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)

Several steroid receptor-associated heat shock proteins can bind to FK506 as immunophilins. This has led to speculation that the steroid receptor and immunophilin signal transduction pathways are functionally interrelated. Indeed, in vitro work showed that FK506 treatment of intact L929 cells which were stably transfected with various reporter plasmids resulted in a potentiation of glucocorticoid hormone-induced glucocorticoid receptor-mediated gene transcription. These findings have raised the possibility of additive or synergistic immunosuppressive effects of FK506 and glucocorticoids. We tested this hypothesis in a canine model of GVHD prevention. Two groups of dogs were given 9.2 Gy total body irradiation followed by hematopoietic grafts from unrelated DLA-nonidentical donors. Among the first group of four recipients which were given FK506 and glucocorticoids, one rejected the graft, while three developed acute GVHD and died from associated complications between days 14 and 34. In the second group of nine recipients which were given FK506, glucocorticoids and methotrexate (MTX), only one dog became a long-term survivor while eight dogs died between days 21-114 with GVHD (n = 5) or FK506-associated toxicities (n = 3). Thus, addition of glucocorticoids to FK506 or FK506/MTX showed neither synergistic nor additive effects with respect to GVHD prevention in this model, and no survival advantages were seen compared to previously reported results with FK506 alone or FK506 and MTX in combination, respectively.
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PMID:Glucocorticoids fail to enhance the effect of FK506 and methotrexate in prevention of graft-versus-host disease after DLA-nonidentical, unrelated marrow transplantation. 924 17

Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressive activity 100 times that of cyclosporine by weight. The molecular mechanism of action is mediated via an inhibition of the phosphorylase activity of calcineurin by drug-immunophilin complex, resulting in the inhibition of IL-2 gene expression. There are emerging studies now showing significant efficacy of tacrolimus in GVHD prevention in both related and unrelated donor transplantation. Three multicenter randomized studies comparing tacrolimus to cyclosporine have been completed, one each in related and unrelated donor transplantation; the remaining study involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute GVHD in patients who received tacrolimus. One study in sibling donor transplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclosporine, but the survival was similar in patients with non-advanced disease. The remaining two studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the starting i.v. dose of tacrolimus; (3) the suggested whole blood level of tacrolimus and its effect on nephrotoxicity; and (4) whether tacrolimus should be used in patients with advanced malignancy. Future studies using tacrolimus in combination with other immunosuppressants, and its use in patients with advanced malignancy will be warranted.
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PMID:Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation. 972 Jul 34

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: (i) recipient conditioning, (ii) donor T cell activation, and (iii) effector cells mediating GVHD. Standard agents and agents under development to prevent and treat GVHD are discussed. The various pharmacological agents impact on different phases of the GVHD cascade. Sirolimus is a new immunophilin binding agent that appears to be synergistic with tacrolimus and cyclosporin. It also seems to promote allograft tolerance. Mycophenolate mofetil (MMF) is an antimetabolite that is currently under study for prophylaxis and treatment of acute and chronic GVHD; results are encouraging. Other agents such as the purine analogue pentostatin and the monoclonal antibodies alemtuzumab, daclizumab and infliximab are discussed at length within the GVHD context. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for the treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.
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PMID:Emerging therapies for graft-versus-host disease. 1466 92