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)

Rapamycin (RAPA) has been shown to be a highly effective means of reducing the lethality of graft-versus-host disease (GVHD) in B10.BR recipients of allogeneic C57BL/6 donor cells. RAPA-treated mice had no clinical (e.g., weight loss, diarrhea, lethargy) or histologic evidence of classical acute or chronic GVHD but did develop a clinical-pathological syndrome consisting of ulcerative dermatitis, bile duct proliferation, and a nondestructive peribronchiolar pulmonary infiltration. Because RAPA was found to interfere with the deletion of self-reactive T cells, we wondered whether the RAPA-induced syndrome was related to failed negative selection or altered alloreactivity. We now show that the RAPA-induced syndrome is due to effects on mature, donor-derived alloreactive T cells. By titering the number of T cells infused we were able to vary the syndrome incidence. In contrast to the syndrome seen after cyclosporin A (CsA) administration, the RAPA syndrome did not require an intact thymus and the disease could not be adoptively transferred. The addition of CsA (which blocks T-cell cytokine production) to RAPA (which blocks T-cell cytokine response) prevented the generation of this syndrome, suggesting that the tissue manifestations seen in RAPA only treated recipients were caused by cytokine production and release. RAPA also caused this alloimmune syndrome in recipients of minor histocompatibility antigen disparate donor cells, showing that the RAPA effects were not restricted to a single donor-recipient strain combination or to instances in which the donor and recipient were fully major histocompatibility complex disparate. We conclude that RAPA is a highly effective means of preventing murine acute GVHD, and that when combined with CsA, warrants consideration for human investigations.
 ...
PMID:In vivo inhibition of cytokine responsiveness and graft-versus-host disease mortality by rapamycin leads to a clinical-pathological syndrome discrete from that observed with cyclosporin A. 861 33

Over the last few years, improved knowledge of the immunological mechanisms underlying transplant rejection have resulted in the development of new immunosuppressive agents capable of selectively blocking various steps of the immune response. It is anticipated that these agents will prove useful in the treatment of autoimmune disease and graft-versus-host disease. Neoral is a cyclosporin microemulsion characterized by better and more consistent absorption as compared to the conventional galenic form. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin and may have similar indications. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, although they have not yet been proved clinically effective in large studies of solid organ transplant recipients. Mycophenolate mofetil selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in a number of autoimmune disorders. Further clinical work is needed to determine the therapeutic indications for each of these new drugs. Elucidation of their mechanisms of action may help to identify drug combinations providing both enhanced efficacy and improved safety.
 ...
PMID:[New immunosuppressive agents]. 1057 3

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.
 ...
PMID:Emerging therapies for graft-versus-host disease. 1466 92

Methotrexate in combination with a calcineurin inhibitor is a standard graft-versus-host disease (GVHD) prophylactic regimen in allogeneic stem cell transplantation. However, methotrexate is associated with delayed engraftment, mucositis, idiopathic pneumonia syndrome, and other transplant-related complications. Sirolimus, a novel immunosuppressant without methotrexate's toxicities, has been used successfully in solid organ transplantation. We hypothesized that replacing methotrexate with sirolimus would preserve effective prophylaxis of GVHD while minimizing transplant-related toxicity after allogeneic peripheral blood stem cell transplantation. We enrolled 30 patients in a phase II study to test the efficacy of tacrolimus in combination with sirolimus in lieu of methotrexate in preventing GVHD after allogeneic peripheral blood stem cell transplantation from HLA-matched related donors. Grade II GVHD occurred in 3 patients (10%), and no patient developed grade III or IV GVHD. Neutrophil and platelet engraftment were prompt, occurring on days 14 and 13, respectively. All patients survived to hospital discharge (median, 18 days), and peritransplantation toxicity was mild. Four patients developed thrombotic microangiopathy, and 3 patients developed hepatic veno-occlusive disease. Chronic GVHD occurred in 11 patients. Relapse-free and overall survival at 100 days were 93% and 97%, respectively, and were 71% and 67% at 1 year. Causes of death included relapse (n = 6), veno-occlusive disease (n = 1), and late pulmonary toxicity (n = 1). Sirolimus in combination with tacrolimus is a promising alternative to methotrexate-based regimens for GVHD prophylaxis after matched related donor peripheral blood stem cell transplantation. Mucositis was modest, engraftment was prompt, and transplant-related toxicity was modest. Methotrexate-free, sirolimus-based GVHD prophylactic regimens should be tested in randomized trials against the current standard of care.
 ...
PMID:Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation. 1511 32

