Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Marrow transplants were carried out between unrelated donor-recipient pairs of dogs that were homozygous and identical for DLA-A, B, C, and D, i.e., mutually nonreactive in mixed leukocyte culture. Recipients were conditioned for transplantation by 1,200 R of total body irradiation and then treated with intermittent methotrexate for 102 days in order to prevent or delay graft-versus-host disease (GVHD). Of 13 dogs that received transplants, 4 are surviving with good grafts and no GVHD for more than 12 to 20 minutes. Nine died, 6 with GVHD between days 26 and 141, 1 with wasting on day 65, 1 with interstitial pneumonia on day 83, and 1 with graft rejection on day 23. In comparison, the survival of 17 DLA-identical littermates treated in the same manner was significantly better with 16 surviving without GVHD (P less than 0.01), while the survival of 54 DLA-nonidentical littermates was significantly worse with only two surviving without GVHD (P less than 0.025). These results are incompatible with the concept that solely the loci detected by mixed leukocyte culture and serotyping are responsible for GVHD. One or more additional loci appear to be involved. Knowledg e of this locus (loci) is important if marrow grafting between unrelated individuals is to be successful. However, results also indicate that an unrelated "compatible" marrow graft is more likely to succeed than a graft from an incompatible littermate.
 ...
PMID:Marrow grafts between DLA-identical and homozygous unrelated dogs: evidence for an additional locus involved in graft-versus-host disease. 2 45

To test the association of small bile duct destructive lesions in the liver with acute graft-versus-host disease, a blind (coded) histological study was done comparing liver tissue from three groups of dogs given 1,200 R of total-body irradiation: one not given marrow infusions after irradiation, another given autologous hemopoietic grafts, and a third given marrow grafts from DLA-nonidentical unrelated donors. The dogs with unrelated grafts all developed graft-versus-host disease, and their liver histology was distinguished from that of the dogs in the other two groups by three findings: (1) extensive small bile ductule necrosis and atypia; (2) infiltrates of mononuclear cells around and in ductules; and (3) individual hepatocyte necrosis scattered throughout the lobules. Thus, bile duct lesions appear to be a good marker for assessing the presence and severity of hepatic graft-versus-host disease in dogs.
 ...
PMID:Histopathology of hepatic acute graft-versus-host disease in the dog. A double blind study confirms the specificity of small bile duct lesions. 2 92

Transplantation of renal allografts obtained from prospectively selected genotypically DLA-identical donors into supralethally irradiated dogs reconstituted with their own stored bone marrow has produced a state of unresponsiveness to these kidneys in the recipients. Eleven of 18 kidneys transplanted at 12 hours after marrow replacement currently survive with normal function and maintain life in the recipients for 757, 800, 825, 978, 1062, 1092, 1136, 1282, 1373, 1380, and 1381 days, respectively. Similar results occurred in eight of 13 allografts transplanted at 28 hours after marrow replacement, which currently survive for 349, 363, 377, 407,436,470, 485, and 513 days, respectively, and in eight of 13 kidneys grafted at 36 hours after marrow replacement, which are surviving for 197, 247, 298, 324, 337, 396, 443, and 472 days, respectively. Achievement of optimal results is dependent on the specific timing and sequence of each procedure. Only four of 16 recipients of kidneys transplanted at the time of marrow replacement were unresponsive to their allografts. Similarly, only five of 19 recipients of kidneys placed in irradiated dogs at 40 hours before marrow replacement accepted such allografts. When kidney transplants were placed into the recipients 20 hours before removal of marrow, irradiation, and reconstitution with stored marrow, only three of 21 dogs became unresponsive to such ailografts. In five of 12 instances, the recipients were also unresponsive to skin allografts obtained from their respective kidney donors. Such skin grafts currently survive for 606, 673, 687, 701, and 708 days, respectively. The remaining seven skin grafts were rejected at 28, 39,42, 84, 90, 92, and 115 days, respectively. Second- and third-set skin grafts from the same kidney donor were rejected by six of these dogs at 19, 20, 21, 29, 29, and 30 days, and at 21, 22, 23, 24, 27, and 27 days, respectively. Rejection of these skin grafts had no detectable effect on the function and survival of kidney allografts from the same source. Seven of eight skin grafts obtained from other DLA-identical donors were rejected at 13,14,16,25,28,38, and 84 days, respectively; one allograft continues to survive for 708 days. Eleven DLA-incompatible skin allografts placed on the recipients at the same time were rejected within 11-20 days. Supralethal total body irradiation and bone marrow replacement can establish in the adult canine host a privileged phase of immunological reactivity during which exposure to alloantigens produces specific long-term unresponsiveness rather than sensitization. The use of stored autologous rather than allogeneic bone marrow for reconstitution of the irradiated recipient eliminates the hazards of GVH complication usually associated with this procedure. This consideration and the apparent capacity of the tolerant host to maintain a long-term state of unresponsiveness without any further immunosuppressive therapy point to the potential relevance of the results to human transplantation.
 ...
PMID:Induction of unresponsiveness to major transplantable organs in adult mammals: a recapitulation of ontogeny by irradiation and bone marrow replacement. 38 42

