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)

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.
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PMID:Migratory nonparenchymal cells after organ allotransplantation: with particular reference to chimerism and the liver. 774 75

In vitro studies have demonstrated that cyclosporine A (CsA) acts by inhibiting the phosphatase activity of calcineurin, an important mediator of T-cell activation. The relationship of CsA administration in vivo, calcineurin activity, and graft-versus-host disease (GVHD) has yet to be studied. The calcineurin activities of mononuclear cells isolated from 62 bone marrow transplant recipients and 12 normal volunteers were determined and analyzed with respect to administration of CsA, presence or absence of CsA in plasma, and presence or absence of GVHD. Of 62 patients, 33 were taking CsA and 29 were not. Early posttransplant (< 100 days), the calcineurin activity of patients on CsA was significantly lower than that of patients not on CsA (P = .0004) and than that of normal volunteers (P < .0001). Similarly, late posttransplant (> 100 days), the calcineurin activity of patients taking CsA was inhibited compared with normal volunteers (P < .05). The calcineurin activity of patients with acute GVHD who were taking CsA was lower than that of patients on CsA without acute GVHD matched for time posttransplant (P = .02). Calcineurin activity in patients on CsA with chronic GVHD was similar to those without chronic GVHD on drug. In conclusion, calcineurin activity is significantly suppressed by in vivo administration of CsA. The lower calcineurin activity of patients on CsA with acute GVHD suggests that CsA-resistant GVHD is not the result of inadequate suppression of calcineurin activity. These data suggest that if inhibition of calcineurin is the only physiologic target of CsA administration, simply increasing doses of CsA or treatment with other inhibitors of calcineurin, such as FK506, would not be expected to ameliorate GVHD.
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PMID:Inhibition of calcineurin phosphatase activity in adult bone marrow transplant patients treated with cyclosporine A. 794 53

Nine years after receiving a bone marrow transplant for aplastic anemia, a 14-year-old girl with severe pulmonary disease associated with graft-versus-host disease received a double lung transplant. Subsequent to lung transplant, her lung function improved dramatically (FEV1 increasing from 20 to 73 percent predicted normal, residual volume decreasing from 316 to 130 percent predicted normal values). The patient is currently well 15 months after transplant, while receiving immunosuppression consisting of FK506 and azathioprine. Double lung transplantation may offer a therapeutic option for the treatment of graft-versus-host pulmonary disease in selected patients.
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PMID:Pediatric lung transplantation for graft-versus-host disease following bone marrow transplantation. 818 63

The application of lung transplantation to the pediatric population was a natural extension of the success realized in our adult transplant program, which began in 1982. Thirty-two pediatric patients (age range 1 to 18 years) have undergone heart-lung (n = 16), double-lung (n = 14), and single-lung (n = 2) transplantation procedures. The cause of end-stage lung disease was primary pulmonary hypertension (n = 7), congenital heart disease (n = 7), cystic fibrosis (n = 9), pulmonary arteriovenous malformation (n = 2), desquamative interstitial pneumonitis (n = 2), graft-versus-host disease (n = 1), emphysema (n = 1), rheumatoid lung (n = 1), cardiomyopathy (n = 1), and Proteus syndrome (n = 1). Six patients (19%) underwent pretransplantation thoracic surgical procedures. The survival rate was 78% at a mean follow-up of 1.8 years. The survival rate in the 23 recipients without cystic fibrosis was 87% (95% since 1985). The actuarial 1-year survival rate in the nine recipients with cystic fibrosis was 55%. Immunosuppression was cyclosporine (n = 9) or FK 506 (n = 23)-based therapy with azathioprine and steroids. Children were followed up by spirometry, transbronchial biopsy, and primed lymphocyte testing of bronchoalveolar lavage fluid. The mean number of treated episodes of rejection per patient in the groups treated with cyclosporine and FK 506, respectively, was 1.0 and 1.2 at 30 days, 0.67 and 0.38 at 30 to 90 days, and 2.33 and 0.46 at greater than 90 days (p < 0.001, Fisher exact test).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pediatric lung transplantation: expanding indications, 1985 to 1993. 831 44

FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activation of antigen-specific T lymphocytes, a major component in the pathogenesis of graft-versus-host disease (GVHD). This study was designed to obtain first estimates of the safety and efficacy of FK506 monotherapy in the prevention of GVHD following HLA-identical sibling marrow transplantation. Additionally, a subset of patients was studied to define the pharmacokinetic profile of FK506. Twenty-seven adult patients with leukemia or myelodysplasia received FK506 starting the day before transplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion. When clinically possible, FK506 was given orally in two divided doses starting at five times the daily intravenous dose. FK506 doses were adjusted to target a steady state or trough blood level between 10 to 30 ng/mL. These patients were followed for 6 months posttransplant. All patients had sustained marrow engraftment. Frequently noted adverse events included reversible renal dysfunction, diarrhea, fever, nausea, vomiting, and headache. Most patients required FK506 dose reductions associated with elevated serum creatinine. Two (7%) patients relapsed, one of whom died of the disease within the 6-month study period. A second patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of distribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and bioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed grade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indicate that FK506 monotherapy has activity in preventing GVHD. Further studies of FK506 with lower doses to improve tolerability and in combination with other immunosuppressants to augment efficacy are warranted.
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PMID:FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation. 860 72

