Search PubMed⌕ Search

Biomedical subjects

N Murase

Publications and source records attributed to N Murase.

At least 109 records · Page 6Linked to original sources
PubMed1996

Prolonged survival of hamster-to-rat pulmonary xenografts by tacrolimus (FK506) and cyclophosphamide.

BACKGROUND: Severe shortage of donor organs in clinical lung transplantation prompted us to investigate the potential use of pulmonary xenografts. The purpose of this study was to determine whether an immunosuppressive regimen of tacrolimus (FK506) and cyclophosphamide would prolong the survival of hamster-to-rat pulmonary xenografts. METHOD: Left lung transplantation was done with male Golden Syrian hamsters used as donors and inbred male Lewis rats as recipients. Control animals (n = 10) received no immunosuppressive drugs whereas experimental animals (n = 6) were treated with tacrolimus and cyclophosphamide. Tacrolimus was administered intramuscularly at a dosage of 2 mg/kg per day on postoperative days 0 to 4, followed by 1 mg/kg per day on days 5 to 29 and 0.5 mg/kg per day on days 30 to 99. Cyclophosphamide (8 mg/kg per day) was administered orally from the day before transplantation to day 8. After transplantation the animals were monitored by chest radiography. Recipient animals were killed at timed intervals (days 60 and 100) and when the chest radiograph showed complete opacification of the transplanted lung. At necropsy, pulmonary xenografts were examined histologically for evidence of rejection, which was graded on a scale of 0 (no rejection) to 4 (severe rejection). Antihamster lymphocytotoxic antibody titer was also measured in recipient animals after transplantation. RESULTS: Pulmonary xenografts in the control animals had a median [correction of medium] survival time of 3 days, whereas the median survival in treated animals was more than 74 days. All pulmonary xenografts in control animals had severe rejection on day 3 after transplantation, whereas those in the treated animals had no rejection on days 60 and 100. The lymphocytotoxic antibody titers in control animals increased from 1:16 before operation to 1:4096 on day 3 (p < 0.01). In the treated animals, the lymphocytotoxic antibody titer on day 21 was 1: 8, which was not different from the preoperative value (1:16). CONCLUSION: These results indicate that a combination of tacrolimus and a short course of cyclophosphamide prolongs the survival of pulmonary xenografts in a hamster-to-rat model.

Animals↗
PubMed1996

[Hepatic intra-arterial 5-fluorouracil and CDDP administration in patients with colorectal cancer metastasis to the liver].

Eleven patients with hepatic metastasis from colorectal cancer were treated by combined chemotherapy with 5-FU and CDDP. Metastatic tumor was not resected or incompletely removed in all cases. 5-FU (180 mg/m2/day) as a 7-day continuous hepatic arterial infusion (HAI) with CDDP (10 approximately 20 mg/2 weeks) or intermittent high dose 5-FU HAI (1,000 mg/m2/5 h) with CDDP (10 approximately 20 mg/2 weeks) was administered, followed by a one-week rest. The overall response rate was 63.8%. There was a significant prolongation in overall survival compared with controls. Drug-related toxicity was observed in 10 cases (91.0%), but nothing serious. Survival can be prolonged with almost normal quality of the life in patients with colorectal liver metastasis.

Adult↗
PubMed1996

[Clinical intestinal transplantation at the University of Pittsburgh: an update].

From May 1990 until August 1996, 87 patients received 92 intestinal transplantation, including an isolated graft (n = 33), combined liver and intestinal grafts (n = 41), and abdominal multivisceral grafts (n = 13). There were 52 children (mean age 3.3 years) and 35 adult patients (mean age 32.6 years). Of these, 29 patients received the colon as a composite of the intestinal graft, and 11 recent patients were given unmodified donor bone marrow cells simultaneously. Postoperative immunosuppression was with Tacrolimus and low-dose steroids, to which either azathioprine, mycophenolate, or cyclophasphamide was added supplementarily. One-, three-, and five-year patient and graft survival was 73% and 64%, 44% and 36%, and 444% and 36%, respectively. There was no statistical difference in patient and graft survival after different types of intestinal transplantation. Although overall patient and graft survival did not differ between pediatric patients and adult recipients, isolated graft survival children was higher than that of adult recipients (57% versus 11% at three years). Transplantation of the grafts from CMV seropositive donors and the inclusion of the colon in the intestinal graft worsened the survival in adult recipients, but not in children. The influence of simultaneous bone marrow transplantation on the outcome is undetermined due to the short follow-up period. Intestinal transplantation has become feasible, but still requires improved immunosuppression and graft dysmotility management to be a clinical practice.

