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

FK506 and cyclosporine were used for the prevention of acute graft-versus-host disease. Acute GVHD was induced in Lewis rats by total-body irradiation and subsequent reconstitution with allogeneic (ACI) bone marrow and spleen cells (BMTx). GVHD was assessed by both clinical and histologic parameters during the experiment duration of 60 days, and longer for selected animals. All untreated BM recipients died within 26 days from severe acute GVHD. GVHD was prevented with CsA during the period of immunosuppressive therapy, but it appeared within a few days afterward. FK506-treated BM recipients were also protected, but they had a markedly prolonged GVHD-free period after therapy was discontinued. Most such animals eventually developed GVHD but with notable exceptions. Maintenance therapy with doses of FK506 as low as 0.1 mg/kg every other day (1/20 of daily induction dose) was infallible insurance against delayed GVHD. The relevance of these findings to GVHD caused by lymphoid-containing solid organs such as the intestine was discussed.
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PMID:Prevention of graft-versus-host disease following allogeneic bone marrow transplantation in rats using FK506. 171 63

Colon transplantation has been proposed as a method to improve the function of an intestinal allograft. The present study examined the risk of colon rejection and the effect of FK506 on colon rejection in BN-->LEW rats with orthotopic bowel transplants. The first 4 groups included rats with untreated allografts (group 1), rats with isografts treated with 0.6 mg/kg FK506 (group 2), rats with allografts treated with 0.6 mg/kg FK506 (group 3), and rats with allografts treated with 0.4 mg/kg FK506 (group 4). In each of these groups (10-12 rats), half of the animals received a small bowel graft only (SB), while the other half received a small bowel, ascending colon, and cecum graft (SBC). The animals were followed daily until they died or were killed at 4 weeks. In group 5, an additional 18 untreated rats with SBC allografts were randomly killed on the third, fifth, seventh, and tenth postoperative days to study the sequential histopathologic and immunopathologic changes of colon rejection. There was no difference in survival, body weight, nutritional parameters, or bacterial contamination after SB and SBC transplantation. Intestinal transit was slower after SBC than SB transplantation (P < 0.05). Sequential histopathologic studies revealed that (1) the severity and time course of colon rejection was similar to small intestine rejection, and (2) the features of colon rejection were similar to ulcerative colitis. There was no evidence of graft-versus-host disease after SBC transplantation. In summary, adding a segment of large bowel to a small bowel allograft does not increase the risk of rejection or surgical complications. The transplanted colon slows intestinal transit. Treatment with FK506 effectively prevents colon rejection. These data suggest that adding a colon graft may improve the outcome of clinical small bowel transplantation.
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PMID:Treatment with FK506 prevents rejection of rat colon allografts. 751 86

Studies were undertaken to determine whether the doses of FK506 that are effective for acute GVHD prophylaxis following lethal irradiation and bone marrow transplantation (BMT) would also suppress myeloid cell reconstitution. FK506 (3 mg/kg/day) abrogated acute lethal graft versus host disease (GVHD) in lethally irradiated C57BL/10SnJ (H-2b) recipient mice given histoincompatible BM plus spleen cells from B10.BR (H-2k) donors and this dose was used in all of the studies. Endogenous and exogenous myeloid repopulation was studied in mice given daily injections of either FK506, an equivalent amount of carrier solvent or no treatment throughout the interval between total body irradiation (TBI) and the day of assay. Repopulation was studied after 400 or 500 cGy TBI (endogenous) and after 950 cGy TBI plus injection with syngeneic BM (exogenous). No consistent adverse effects of FK506 were seen during either exogenous or endogenous recovery. Parameters studied included hematocrit (Hct), WBC count, cells per humerus, spleen weight, splenic colony-forming units, % spleen or BM 59Fe uptake and colony forming cells per humerus. Similarly, when lethally irradiated secondary recipients were reconstituted with BM from FK506 treated primary recipients (lethal irradiation plus exogenous BM), no consistent effects were observed. These data suggest that FK506 given to prevent GVHD would not compromise the myeloid recovery that is critical for survival in the interval of time following shortly after BMT.
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PMID:Short-term myeloid reconstitution following TBI is not adversely affected by doses of FK506 that abrogate lethal GVHD. 752 89