Clinically, FK506 is superior to CsA after solitary small bowel transplantation (SBTx). Development of diarrhea after SBTx has been the rationale for adding the colon to small bowel grafts. However, the additional lymphoid and bacterial content transferred with total small plus large bowel transplants (TBTx) might aggravate the alloimmune response-rejection and graft-versus-host disease (GVHD)-and increase the risk of infection. We studied the incidence of rejection, GVHD, and infection after TBTx and the impact of CsA versus FK506. We performed orthotopic TBTx with portal drainage after total enterectomy in outbred Yorkshire Landrace pigs, divided into 3 groups: control pigs (n=6) received no immunosuppression; CsA pigs (n= 14) received CsA (5 mg/kg), antilymphocyte globulin (10 mg/kg for 10 days), prednisone (2 mg/kg), and AZA (2.5 mgtkg); and FK506 pigs (n=9) received FK506 (0.2 mg/kg) and prednisone (2 mg/kg). Trough CsA whole blood levels were >400 ng/ml for the first 7 days and >200 ng/ml thereafter. FK506 levels were > 15 ng/ml. We excluded from further analysis 5 early deaths (<3 days) due to anesthesiologic (n=2) or technical reasons (n=3). Median survival of control pigs was 9.5 days (range, 4-13). Cyclosporine did not extend survival: median, 9 days (range, 5-31) (P=0.6). FK506 prolonged survival: median, 37 days (range, 21-49) (P<0.001 vs. control and CsA pigs). Of FK506 pigs, 60% gained weight (+75 g/day), whereas 100% of controls and 75% of CsA pigs lost weight (-550 g/day and -300 g/day, respectively). All control pigs died of rejection within 2 weeks versus none of the FK506 pigs. However, 36% of CsA pigs died of rejection. Groupwise comparison showed less rejection in FK506 versus control pigs (P<0.001) and in FK506 versus CsA pigs (P<0.03), but no difference between CsA and control pigs. None of the control pigs died of GVHD versus 18% of CsA pigs (by day 31) and 37% of FK506 pigs (by day 49). Groupwise comparison showed increased GVHD in FK506 versus control pigs (P<0.001) and a tendency toward increased GVHD in FK506 versus CsA pigs (P=0.08). None of the control pigs died of infection alone versus 22% of CsA pigs (by day 31) and 67% of FK506 pigs (by day 49). Groupwise comparison showed increased infection in FK506 versus control pigs (P<0.001). We detected significant endotoxemia early and late postoperatively. But we saw no specific correlation between endotoxemia, rejection, GVHD, or infection. Based on this study, we have drawn several conclusions: (1) In untreated pigs, TBTx provokes a severe rejection response, but no lethal GVHD. (2) Cyclosporine and particularly FK506 pigs have a high incidence of infection and lethal GVHD, a complication that we had not seen after solitary SBTx. (3) FK506 is superior to CsA in controlling rejection and in prolonging graft and recipient survival; FK506, however, does not reduce GVHD, but rather tends to augment it. (4) TBTx causes endotoxemia. As with solitary SBTx, FK506 is superior to CsA after TBTx. However, longterm survival is difficult to achieve on FK506 recipients because of the development of GVHD and infection.
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PMID:Combined transplantation of small and large bowel. FK506 versus cyclosporine A in a porcine model. 868 44

Total parenteral nutrition (TPN) is used routinely to maintain patients with the Short Bowel Syndrome (SBS). Until recently, TPN has been the only available therapeutic modality for patients with SBS. Currently, it is the treatment of choice for such individuals and occasionally, when the loss of bowel is extensive, it may be the only way of maintaining life. Unfortunately, TPN is expensive and markedly restrains an individual's lifestyle. Despite the overall success of TPN, the numerous risks associated with its use and the many complications of having an intravenous indwelling for years have served as the stimulus for alternative treatments such as small bowel transplantation (SBT). The first attempts at small bowel transplantation in clinical medicine were by Detterling almost 25 years ago. Patient death or graft loss in these early attempts was caused by the failure to control graft rejection and/or the inability to prevent Graft Versus Host Disease (GVHD). A stimulus for renewed clinical interest in SBT was provided by Starzl et al in 1988 with a report of prolonged graft survival without graft rejection or GVHD in a patient who was the recipient of a multivisceral graft consisting of the entire small bowel and other abdominal organs. Since 1964, 78 Small Bowel transplants have been performed in humans. Several variations of the multivisceral procedure in which the liver and the small bowel constitute the major components of the graft were adopted. The longest survival has been in a child who is still alive with a working graft for more than two years, as reported by Goulet from Paris in 1989. The introduction in SBT of the new immunosuppressive agent FK 506 had provided results which are superior to those achieved with Cyclosporine A (CsA). This latter observation prompted the Pittsburgh group to initiate a large series of isolated and composite intestinal grafts. The remarkable results have demonstrated the clinical utility of intestinal transplantation. This paper will try to summarize the history of the small bowel transplantation until the end of the year 1992, with the current progress in use today.
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PMID:Small bowel transplantation: current progress and clinical application. 871 29

