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N Murase

Publications and source records attributed to N Murase.

At least 145 records · Page 8Linked to original sources
PubMed1994

Migratory nonparenchymal cells after organ allotransplantation: with particular reference to chimerism and the liver.

Evidence has been summarized that the migration from organ allografts of donor leukocytes of bone marrow origin and their ubiquitous persistence in recipient tissues is the previous unrecognized seminal explanation for allograft acceptance, and the first stage in the development of donor-specific nonreactivity (tolerance). The unusual immunologic privilege of the liver (called hepatic tolerogenicity) has been explained by its heavy content of leukocytes and its diverse lineage profile that includes precursor dendritic cells. In a direct extension of this new and generically applicable paradigm of transplantation immunology, unconditioned patients have been infused with donor bone marrow cells on the day of cadaveric liver, renal, and heart transplantation and treated otherwise with standard FK506-prednisone immunosuppression. All of the first 16 patients on this protocol have good whole organ function 2.5 to 13 months later. Using flow cytometry and qualitative or quantitative PCR techniques to detect donor HLA alleles, and with study of Y chromosomes in female recipients of male organs, persistent multilineage leukocyte chimerism was regularly found in the blood of these recipients. Rejection was diagnosed and successfully treated in 9 (56%) of these first 16 patients and transient GVHD in 2 (12.5%). Sustained donor-specific hyporeactivity as early as 40 days postoperatively was demonstrable with in vitro tests in the majority of these recipients.

Animals↗
PubMed1993

Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease.

BACKGROUND: Liver transplantation for type IV glycogen storage disease (branching-enzyme deficiency) results in the resorption of extrahepatic deposits of amylopectin, but the mechanism of resorption is not known. METHODS: We studied two patients with type IV glycogen storage disease 37 and 91 months after liver transplantation and a third patient with lysosomal glucocerebrosidase deficiency (type 1 Gaucher's disease), in whom tissue glucocerebroside deposition had decreased 26 months after liver replacement, to determine whether the migration of cells from the allograft (microchimerism) could explain the improved metabolism of enzyme-deficient tissues in the recipient. Samples of blood and biopsy specimens of the skin, lymph nodes, heart, bone marrow, or intestine were examined immunocytochemically with the use of donor-specific monoclonal anti-HLA antibodies and the polymerase chain reaction, with preliminary amplification specific to donor alleles of the gene for the beta chain of HLA-DR molecules, followed by hybridization with allele-specific oligonucleotide probes. RESULTS: Histopathological examination revealed that the cardiac deposits of amylopectin in the patients with glycogen storage disease and the lymph-node deposits of glucocerebroside in the patient with Gaucher's disease were dramatically reduced after transplantation. Immunocytochemical analysis showed cells containing the HLA phenotypes of the donor in the heart and skin of the patients with glycogen storage disease and in the lymph nodes, but not the skin, of the patient with Gaucher's disease. Polymerase-chain-reaction analysis demonstrated donor HLA-DR DNA in the heart of both patients with glycogen storage disease, in the skin of one of them, and in the skin, intestine, blood, and bone marrow of the patient with Gaucher's disease. CONCLUSIONS: Systemic microchimerism occurs after liver allotransplantation and can ameliorate pancellular enzyme deficiencies.

Adult↗
PubMed1993

Rat liver lipids during ex vivo warm and cold ischemia and reperfusion.

Rat livers were flushed and stored ex vivo in Krebs-Henseleit buffer at 37 degrees C for 3 hr or in University of Wisconsin solution at 2 degrees C for 48 hr. After this they were perfused with recirculated Krebs-Henseleit solution at 37 degrees C for 1 hr. Levels of phospholipids (PL), free fatty acids (FFA), and conjugated dienes were determined at various times during ischemia and after 1 hr of reperfusion. After 3 hr warm ischemia, total PL content decreased by about 30% primarily because of decreases in phosphatidylcholine and phosphatidylethanolamine. One hour of reperfusion normalized PL levels. Total PL content was unchanged up to 48 hr of cold ischemia because of offsetting alterations in levels of PL classes. FFA accumulation during warm ischemia was about half that during cold ischemia. Conjugated diene concentration increased fivefold during warm ischemia but was unchanged during cold ischemia. Low PL levels and FFA accumulation along with production of conjugated dienes suggest that lipid oxidation is a major mechanism of PL degradation during warm, but not cold, ischemia of the liver.

Animals↗
PubMed1993

Donor cell chimerism permitted by immunosuppressive drugs: a new view of organ transplantation.

One line of thought in organ transplantation feels that immunosuppressive drugs can lead to tolerance induction by allowing a previously unrecognized common mechanism of cell migration and microchimerism to occur, persist, and in some cases, become drug independent. It has been recognized that there is a spectrum of susceptibility of different organs to cellular rejection and that the variable ability of these organs to induce donor-specific nonreactivity reflects their comparative content of migratory leukocytes. Here, Thomas Starzl and colleagues discuss how many of the enigmas of transplantation immunology can be explained by this chimerism.

Animals↗
PubMed1993

Donor cell chimerism permitted by immunosuppressive drugs: a new view of organ transplantation.

