Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunological status of Lewis (LEW) recipients of indefinitely surviving (greater than 400 days) orthotopic Brown-Norway (BN) small bowel allografts was investigated 1 to 1 1/2 years after cessation of immunosuppressive therapy with either cyclosporine or FK506 and compared with recipients of syngeneic grafts. A normal proliferative response (as measured by a mixed lymphocyte culture) of recipient peripheral lymph node lymphocytes in response to the donor-specific (BN) and the third-party (ACI) antigen, was observed in all experimental groups. Cytolytic T cell generation (as measured by a standard 51Cr-release cytotoxicity assay) in response to the donor-specific (BN) and the third-party (ACI) antigen was observed also in all groups. A FACS analysis of allograft-recipient splenocytes showed no evidence for systemic lymphoid chimerism. BN or ACI skin grafts transplanted onto recipients of allogeneic and syngeneic small bowel grafts were rejected completely in 12-17 days, while the intestinal grafts remained functional. Immunohistologic evaluation of the allografts, using anti-BN class I and anti-Lewis class II monoclonal antibodies showed anti-BN staining on the epithelial and endothelial structures, whereas the mononuclear cells in the lamina propria stained positively with the anti-LEW monoclonal antibody. However, lymphoid depletion and scarring of Peyer's patches and mesenteric lymph nodes as well as focal obliterative mesenteric arteriopathy, indicative of an indolent chronic rejection, were observed. These data demonstrate that recipients of indefinitely surviving small bowel allografts remain immune competent and do not retain the intestinal graft on the basis of specific hyporesponsiveness to the donor antigens.
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PMID:Evidence that indefinite survival of small bowel allografts achieved by a brief course of cyclosporine or FK506 is not due to systemic hyporesponsiveness. 138 85

Lewis recipients of orthotopic ACI livers had permanent graft acceptance induced with 3 doses of i.m. FK506 in the early postoperative period. They were studied 100 and 300 days posttransplantation. The recipients rejected ACI as well as Brown Norway (BN) (third-party) skin grafts, and had lymphocytes with substantial reactivity by mixed lymphocyte culture testing against ACI and third-party (BN) alloantigens. Lymphocyte subset redistribution had not occurred in the peripheral blood or spleens of these animals, and there was no evidence of suppressor cell activation by in vitro and in vivo tests. Graft-versus-host reactivity in splenic lymphoid tissues of these recipients was demonstrated with the popliteal lymph node assay. Attempts at adaptive transfer with recipient lymphocytes were unsuccessful. Heart graft acceptance was far more difficult to accomplish than liver graft acceptance, and probably was never permanent. ACI heart graft prolongation in LEW recipients after a brief induction with FK506 lasted for no more than 3 months in most animals. The temporary heart graft acceptance was specific for hearts of the original ACI donor strain but not for ACI skin. Results of studies of lymphocyte subsets and suppressor cell activity were similar to those in the liver recipients. These studies illustrate how poorly graft acceptance is understood and how badly further work is needed to clarify its mechanism.
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PMID:FK506 suppression of heart and liver allograft rejection. II: The induction of graft acceptance in rats. 170 May 4

Donor- and organ-specific unresponsiveness to Brown Norway (BN) heart allografts was achieved in Lewis (LEW) rats by giving intrathymic donor bone marrow cells (ITBMC) and immunosuppression at the time of transplantation. Antilymphocyte serum (ALS) (1 ml, days 0, 2, 4) extended graft survival to a median survival time (MST) of 29.5 days (n = 6), while ALS + ITBMC extended survival to over 120 days (n = 6). FK506 (1 mg/kg, days 0, 2, 4, 6, 8) too prolonged survival in the FK + ITBMC (n = 6; MST > 140 days) and FK (n = 5; MST > 140 days) groups. BN skin grafting provoked the rejection of long-surviving BN heart grafts in the FK group (n = 5; MST = 14 days), but did not do so in either the ALS + ITBMC (n = 2; MST > 100 days) or the FK + ITBMC (n = 4; MST > 93 days) groups. In the FK + ITBMC group, two of the rats which rejected BN skin grafts received a second BN heart, resulting in the graft being accepted indefinitely (> 100 days) without causing the rejection of the first BN heart grafts. These facts suggest that ITBMC and concurrent T cell depletion are decisive for induction of unresponsiveness by this protocol. BN and WF (Wistar Furth) skin grafts were eventually rejected in the LEW rats which accepted BN heart grafts. Persistent allogeneic chimerism was demonstrated in the graft and recipient spleen, suggesting that chimerism may be one of the possible mechanisms of unresponsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Organ-specific unresponsiveness induced by intrathymic injection of donor bone marrow cells and a short course of immunosuppression in the rat heart transplantation model. 752 42