The pharmacokinetics, safety, and efficacy in marrow transplantation of FK506-based immunosuppression for graft-versus-host disease (GVHD) prophylaxis was evaluated in an open label pilot study of 18 patients. Patients more than 12 years of age (median, 35 years; range, 15 to 50 years) with advanced hematologic malignancies receiving HLA-matched sibling marrow grafts were randomized to receive FK506 alone, FK506 and methotrexate (MTX), or FK506 and methyl-prednisolone. Of 17 evaluable patients, all had evidence of sustained marrow engraftment. The median time to an absolute neutrophil count of greater than 500/microL was 15 days for patients receiving FK506 alone or FK506 plus methylprednisolone and 23 days for FK506 plus short MTX. Pharmacokinetic studies did not show any significant difference in clearance of FK506 when administered alone or in combination with methylprednisolone or MTX. The mean bioavailability after oral administration in these same three groups was 0.49 +/- 0.1, 0.27 +/- 0.12, and 0.16 +/- 0.08, respectively (P = .003). The decrease in bioavailability may have resulted from an exacerbation of radiation-induced gastroenteritis by MTX. The most significant adverse effect associated with the administration of FK506 was nephrotoxicity, which occurred in 14 of 18 patients (78%). The mean glomerular filtration rate, determined by clearance of (99MTc)DTPA, decreased to 56% (+/- 18%) of the pretransplant baseline level by week 8 (P = .002). Eight of 18 patients (44%) developed grades II-IV acute GVHD, predominantly of the skin and gastrointestinal tract. The actuarial probability of transplant-related mortality during the first 100 days was 24%. The actuarial probability of 1-year disease-free survival was 39%. In conclusion, although bioavailability of FK506 may be affected in patients receiving MTX, this study suggests that FK506 may have a role in the management of patients after allogeneic marrow transplantation.
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PMID:Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study. 754 71

1. In an unselected adult renal transplant population, FK506 as the primary immunosuppressive agent yielded one- and 2-year actuarial patient survival rates of 95% and 93% and one- and 2-year actuarial graft survival rates of 89% and 83%, respectively. Forty-nine percent of successfully transplanted patients were weaned off steroids. 2. In pediatric renal transplant patients, FK506 has been associated with 100% one- and 3-year actuarial patient survival rates and 98% and 85% one- and 3-year actuarial graft survival rates, respectively. Sixty-two percent of successfully transplanted patients were taken off prednisone, with dramatic improvements in height. 3. FK506 has been used successfully in rescuing 70-74% of adult or pediatric renal transplant patients with an acute rejection that failed conventional therapy. 4. Kidney/bone marrow transplantation under FK506 therapy has been successfully performed without graft-versus-host disease and with routine augmentation of chimerism. 5. The side effects of FK506 included nephrotoxicity, neurotoxicity, and diabetogenicity; they were comparable to those seen with CsA. 6. FK506 is an important new addition to the immunosuppressive armamentarium in renal transplant patients.
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PMID:Renal transplantation at the University of Pittsburgh: the impact of FK506. 754 44

A phase II study of the efficacy and safety of FK506, a new potent immunosuppressant, has been conducted in 49 patients with GVHD after allogeneic BMT. Eighteen patients with acute GVHD and 31 with chronic GVHD entered the study. FK506 was administered at an initial dose of 0.05 mg/kg i.v. or 0.15 mg/kg orally twice a day to those whose GVHD had become uncontrollable with cyclosporin and/or other immunosuppressants. The response to FK506 was evaluated in 13 patients with acute and 26 with chronic GVHD. A marked response was observed in 5 and a good response in 2 of 13 patients with acute GVHD. For those with chronic GVHD, the response was marked in 2 patients, good in 10 and poor in 8. The most common adverse effects were renal toxicity (53.1%), followed by nausea and vomiting (30.6%) and a feeding of warmth (18.4%). There was a correlation between renal toxicity and whole blood levels of FK506. The dose should be adjusted to keep a trough level between 15 and 25 ng/ml. FK506 is promising in the treatment of both acute and chronic GVHD, even if it is intractable with other immunosuppressants, and may be most effective if administered early in the course of GVHD.
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PMID:FK506 treatment of graft-versus-host disease developing or exacerbating during prophylaxis and therapy with cyclosporin and/or other immunosuppressants. Japanese FK506 BMT Study Group. 758 Oct 86

