Strategies in chronic rejection of transplanted organs: a current view on pathogenesis, diagnosis, and treatment.
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Biomedical subjects
Publications and source records attributed to E Larsson.
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Expression of B-type receptors for platelet-derived growth factor (PDGF) in frozen sections of blood vessels from tissues affected by abnormal vascular cell proliferation was investigated by immunohistochemical techniques and compared with expression of these receptors in blood vessels of normal tissues. Receptors were not expressed, or expressed at low levels, in vessels of normal tissues. In contrast, a pronounced expression of PDGF B-type receptors was seen on vascular smooth muscle cells in atherosclerotic plaques, rejected kidneys, and chronic synovitis. These observations suggest induction of PDGF B-type receptors on vascular smooth muscle cells in inflamed tissues, which would render such cells responsive to growth stimulation by PDGF released from captured platelets, or produced locally (eg, by inflammatory cells or smooth muscle cells). Autocrine or paracrine stimulation of cell growth caused by the effect of PDGF on cells with induced receptors may be important in the formation of the proliferative lesions found in atherosclerosis and in certain forms of chronic inflammation.
We examined the RNA expression of a human endogenous provirus, termed ERV3, in 170 human tissue and cell specimens. The highest expression was found in normal placental chorionic villi as mRNAs of 9, 7.3, and 3.5 kb. The 7.3-kb RNA species was found only in the placenta. ERV3 mRNA was expressed in most other normal and malignant tissues at a level which was 2-10% of that seen in placenta. However, several tissues and tumor cell lines had higher transcriptional levels, equal to 10-60% of the placental level. In contrast, an almost complete abrogation of ERV3 mRNA expression was noted in choriocarcinoma cell lines and in an invasive hydatidiform mole tissue biopsy. This abrogation was not linked to deletions or rearrangements of the ERV3 genome. It appeared to be unassociated with methylation because the ERV3 provirus was similarly methylated in the DNA of placental chorionic villi and choriocarcinoma cells, and ERV3 transcription in choriocarcinoma cells was not induced by 5-azacytidine. These results suggest that the loss of ERV3 mRNA expression is associated with susceptibility to choriocarcinoma.
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Messenger RNA expression of a human endogenous provirus, ERV3, has been characterized in 170 specimens of normal and malignant human tissues and cells. In contrast to the high expression in first-trimester and full-term placental chorionic villi, most other human tissues expressed ERV3 mRNAs at a level of 2-30% of placenta. However, ERV3 mRNAs were not detected in choriocarcinoma tumor cell lines. These studies suggest that the ERV3 provirus may have been preempted for a biological function and disruption of its mRNA expression results in choriocarcinoma.
Small-bowel transplantation (SBT) using an nonsuture cuff technique was carried out on 137 rats. Preparation of the donor graft was carried out according to conventional procedures. Graft perfusion was done at a fixed pressure of 35 cm water. The left renal vessels of the recipient were dissected, the native kidney removed, and the graft was connected to the vessels by a nonsuture cuff technique. Of the animals, 92% survived for at least 5 days posttransplant. Three different combinations were investigated: (1) isografts; (2) semisyngeneic grafts from nontreated Lewis----(Lewis x DA) F1 hybrids; and (3) semisyngeneic grafts from rabbit antilymphocyte globulin (ALG)-pretreated Lewis----(Lewis x DA) F1. In group 1, 80% of the grafts were unaffected after 1 month; flow studies showed slight or no impairment of circulation in the graft. In group 2, the recipients developed clinical signs of graft-versus-host disease (GVHD) after 1 week, and at the end of the 2nd week the animals showed signs of severe illness, leading to death due to GVHD. There was also a higher percentage of complications in this group. In group 3, 65% of the animals died. However, 27% showed intact grafts and no signs of GVDH after 1 month, indicating that antibody pretreatment of the donor may successfully prevent GVHD SBT.
The presence of alpha 2-macroglobulin (alpha 2M) was detected with the avidin-biotin technique in more than 20-yr-old paraffin blocks from human sarcomas. alpha 2M was found mainly in the cytoplasm of the tumor cells, and almost all tumor cells were positive. This serum glycoprotein, which is a major plasma proteinase inhibitor with a wide specificity, was also shown to be synthesized and secreted by all three cell lines derived from primary sarcomas but was not detected in cultures of the autologous skin fibroblasts. For the detection of alpha 2M in situ and in vitro an antiserum to tumor-associated alpha 2-macroglobulin was used.
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In a rat heart transplantation model, permanent graft survival was achieved by anti-thymocyte globulin (ATG) treatment of Wistar Kyoto (WKy) recipients before grafting with PVG/c hearts. Nine hearts with palpable and electrocardiographic (ECG) function 8-20 months after transplantation were studied with histological and immunohistochemical methods. The dominating findings were fibrosis, intimal thickening, thrombosis of vessels, cellular infiltrates, and a high number of cells expressing class II antigens. These findings suggest that reactions compatible with a chronic rejection can be found in long-term surviving rat heart allografts. This rat model may thus be used in further studies of a chronic rejection process.
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The MHC restriction of the antibody response and development of arthritis after immunization with autologous or heterologous type II collagens in mice have been investigated. Mice from three different H-2q-carrying strains (DBA/1, NFR/N and B10.G) with different non-MHC genes, as well as B10-congenic strains carrying wild type H-2q-related or H-2r haplotypes, were susceptible for collagen arthritis. All strains tested developed an antibody response cross-reacting with autologous type II collagen after immunization with heterologous type II collagen; H-2q predisposes for a high response against chick, rat and bovine type II collagen, H-2r and H-2b for a high response against bovine type II collagen. Only mouse strains with H-2q, H-2r, H-2w3 or H-2w17 were responders to mouse type II collagen, and only these strains developed arthritis after immunization with heterologous or autologous type II collagens. These findings indicate that the ability to mount an immune response against autologous type II collagen is a prerequisite for the susceptibility to collagen arthritis. A cross-reactive autoimmune response after immunization with various heterologous type II collagen may enhance further the development of arthritis.
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Three polyadenylated RNAs, 9, 7.3, and 3.5 kilobases long, of a human endogenous retrovirus, ERV3, are abundant in human placental chorion, representing about 0.03 to 0.05% of the total mRNA. We characterized the structure of these mRNAs by Northern blot and S1 nuclease mapping analyses. We found that all three RNAs were spliced mRNAs that lacked 5.9 kilobases of proviral sequence, including the gag gene and most of the pol gene. In contrast to the transcription pattern usual for other retroviruses, the transcription pattern of the ERV3 provirus did not include a genome-length mRNA. All three of the ERV3 mRNAs initiated transcription at the same point in the 5' long terminal repeat (LTR) and contained identical splice junctions in the provirus. The 3.5-kilobase RNA was a typical subgenomic proviral mRNA, with its polyadenylation site in the 3' LTR. The two larger ERV3 mRNAs, however, extended through the polyadenylation site in the 3' LTR and were spliced at a second position approximately 370 nucleotides downstream from the 3' LTR. This finding suggests that when the ERV3 retrovirus integrated at this genomic locus in an ancestor of humans, it integrated within or adjacent to a cellular gene.
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