We previously reported an synergism between methotrexate and tacrolimus (FK506) in preventing graft-versus-host disease (GVHD) in dogs given DLA-nonidentical unrelated marrow grafts after 9.2 Gy of total body irradiation (TBI). Methotrexate was given at 0.4 mg/kg i.v. on days 1, 3, 6 and 11 and FK506 at 0.15 mg/kg/day i.m. on days 0-8 and 0.5 mg/kg/day orally on days 9-90. Half of the dogs became long-term survivors. A major toxicity was gastrointestinal, and 25% of dogs died with intussusception. The current study addresses the problem of intussusception by making changes in drug doses used. In one group of dogs, FK506 was reduced to 0.075 mg/kg i.m. on days 1-8, while methotrexate was administered per original schedule. In a second group, methotrexate was reduced to a single dose on day 7, while FK506 was either administered per the original or reduced-dose schedule. None of the 17 current dogs developed intussusception, however, all but two dogs died with GVHD (n = 12) or graft failure (n = 3). Only two dogs survived after transient GVHD. Results show that there is little room for maneuvering FK506 or methotrexate doses, and hopes of reducing gastrointestinal toxicity by dose modifications while retaining the ability to prevent GVHD were not fulfilled.
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PMID:Tacrolimus (FK506) and methotrexate regimens to prevent graft-versus-host disease after unrelated dog leukocyte antigen (DLA) nonidentical marrow transplantation. 872 70

Tacrolimus is a more potent and satisfactory immunosuppressant than CyA for combination therapy with prednisone. In randomized trials comparing the 2 drugs, the ability of tacrolimus to rescue intractably rejecting grafts on the competing CyA arm allowed equalization of patient and graft survival on both arms when the intent-to-treat analytic methodology was applied. The ability of tacrolimus to systematically rescue the treatment failures of CyA suggested, as a matter of common sense, that it is the preferred baseline drug for hepatic transplantation. This conclusion was supported by analysis of secondary end points, including the ability to prevent rejection. Hepatic-intestinal, multivisceral and isolated intestinal transplantation became feasible on a practical basis only after the advent of tacrolimus. Nevertheless, better management strategies must be devised before intestinal transplantation, alone or with other abdominal viscera, will meet its potential. One such strategy is based on the discovery of the presence of previously unsuspected, low-level donor leukocyte chimerism in long-surviving allograft recipients. We believe that this chimerism is the essential explanation for the feasibility of organ transplantation and a link to the acquired neonatal tolerance demonstrated by Billingham, Brent and Medawar (32). The hematolymphopoietic chimerism in organ recipients explains why weaning to a drug-free state in selected long-term survivors is frequently feasible and particularly if the allograft is a liver. Weaning should never be attempted without a stepwise protocol and careful monitoring of graft function. Recognition of the natural chimerism that develops after whole organ transplantation has led to efforts to augment it with perioperative donor BM infusion. This procedure has been shown to be free of significant complications (including GVHD) in all kinds of whole organ recipients, including those given intestine. The prospects of clinical xenotransplantation must be evaluated in the same context of chimerism as that delineated for allotransplantation with the discovery of spontaneous chimerism. Before addressing chimerism-related questions in xenotransplantation, the additional barrier of the complement activation syndromes that cause hyperacute rejection will have to be surmounted. Although measures to effectively transplant xenografts have so far eluded us, the availability of the more potent drug, tacrolimus, and recognition of the seminal basis of allograft (or xenograft) acceptance via chimerism has inserted an element of reality into the largely wishful thinking that has been evident in discussions about the future of xenotransplantation.
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PMID:The current status of hepatic transplantation at the University of Pittsburgh. 879 62

Three patients who developed acute onset of cerebral blindness within 5-47 days of BMT using tacrolimus (FK506) as primary GVHD prophylaxis are described. This syndrome has been described with the use of cyclosporin A (CsA) and FK506 in solid organ transplant recipients. CsA-induced cerebral blindness has also been noted in BMT recipients but to date there have been no reports of this complication in BMT patients receiving FK506. We have noted a striking similarity in the clinical and radiographic presentations between these patients and those with CsA-associated cerebral blindness. Reversibility within 1-2 weeks of onset and the potential for substitution of CsA for FK506 in these patients is described.
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PMID:Tacrolimus (FK506)-induced cerebral blindness following bone marrow transplantation. 887 19


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