A novel immunosuppressant, succinyl acetone (4,6-dioxoheptanoic acid), was studied in dogs. Results with bolus intravenous injections at doses ranging from 50 to 1600 mg/kg showed dose-dependent alpha and beta half-lives, ranging from 30 to 80 min and 7 to 27 hr, respectively. Results suggested that continuous i.v. infusion was necessary to maintain constant plasma levels. Four dogs were given 9.2 Gy total-body irradiation and autologous marrow transplants along with continuous i.v. infusion of succinyl acetone at 50, 100, 200, or 400 mg/kg/day for 21 days, and all four had rapid, sustained hematopoietic engraftment. However, two of the four dogs receiving 200 and 400 mg succinyl acetone/kg/day, respectively, developed bilateral hind-limb ataxia, with histologically confirmed cerebellar lesions in the dog given the higher dose, thus establishing a potential dose-limiting neurotoxicity. Prevention of graft-versus-host disease was studied in recipients of allogeneic marrow. Dogs were given 9.2 Gy TBI, followed by hematopoietic grafts from unrelated DLA-nonidentical or DLA-haploidentical littermate dogs. Succinyl acetone was given as continuous infusion for 21 days after transplant at doses of 100-300 mg/kg/day. Starting succinyl acetone on the day of marrow infusion in four dogs failed to prevent rapid onset of acute GVHD, and dogs survived no longer than controls. Starting succinyl acetone 3 days before transplant delayed the onset of acute GVHD and prolonged survival significantly compared with that of dogs not given postgrafting immunosuppression (P = 0.008); survival was comparable to that in previously reported dogs given either methotrexate or cyclosporine as postgrafting immunosuppression (P = 0.88 and 0.99, respectively). Seven of the sixteen allogeneic recipients developed evidence of neurotoxicity during succinyl-acetone infusion. Neurological dysfunctions were manifested by hind-limb ataxia and posterior paresis. In conclusion, succinyl acetone significantly delayed the onset of GVHD and prolonged survival of DLA-nonidentical marrow graft recipients but did not induce graft-host tolerance and was associated with dose-limiting neurotoxicity.
 ...
PMID:Pharmacologic, toxicologic, and marrow transplantation studies in dogs given succinyl acetone. 144 Aug 68