Adult↗
PubMed1996

[Treatment of spasticity with botulinum toxin and muscle afferent block].

Spasticity is partly caused by disinhibition of spinal stretch reflex activity and blocking of the group Ia afferents may improve its clinical symptoms. Since muscle afferent block has been successfully used for treating dystonia, this method may become useful for treating spasticity as well. We injected diluted lidocaine (0.5%, 50 ml/session) and ethanol (5 ml) into thigh adductors (for leg crossing), medial hamstrings (for medial rotation of the leg), quadriceps femoris (for hyperextension of the knee), tibialis posterior and triceps surae muscles (pes equinovarus deformity), biceps brachii and forearm flexors (for flexion deformities of the upper extremity) in 12 patients with spasticity. Although the duration of action was short (< 1 day) at first, it was gradually prolonged to several weeks by repeating the injection every 3-4 days. The final outcome was comparable to that obtained by botulinum toxin injection in the same group of patients. This method may prove its promise as a means of treating spasticity.

Adult↗
PubMed1995

The changing immunology of organ transplantation.

The engrafted organ becomes a chimera as the recipient's leukocytes station themselves in the transplant. Remarkably, the recipient becomes chimeric as well, in a reverse migration involving immune cells from the graft. Interactions between donor and recipient cells are tolerogenic--a process with implications for the goal of graft acceptance with minimal immunosuppression.

Cell Movement↗
PubMed1995

Variable chimerism, graft-versus-host disease, and tolerance after different kinds of cell and whole organ transplantation from Lewis to brown Norway rats.

The bidirectional paradigm of tolerance involving reciprocal host vs. graft and graft vs. host reactions was examined after Lewis (LEW)-->Brown Norway (BN) transplantation of different whole organs (liver, intestine, heart, and kidney) or of 2.5 x 10(8) LEW leukocytes obtained from bone marrow, spleen, lymph nodes, and thymus. The experiments were performed without immunosuppression or under 14 daily doses of postoperative tacrolimus, which were continued in weekly doses to 100 days in a "continuous treatment" subgroup, and to 27 days in a short treatment group. Without immunosuppression, all organs and cell suspensions failed to engraft or were acutely rejected. GVHD (usually fatal) was always caused when either the long or short treatment was used for recipients of intestinal grafts and cell suspensions of spleen and lymph nodes. In contrast, both immunosuppressive protocols allowed engraftment of bone marrow cells, liver, heart, and kidney without clinical GVHD, whereas thymus cell suspensions and small doses of whole blood neither engrafted nor caused GVHD. At 100 days, now drug-free for 73 days, the liver, bone marrow, and heart recipients were tolerant in that they accepted all challenge LEW heart and/or liver grafts for 100 more days despite in vitro evidence of donor-specific reactivity (split tolerance). At 200 days, histopathologic studies of the challenge livers were normal no matter what the priming graft. However, the still-beating challenge hearts had a spectrum from normal to severe chronic rejection that defined the tolerogenicity of the original primary grafts: liver best-->bone marrow next-->heart least. Both the GVHD propensity and tolerogenicity in these experiments were closely associated with recipient tissue chimerism 30 and 100 days after the experiments began. The tissue chimerism was invariably multilineage, but the GVHD outcome was associated with T cell over-representation. These observations provide guidelines that should be considered in devising leukocyte augmentation protocols for human whole organ recipients. The results are discussed in relation to the historical tolerance studies of Billingham, Brent, and Medawar; Good; Monaco; and Calne.

Animals↗
PubMed1995

Hamster to rat kidney xenotransplantation. Effects of FK 506, cyclophosphamide, organ perfusion, and complement inhibition.

Hamster to rat renal xenotransplantation was performed with recipient nephrectomies. Recipients were treated beginning on day 0 with continuous FK 506 monotherapy, a 7-day or open-ended monotherapeutic course of cyclophosphamide (CP), and the two drug regimens combined. CP alone (10 mg/kg/day) prevented a xenospecific antibody response and tripled median survival of the kidney (defined as recipient death) from 6 (control) to 18.5 days whereas FK 506 alone had no effect. The drugs in combination were no better than CP alone (15 days) unless the 5-day course of CP was given at a higher dose (15 mg/kg) and started 3 days preoperatively (79 days). In further experiments, adjuvant measures were added to the minimally effective FK 506/7-day CP regimen which gave a median survival of only 15 days. In the most successful modification, intraoperative antibody depletion by the temporary transplantation of third party hamster liver or en bloc kidneys increased median survival from 15 to 34 and 48 days, respectively. An intraoperative i.v. dose administration of the anticomplement drug K76 instead of antibody depletion increased survival to 26 days. Although the events of kidney rejection were similar to those of heart xenografts and partially forestalled by the antibody inhibiting CP treatment, or by antibody depletion, survival for > 100 days was accomplished in only 5 of 86 treated animals. The poorer survival previously reported with cardiac xenotransplantation is largely explained by the life support requirement of the kidneys. Renal failure was responsible for almost all deaths before 60 days, and subnormal renal failure was a pervasive adverse factor thereafter, frequently caused by pyelonephritis which is suspected to have had an immunologic etiology.