One line of thought in organ transplantation feels that immunosuppressive drugs can lead to tolerance induction by allowing a previously unrecognized common mechanism of cell migration and microchimerism to occur, persist, and in some cases, become drug independent. It has been recognized that there is a spectrum of susceptibility of different organs to cellular rejection and that the variable ability of these organs to induce donor-specific nonreactivity reflects their comparative content of migratory leukocytes. Here, Thomas Starzl and colleagues discuss how many of the enigmas of transplantation immunology can be explained by this chimerism.

Animals↗
PubMed1993

Graft-versus-host disease after brown Norway-to-Lewis and Lewis-to-Brown Norway rat intestinal transplantation under FK506.

In LEW rats treated daily with variable doses of FK506 for 14 days and weekly thereafter, successful intestinal transplantation from fully allogeneic BN donors never was complicated by fatal GVHD. In contrast, with LEW-to-BN transplantation, rejection was difficult to control and GVHD developed after the end of the daily treatment. However, FK506 in high daily doses continued after the initial 14-day course could prevent this GVHD or even reverse it after allowing its onset. Further experiments did not clarify why the BN rat was an "easy" donor and "difficult" recipient. In unaltered animals the lymphocyte population of normal LEW rats had a higher proportion of T cells, fewer B cells, and a lower CD4:CD8 ratio than normal BN rats. However, one-way MLR reactions of the BN and LEW combinations were generally similar in either direction and not affected differently by the addition of FK506 to the medium. The two-way lymphocyte traffic from graft to host lymphoid organs and vice versa also was similar with BN-to-LEW and LEW-to-BN models. The BN rat may be a useful tool to investigate inadequately explained mechanisms of GVHD.

Animals↗
PubMed1993

Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs.

Heterotopic hamster hearts transplanted to unmodified LEW rats underwent humoral rejection in 3 days. Survival was prolonged to a median of 4 days with 2 mg/kg/day FK506. As monotherapy, 15 mg/kg/day cyclophosphamide greatly prolonged graft survival--far more than could be accomplished with RS-61443, brequinar (BQR), mizoribine, methotrexate, or deoxyspergualin. However, when FK506 treatment, which was ineffective alone, was combined with a short induction course (14 or 30 days) of subtherapeutic BQR, RS-61443, or cyclophosphamide, routine survival of heart xenografts was possible for as long as the daily FK506 was continued. In addition, a single large dose of 80 mg/kg cyclophosphamide 10 days preoperatively allowed routine cardiac xenograft survival under FK506. The ability of these antimetabolites to unmask the therapeutic potential of FK506 correlated, although imperfectly, with the prevention of rises of preformed heterospecific cytotoxic antibodies immediately postoperatively. As an adjunct to FK506, azathioprine was of marginal value, whereas mizoribine, methotrexate, and deoxyspergualin (DSPG) were of intermediate efficacy. After orthotopic hepatic xenotransplantation, the perioperative survival of the liver with its well-known resistance to antibodies was less dependent than the heart on the antimetabolite component of the combined drug therapy, but the unsatisfactory results with monotherapy of FK506, BQR, RS-61443, or cyclophosphamide were changed to routine success by combining continuous FK506 with a short course of any of the other drugs. Thus, by breaking down the antibody barrier to xenotransplantation with these so-called antiproliferative drugs, it has been possible with FK506 to transplant heart and liver xenografts with consistent long-term survival of healthy recipients.

Animals↗
PubMed1993

Suppression of autoimmune thyroid disease by FK 506: influence on thyroid-infiltrating cells, adhesion molecule expression and anti-thyroglobulin antibody production.

Autoimmune thyroid disease was induced in female PVG/c rats by neonatal thymectomy, followed by sublethal, whole body x-irradiation. Disease development, assessed by histological evidence of lymphocytic thyroiditis and circulating levels of anti-thyroglobulin antibodies, was reduced significantly by a 3-week course of FK 506 (0.5 or 1.5 mg/kg per day) commencing after the detection of autoantibody production. Thyroid-infiltrating mononuclear cells (MNC) in untreated rats stained predominantly for CD4+ and MHC class II antigen which was expressed widely on dendritic cells. Fewer infiltrating cells expressed TCR alpha/beta, CD5, CD8 or LFA-1 beta. Intercellular adhesion molecule-1 (ICAM-1) was observed on MNC, vascular endothelial cells and a minority of residual thyroid epithelial cells. FK 506 administration reduced markedly the incidence of infiltrating TCR alpha/beta +, CD5+, CD4+, CD8+, and LFA-1 beta + cells and the expression both of MHC class II antigens and ICAM-1 on MNC, endothelial cells and thyrocytes. Compared with normal PVG/c rats, there were reduced incidences of CD4+ CD8- and CD4- CD8+ lymphocytes and an elevation in the CD4+/CD8+ cell ratio in the spleens of animals with autoimmune thyroiditis. These changes were partially reversed by FK 506. Systemic drug levels estimated by enzyme immunosorbent assay were in excess of those known to blockade cytokine production by CD4+ T lymphocytes in vitro and some evidence of minor renal dysfunction was observed. The results are consistent with a therapeutic effect of FK 506 mediated via interference with CD4+ T lymphocyte function and adhesion molecule-dependent cytotoxic effector mechanisms.

Animals↗