The yeast TOR1 and TOR2 proteins were previously discovered as putative targets of the immunosuppressive drug rapamycin. Although their cellular function is unknown, they are predicted to be at least 215 kDa in size and possess a C-terminal phosphatidylinositol (PI) kinase-related domain. We previously identified a conserved Ser residue, within the PI kinase-related domain of both yeast TOR proteins (Ser1972 in TOR1; Ser1975 in TOR2), as being the site of missense mutations conferring dominant rapamycin resistance. The Ser1972/1975 residue of yeast TOR is conserved in mammalian TOR homologs. One possibility is that this residue is critical for a direct interaction between TOR and the FKBP12-rapamycin complex. There is very recent biochemical evidence for an interaction between mammalian TOR and FKBP12-rapamycin (Brown, E. J., Albers, M. W., Shin, T. B., Ichikawa, K., Keith, C. T., Lane, W. S., and Schreiber, S. L. (1994) Nature 369, 756-758; Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P., and Snyder, S. H. (1994) Cell 78, 35-43). Using the yeast two-hybrid system, we now have obtained genetic proof of a physical interaction between FKBP12-rapamycin and TOR and have demonstrated that this interaction requires the conserved Ser residue. We have found that a small fragment of wild-type yeast TOR2 spanning Ser1975 is capable of interacting with human FKBP12 in the presence of rapamycin, whereas an Arg1975 mutant fails to interact. This effect is dependent upon rapamycin and is antagonized by FK506.
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PMID:Interaction between FKBP12-rapamycin and TOR involves a conserved serine residue. 752 5

Rat small bowel transplantation was performed in three groups: syngeneic graft, Lewis to Lewis; allogeneic graft, Brown Norway to Lewis; and allogeneic graft with the immunosuppressant FK506 (1 mg/kg). Standard histology and bromodeoxyuridine (BrdU) labelling immunohistochemistry were applied to evaluate the in situ spontaneous proliferating status of the mononuclear cells in the graft lymphoid tissue. In untreated allograft, BrdU-labelling index (BLI) in lamina propria lymphocytes increased significantly on the 5th post-operative day (POD), when no sign of rejection was detected in the villous architecture, compared with isograft (11.8 +/- 2.0% vs 1.9 +/- 0.5%, P < 0.05). Changes in the BLI of lamina propria lymphocyte were also detected on the 3rd and 7th POD, although there were statistically less significant than on the 5th POD. In intraepithelial lymphocytes the changes in BLI were more probably caused by ischaemic damage than immunological reaction. In Peyer's patches and mesenteric lymph nodes, elevation of BLI was specific to rejection like that seen in lamina propria lymphocytes. By administration of FK506, both the elevation of BLI and the histopathological changes were suppressed successfully except for a transient elevation of BLI in Peyer's patches and mesenteric lymph nodes on the 3rd POD.
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PMID:In situ proliferating status of mononuclear cells in rat small bowel grafts. 754 42