We studied whether treatment of dogs with recombinant human granulocyte colony-stimulating factor (rhG-CSF), after 920 cGy total body irradiation (TBI) and transplantation of 3.3 +/- 1.0 x 10(8) bone marrow cells per kilogram from a DLA-identical littermate, accelerated hematopoietic recovery and influenced the incidence of subsequent marrow graft failure or graft-versus-host disease (GVHD). Ten animals were treated with 100 micrograms rhG-CSF/kg/d from days 1 through 10 after TBI. Results were compared with those of historical control of 14 dogs not administered rhG-CSF. Neither group of dogs received GVHD prophylaxis. The median time to recovery of 1,000 neutrophils/mm3 was 8 days for dogs administered rhG-CSF compared with 14 days in controls (logrank test: P less than .03). The median time to reach 100 monocytes/mm3 was 17 days in G-CSF-treated dogs compared with 49 days in controls (P less than .002). The median time to attain 500 lymphocytes/mm3 was 15 days versus 31 days, respectively (P less than .01). The median time to reach 20,000 platelets/mm3 was 26 versus 20 days (P = .68). Graft failure occurred in 1 of 10 G-CSF-treated dogs versus 2 of 14 controls (two-tailed Fisher's exact test: P = 1.00). GVHD was seen in 4 of 9 rhG-CSF-treated dogs compared with 1 of 12 controls (P = .12). Two G-CSF-treated dogs died of GVHD versus none of the controls (P = .17). No unusual toxicities were seen in dogs receiving rhG-CSF. In summary, rhG-CSF significantly accelerated recovery of neutrophils, monocytes, and lymphocytes after DLA-identical littermate marrow transplantation without altering platelet recovery. Graft failure was not seen more often than in controls, but there was a trend toward an increased incidence of GVHD.
 ...
PMID:Recombinant human granulocyte colony-stimulating factor accelerates hematopoietic recovery after DLA-identical littermate marrow transplants in dogs. 169 48

The effects of trimetrexate following marrow transplantation were studied in a dog model. Four animals were given 9.2 Gy total body irradiation (TBI), autologous marrow, and either trimetrexate alone (0.4 mg/kg on days 1, 3, 6, and 11) or combined with cyclosporine (CSP) (15 mg/kg per day i.m. on days 1-7, then orally until day 25, then taper). All four animals engrafted normally, demonstrating that trimetrexate at this dose is tolerable. Ten additional animals were given a similar dose of TBI followed by marrow and buffy coat cells from littermate donors differing for one DLA haplotype. Trimetrexate and CSP were given as noted above. Four of the 10 animals died, one with septicemia prior to engraftment (day 14), one with intussusception (day 28), one with graft failure (day 32) and one with a tracheal abscess without graft-versus-host disease (GVHD) (day 67). Six dogs survived in excess of 100 days; one of the six developed chronic GVHD. These results are superior to those previously achieved with either methotrexate or CSP as single agents and are roughly equivalent to results achieved with a combination of methotrexate and CSP in similarly mismatched donor-recipient pairs.
 ...
PMID:Use of trimetrexate for the prevention of graft-versus-host disease. 252 87

Myasthenia gravis and focal polymyositis occurred in a dog following successful transplantation of DLA-identical fetal liver hematopoietic cells. There was no evidence of acute or chronic graft-versus-host disease. Antibodies to acetylcholinesterase receptor and immune complexes reactive with myoneural junctions were demonstrated, as well as focal inflammation with perifascicular and type 2 muscle atrophy. The dog responded to treatment with prednisolone and pyridostigmine.
 ...
PMID:Myasthenia gravis and polymyositis in a dog following fetal hematopoietic cell transplantation. 286 26