Animals↗
PubMed1995

A new protocol for the propagation of dendritic cells from rat bone marrow using recombinant GM-CSF, and their quantification using the mAb OX-62.

Bone marrow (BM)-derived dendritic cells (DC) are the most potent known antigen (Ag) presenting cell in vivo and in vitro. Detailed analysis of their properties and mechanisms of action requires an ability to produce large numbers of DC. Although DC have been isolated from several rat tissues, including BM, the yield is uniformly low. We describe a simple method for the propagation of large numbers of DC from rat BM and document cell yield with the rat DC marker, OX-62. After depletion of plastic-adherent and Fc+ cells by panning on dishes coated with normal serum, residual BM cells were cultured in gelatin coated flasks using murine rGM-CSF supplemented medium. Prior to analysis, non-adherent cells were re-depleted of contaminating Fc+ cells. Propagation of DC was monitored by double staining for FACS analysis (major histocompatibility complex (MHC) class II+/OX-62+, OX-19-). Functional assay, morphological analysis and evaluation of homing patterns of cultured cells revealed typical DC characteristics. MHC class II and OX-62 antigen expression increased with time in culture and correlated with allostimulatory ability. DC yield increased until day 7, when 3.3 x 10(6) DC were obtained from an initial 3 x 10(8) unfractionated BM cells. Significant numbers of DC can be generated from rat BM using these simple methods. This should permit analysis and manipulation of rat DC functions in vivo and in vitro.

Animals↗
PubMed1995

Microchimerism, dendritic cell progenitors and transplantation tolerance.

The recent discovery of multilineage donor leukocyte microchimerism in allograft recipients up to three decades after organ transplantation implies the migration and survival of donor stem cells within the host. It has been postulated that in chimeric graft recipients, reciprocal modulation of immune responsiveness between donor and recipient leukocytes may lead, eventually, to the induction of mutual immunologic nonreactivity (tolerance). A prominent donor leukocyte, both in human organ transplant recipients and in animals, has invariably been the bone marrow-derived dendritic cell (DC). These cells have been classically perceived as the most potent antigen-presenting cells but evidence also exists for their tolerogenicity. The liver, despite its comparatively heavy leukocyte content, is the whole organ that is most capable of inducing tolerance. We have observed that DC progenitors propagated from normal mouse liver in response to GM-CSF express only low levels of major histocompatibility complex (MHC) class II antigen and little or no cell surface B7 family T cell costimulatory molecules. They fail to activate resting naive allogeneic T cells. When injected into normal allogeneic recipients, these DC progenitors migrate to T-dependent areas of host lymphoid tissue, where some at least upregulate cell surface MHC class II. These donor-derived cells persist indefinitely, recapitulating the behavior pattern of donor leukocytes after the successful transplantation of all whole organs, but most dramatically after the orthotopic (replacement) engraftment of the liver. A key finding is that in mice, progeny of these donor-derived DC progenitors can be propagated ex vivo from the bone marrow and other lymphoid tissues of nonimmunosuppressed spontaneously tolerant liver allograft recipients. In humans, donor DC can also be grown from the blood of organ allograft recipients whose organ-source chimerism is augmented with donor bone marrow infusion. DC progenitors cannot, however, be propagated from the lymphoid tissue of nonimmunosuppressed cardiac-allografted mice that reject their grafts. These findings are congruent with the possibility that bidirectional leukocyte migration and donor cell chimerism play key roles in acquired transplantation tolerance. Although the cell interactions are undoubtedly complex, a discrete role can be identified for DC under well-defined experimental conditions. Bone marrow-derived DC progenitors (MHC class II+, B7-1dim, B7-2-) induce alloantigen-specific hyporesponsiveness (anergy) in naive T cells in vitro. Moreover, costimulatory molecule-deficient DC progenitors administered systemically prolong the survival of mouse heart or pancreatic islet allografts. How the regulation of donor DC phenotype and function relates to the balance between the immunogenicity and tolerogenicity of organ allografts remains to be determined.

Animals↗