Conventional allogeneic bone marrow transplantation after myeloablation can prevent experimental autoimmunity and has been proposed as treatment for humans. However, trace populations of donor hematolymphoid cells persisting in solid organ allograft recipients have been associated in some circumstances with therapeutic effects similar to replacement of the entire bone marrow. We therefore examined whether inducing hematolymphoid microchimerism without myeloablation could confer the ability to resist mercuric chloride (HgCl2)-induced autoimmunity. Brown-Norway (BN) rats were pretreated with a syngeneic or allogeneic bone marrow infusion under transient FK506 immunosuppression before receiving HgCl2. They were compared with BN rats receiving either no pretreatment (naive) or FK506 alone. Administration of HgCl2 to naive BN rats induced marked autoantibody production, systemic vasculitis and lymphocytic infiltration of the kidneys, liver and skin in all of the animals and a 47% mortality. In contrast, BN rats pretreated with HgCl2-resistant allogeneic Lewis bone marrow and transient FK506 showed less clinical disease and were completely protected from mortality. More specifically, IgG anti-laminin autoantibody production was decreased by 40% (P < 0.05), and there was less histopathological tissue injury (P < 0.005), less in vitro autoreactivity (P < 0.05), less of an increase in class II MHC expression on B cells (P < 0.01), and 22% less weight loss (P < 0.01), compared with controls. Protection from the experimental autoimmunity was associated with signs of low grade activation of the BN immune system, which included: increased numbers of circulating B and activated T cells before administration of HgCl2, and less autoreactivity and spontaneous proliferation in vitro after HgCl2.
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PMID:Allogeneic hematolymphoid microchimerism and prevention of autoimmune disease in the rat. A relationship between allo- and autoimmunity. 855 Aug 37

Cyclosporine (CsA) and FK506 are structurally unrelated immunosuppressants, but function in similar ways. FK506 and rapamycin (RAPA), on the other hand, have structural similarities, but act by different mechanisms to yield immunosuppression. Besides their immunosuppressive action, CsA and FK506 are known to interfere with T-cell development. CsA treatment after lethal X-irradiation and syngeneic bone marrow transplantation results in autoimmune disease, which is referred to as CsA-induced autoimmunity. In this study, we examined the effect of RAPA on T-cell development by flow cytometry and immunohistochemistry in female Lewis and Brown Norway rats. Irradiation and syngeneic bone marrow transplantation were performed before a 4-week course of RAPA administration to determine de novo T-cell development in relation to possible autoimmune phenomena. RAPA interfered with the maturation of thymocytes to the CD4+CD8+ DP stage, which resulted in a relative increase in TCRalphabeta(-) immature thymocytes, localized in a rim along the outer cortex. The thymus of RAPA-treated animals had a thinner cortex, leading to stronger thymic atrophy. In the periphery, only a few T cells were observed at the end of RAPA treatment. In the Lewis rat, a normal CD4/CD8 T-cell ratio and an increased Th1/Th2 ratio was observed within the T-cell population. Six weeks after cessation of RAPA therapy, the T-cell compartment was restored to normal, with respect to number and phenotype. In Brown Norway rats, however, T-cell areas were barely detectable at the end of RAPA treatment. The CD4/CD8 T-cell ratio was decreased as a result of a lower number of CD4 T cells; the Th1/Th2 ratio was increased but Th2 remained higher. Similar to Lewis rats, the situation was almost normalized 6 weeks after cessation of RAPA administration. However, Brown Norway rats, in contrast to Lewis rats, showed T-cell infiltration and concomitant induction of MHC class II in the submandibular salivary gland, as well as insulitis, in the pancreas. Possible relationships to Sjogren's disease and diabetes remain to be established.
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PMID:Effect of in vivo rapamycin treatment on de novo T-cell development in relation to induction of autoimmune-like immunopathology in the rat. 887 95