Steroid-resistant graft-versus-host disease (GVHD) is an often lethal complication of bone marrow transplantation (BMT). FK506 (tacrolimus) is a new potent immunosuppressant which has been shown to be superior to conventional immunosuppression in the prevention and treatment of graft rejection in recipients of solid organ transplants. To determine whether FK506 is effective in the treatment of steroid-resistant acute GVHD, 6 children with biopsy-proven severe GVHD were studied. FK506 was administered as intravenous or oral therapy and the dose was adjusted to achieve serum levels between 0.5 and 1.0 microgram/ml by ELISA. Steroid doses were tapered based on clinical grading in each organ. Within 1-2 days, improvement occurred in skin and gut in all patients, and in liver in 3 patients. Toxicity attributable to FK506 was similar to that described in solid organ transplant patients and included neurotoxicity, nephrotoxicity and gastrointestinal effects. While FK506 is effective in the treatment of steroid-resistant acute GVHD, toxicity may limit its use. Further studies evaluating FK506 as GVHD prophylaxis and treatment of less advanced GVHD are needed.
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PMID:FK506 (tacrolimus) in the treatment of steroid-resistant acute graft-versus-host disease in children undergoing bone marrow transplantation. 758 Oct 88

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.
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PMID:Graft-versus-host disease after brown Norway-to-Lewis and Lewis-to-Brown Norway rat intestinal transplantation under FK506. 767 53

Multivisceral transplantation, combined liver-intestine transplantation, and isolated small bowel transplantation are very similar procedures that were first developed in the 1950s. If the viscera can be conceptualized as a cluster of grapes hanging from its arterial stems, the three procedures are characterized by virtually identical vascular anastomoses, with exclusion or inclusion of as many viscera (grapes) as necessary; however, these procedures languished for nearly four decades because of the imperfect immunosuppressive regimens of the 1960s, 1970s, and 1980s. Finally, after the development of FK506, pediatric patients may undergo intestinal transplantation with the hope for long-term survival. These procedures are reserved for TPN-dependent children with permanent intestinal insufficiency. Candidacy for transplantation is also predicated on development of potentially fatal TPN complications such as cholestasis, recurrent sepsis, or thrombosis of access sites. Since 1990, 32 pediatric patients have undergone intestinal transplantation at the University of Pittsburgh, with an overall survival of 65%. Immunosuppression has been accomplished with a combination of corticosteroids, FK506, and prostaglandin E1. Although GVHD has not been a major problem, most patients have experienced rejection episodes requiring intensification of immunosuppression with a steroid bolus, a steroid recycle, an increase in FK506 dosage, or addition of OKT3. CMV has caused little morbidity, but EBV-related PTLD has affected 20% of all patients. It has not been possible to discontinue immunosuppression in the face of PTLD without engendering severe small intestinal rejection. Other problems have included recurrent sepsis, intestinal dysmotility, and persistent food avoidance. Future therapeutic trends are likely to include the performance of combined bone marrow-visceral transplant to induce a chimeric tolerogenic state and to lessen the need for long-term immunosuppression.
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PMID:Small bowel transplantation in infants and children. 769 29

Small bowel transplantation trials before cyclosporine was unavailable because of rejection, graft-versus-host disease and technical problems. With the discovery of cyclosporine, and another immunosuppressors like prednisone, antithymocyte globulin, azathioprine, OKT3 and the recent rapamycin, mycophenolate mofetil, deoxyspergualin, FK506, mizoribine and brequinar sodium, the prognosis for small bowel transplanted patients is better than before.
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PMID:[Is the intestinal transplant a reality?]. 763 30


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