Sirolimus is a novel macrolide immunosuppressant widely used in solid organ transplantation. We have conducted three clinical trials using this compound as prophylaxis against GVHD after allogeneic stem cell transplantation. Our studies have demonstrated excellent GVHD control even when mismatched and unrelated donors were used. The morbidity and mortality associated with transplantation were reduced due to the omission or reduction in methotrexate dose. Furthermore, CMV reactivation and fungal infection rates were low. However, we have noted that sirolimus may be associated with increased rates of thrombotic microangiopathy after transplantation. Sirolimus has other uses, such as the treatment of established acute and chronic GVHD, and may be useful for treatment of post transplant lymphoproliferative disorder and perhaps as an antineoplastic agent against a wide variety of hematologic and solid neoplasms.
 ...
PMID:Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation. 1527 8

Successful hematopoietic cell transplantation (HCT) from an allogeneic donor ideally should produce tolerance to recipient alloantigens while preserving anti-infectious and antitumor immunity. Rapamycin together with costimulation blockade can induce tolerance in organ allograft models by inhibiting G(1) --> S-phase progression and promoting T-cell apoptosis. In contrast to blocking costimulation through CD28, administration of agonistic CD28-specific antibody 37.51 partially prevents lethal graft-versus-host disease (GVHD) by selective depletion of alloreactive T cells in mice. We hypothesized that combining rapamycin with agonistic CD28 treatment would improve GVHD control by tolerizing a small subset of alloreactive T cells that might escape effects of the CD28-specific antibody. A short course of rapamycin plus agonistic CD28 treatment showed synergism at suboptimal doses, was highly effective in preventing lethal GVHD, and was superior to rapamycin plus CD28 blockade in a major histocompatibility complex class I- and II-mismatched HCT model. The combination treatment reduced the number of proliferating, alloreactive cells in the recipient, promoted donor B- and T-cell reconstitution, and reduced inflammatory cytokine levels. Administration of rapamycin plus agonistic CD28 antibodies offers a promising new therapeutic approach to facilitate tolerance after HCT.
 ...
PMID:Prevention of lethal acute GVHD with an agonistic CD28 antibody and rapamycin. 1545 4

We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.
 ...
PMID:Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. 1604 15

Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P=.03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P=.04). Only the use of sirolimus (exact odds ratio, 3.49; P=.02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P=.0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P=.02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.
 ...
PMID:Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. 1598 55

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid-resistant cGVHD. Thirty-five patients who developed GVHD after day 100 post-transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count > or = 100 x 10(9)/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD-free survival are warranted.
 ...
PMID:Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. 1604 91

Sirolimus is increasingly used in transplantation for prevention and treatment of graft-versus-host disease and organ rejection. Voriconazole is contraindicated when used concomitantly with sirolimus because of a substantial increase in sirolimus drug exposure with unadjusted dosing, but voriconazole is also considered the best initial treatment of invasive aspergillosis and other fungal infections. Patients who received voriconazole and sirolimus concomitantly were identified by a review of the medical records of all allogeneic hematopoietic stem cell recipients at our institution from September 1, 2002, to June 1, 2005. Data including baseline characteristics, indications for both drugs, and potential adverse effects were evaluated. Eleven patients received voriconazole and sirolimus concomitantly for a median of 33 days (range, 3-100 days). In 8 patients whose sirolimus dose was initially reduced by 90%, trough sirolimus levels were similar to those obtained before the administration of voriconazole; no obvious significant toxicity from either drug was observed during coadministration. Serious adverse events were observed in 2 patients in whom sirolimus dosing was not adjusted during voriconazole administration. Sirolimus and voriconazole may be safely coadministered if there is an empiric initial 90% sirolimus dose reduction combined with systematic monitoring of trough levels.
 ...
PMID:Voriconazole and sirolimus coadministration after allogeneic hematopoietic stem cell transplantation. 1663 90


1 2 3 4 5 Next >>