Orthotopic left lung grafts from Brown Norway (BN) donors were transplanted to Lewis (LEW) rat recipients which had been treated with a single dose of FK506 10mg/kg body weight intramuscularly on postoperative day 3. Although the lungs were rejected with a median survival time of 7 days, with a range of 6-8 days in the untreated controls, maximum survival was prolonged to 60 days. The major adverse effects of this therapy were reduction of feeding, loss of body weight, and diarrhea. One of the 7 rats died on the 21st postoperative day due to anorexia. The effects of this therapy were investigated by histopathological examination and flow cytometric analysis using monoclonal antibodies against rat lymphocytes: OX-39 (anti-interleukin 2 receptor (IL-2R)) and OX-6 (anti-class II MHC). Histopathologically, the lung allografts showed mild perivascular and peribronchiolar cuffs of mononuclear cells, while marked reduction of the thymic medulla with FK506 treatment was also observed. Flow cytometric analysis of the transplanted lung showed no significant changes. Regarding the thymus, the percentages of positive cells labeled with OX-39 and OX-6 were significantly suppressed after this treatment. In the spleen, the number of OX-6-positive cells significantly decreased. The results using this therapy thus suggest that the suppression of IL-2R and MHC class II expression was systemically maintained for a long time.
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PMID:Effect of a single injection of high-dose FK506 on lung transplantation in rats. 901 63

Somatostatin (SS) was originally described as a growth hormone release inhibiting factor synthesised in the hypothalamus. Recently, SS and its receptor (SSTR) have been demonstrated in lymphoid tissues and seem to play a regulatory, largely inhibitory, role in immune responses. The aim of the present study was to check the immunosuppressive effect of a SS derived peptide, the octreotide (SMS 201-995) and to verify whether this molecule acted synergistically with FK506. An immunosuppressive effect of SMS was observed on the proliferation of rat spleen cells induced in vitro, either by polyclonal mitogens such as PHA or by alloantigens. With PHA stimulation, 10(-14) M SMS significantly enhanced the immunosuppressive action of 0.00001 microg/ml FK506. The addition of SMS in MLR (10(-11)-10(-9)M) increased the antiproliferative effect of both 0.0001 microg/ml and 0.00001 microg/ml FK506. In consideration of the extremely low concentration of both drugs that was required to obtain a good immunosuppression in vitro, we verified the association of FK506 and SMS in vivo in an allogeneic skin graft model that used Lewis (Lew) rats as donors and Brown Norway (BN) rats as recipients. BN treated with 0.1 mg/kg FK506 and 0.5-10 microg/kg SMS showed a significant increase in mean skin allograft survival time when compared to either a monotherapy or control group. None of the animals died or showed signs of drug-related toxicity. In conclusion, a combined therapy of SMS and FK506, administered at lower dosages than those that are considered therapeutic, led to an effective immunosuppression without any undesirable side effects.
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PMID:Evidence that SMS 201-995 enhances the immunosuppressive effect of FK506. 981 92

Eukaryotic translation initiation factor 4E (eIF4E) is the mRNA 5' cap binding protein, which plays an important role in the control of translation. The activity of eIF4E is regulated by a family of repressor proteins, the 4E-binding proteins (4E-BPs), whose binding to eIF4E is determined by their phosphorylation state. When hyperphosphorylated, 4E-BPs do not bind to eIF4E. Phosphorylation of the 4E-BPs is effected by the phosphatidylinositol (PI) 3-kinase signal transduction pathway and is inhibited by rapamycin through its binding to FRAP/mTOR (FK506 binding protein-rapamycin-associated protein or mammalian target of rapamycin). Phosphorylation of 4E-BPs can also be induced by protein synthesis inhibitors. These observations led to the proposal that FRAP/mTOR functions as a "sensor" of the translational apparatus (E. J. Brown and S. L. Schreiber, Cell 86:517-520, 1996). To test this model, we have employed the tetracycline-inducible system to increase eIF4E expression. Removal of tetracycline induced eIF4E expression up to fivefold over endogenous levels. Strikingly, upon induction of eIF4E, 4E-BP1 became dephosphorylated and the extent of dephosphorylation was proportional to the expression level of eIF4E. Dephosphorylation of p70(S6k) also occurred upon eIF4E induction. In contrast, the phosphorylation of Akt, an upstream effector of both p70(S6k) and 4E-BP phosphorylation, was not affected by eIF4E induction. We conclude that eIF4E engenders a negative feedback loop that targets a component of the PI 3-kinase signalling pathway which lies downstream of PI 3-kinase.
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PMID:Translational homeostasis: eukaryotic translation initiation factor 4E control of 4E-binding protein 1 and p70 S6 kinase activities. 1033 Jan 71


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