We evaluated the ability of fetal liver hematopoietic cells to reconstitute hematopoiesis and immunity in lethally irradiated dogs. Nineteen consecutive dogs received transplants of fetal liver cells from donors identical or mismatched for DLA antigens. Six animals received 16 Gy fractionated total body irradiation (TBI) followed by transplantation of DLA-identical fetal liver. Three other dogs received transplants of fetal liver that was homozygous for a DLA haplotype shared by the recipient. No post-transplant immunosuppressive treatment was administered. All nine dogs had rapid and sustained restoration of hematopoiesis and none developed graft-versus-host disease. T and B-lymphocyte function recovered slowly over several months in all animals with sustained engraftment and they remained free of infection in open kennel conditions. These data indicate that a single DLA-identical fetal liver can reconstitute hematopoiesis in lethally irradiated dogs. This conditioning regimen was inadequate for transplantation of DLA-mismatched fetal liver cells; 6 of 6 dogs failed to engraft. We evaluated whether more intensive conditioning with 18 Gy fractionated TBI or 16 Gy TBI followed by post transplant treatment with methotrexate was feasible in 4 dogs. These regimens produced severe mucositis and gastrointestinal toxicity; 2 recipients of DLA-matched fetal liver transplants survived but 2 dogs receiving DLA-haploidentical fetal liver had engraftment but died of toxicity. Further studies are required to develop an effective, yet tolerable conditioning regimen in this setting. Fetal liver transplantation may ultimately be useful as a source of hematopoietic cells for transplantation in human patients if an effective conditioning regimen can be developed to allow engraftment of histoincompatible transplants.
 ...
PMID:Fetal liver cell transplantation in dogs: results with DLA-compatible and incompatible grafts. 286 58

Fetal liver transplants (FLT) were carried out in 25 beagles under various conditions. Graft recipients were prepared with fractionated total body x-irradiation (TBI) of 3 X 6 Gy or 2 X 6 Gy and rescued with cryopreserved fetal liver cells (FLC) from 51- to 52-day-old or 43- to 46-day-old, DLA-identical siblings or DLA-haploidentical, homozygous half-siblings. In all groups, FLC grafts contained comparable numbers of granulocyte-macrophage progenitor cells. Initial engraftment was achieved in all dogs. However, low TBI dose and DLA haplotype disparity between donor and recipient were associated with graft failure in 1/3 and 2/9 recipients, respectively, within 10-16 days of treatment. Lectin-responsive host type lymphocytes circulated for more than 5 weeks, whereas bone marrow metaphases were always of donor sex. Reduced TBI dose and young donor age were associated with delayed granulocyte recovery. Moreover, circulating platelets and total lymphocytes as well as T and B-cell numbers and rose more slowly in recipients of immature FLC grafts than in the other groups. Delayed cutaneous hypersensitivity reactions were normal one year after FLT, whereas the IgM component of the hemagglutinin response to sheep red blood cells was depressed. In mixed leukocyte culture, chimeric lymphocytes were tolerant to host antigens. Nonetheless, clinical and histological signs compatible with low-grade graft-versus-host disease were recorded in 10 or 25 animals. Thus FLT in dogs could be carried out, even across DLA barriers, without severe graft-versus-host disease. However, a low pretransplant TBI dose, incomplete DLA match and young age of the fetal donor were associated with graft rejection and protracted restoration of hemopoiesis and immune functions.
 ...
PMID:Variation of treatment conditions alters the outcome of fetal liver transplantation in dogs. 296 15

We studied the ability of fetal liver cells to reconstitute hematopoiesis and immunity in lethally irradiated dogs. Engraftment and sustained lymphoid and hematopoietic recovery was achieved when the recipients received a preparative regime of high-dose total body irradiation (TBI) alone followed by transplantation of DLA-identical fetal liver. The combination of high-dose TBI and cyclosporine allowed engraftment in DLA-mismatched fetal liver transplants. Typical features of graft-versus-host disease (GvHD) did not occur although autoimmune-like syndromes (myasthenia gravis, immune thrombocytopenia) were observed in some recipients. Hematopoietic recovery was rapid and complete. Recovery of T- and B-lymphocyte function was comparatively delayed, but sufficient to prevent opportunistic infections after the initial 3 months post transplant. These data indicate that cells from a single fetal liver can reconstitute hematopoiesis and immunity in DLA-mismatched recipients and suggest that human fetal liver cell transplantation may be an effective source of stem cells for patients who lack an HLA-identical donor for bone marrow transplantation.
 ...
PMID:Sustained recovery of hematopoiesis and immunity following transplantation of fetal liver cells in dogs. 332 1


1 2 3 4 Next >>