but those within WKY strains were not so small. When SHR lines were compared with WKY lines, the allele distribution in SHR lines was different from that in WKY lines at 3-13 loci. Three genetic markers, the Es-3b, Es-4a and PT1k, were identified as specific markers of SHR (SHRSR) and SHRSP. WKY/Izm, WKY/Hos, and WKY/Jim also carried the PT1k as well as SHR lines, but WKY/N and WKY/NCrj had the RT1l haplotype.
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Pancreatic tumor antigen (PTA) was purified to apparent homogeneity from hamster pancreatic adenocarcinomas by a rapid and simple procedure using column chromatography on Mono P and Superose 6. Amino acid analysis indicated essential similarities between hamster PTA and human pancreatic cancer-associated antigen (PCAA, PCAAc), although differences in the contents of several amino acid residues between the two proteins did suggest species variation. Investigation of the binding pattern of antibody raised against PTA by peroxidase-labeled antibody immunocytochemistry revealed that, whereas PTA is absent or only faintly expressed in normal epithelium, it is very strongly positive in transplantable hamster pancreatic adenocarcinomas induced by nitrosamines. PTA was found to be distributed over the entire surface of neoplastic cells and it was concluded that the presence of PTA on the basolateral surface of malignant pancreatic epithelial cells, where it might have access to the blood circulation, could be one explanation for the observed elevated concentrations of PTA in the serum. PTA is thus a potential marker for hamster neoplastic pancreatobiliary duct-type cells.
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