Cyclosporin a to Prevent Graft-Versus-Host Disease in Man After Allogeneic Bone-Marrow Transplantation

Powles, R; Clink, H.M.; Spence, David; Morgenstern, G. R.; Watson, J. Graham; Selby, P.; Woods, Mary; Barrett, Ann; Jameson, Beryl; Sloane, J P; Lawler, Sylvia D.; Kay, H. E. M.; Lawson, D.; McElwain, T. J.; Alexander, Peter

doi:10.1016/s0140-6736(80)90881-8

Cited by 384 publications

(84 citation statements)

References 8 publications

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“…CsA was capable of ablating or at least inhibiting GVHD during its administration, but a fatal syndrome ensued approximately 1 month following cessation of treatment. Though early studies by Tutschka et al (17) had been promising, many investigators have demonstrated that CsA is not completely effective in the prevention of GVHD following bone marrow (18,19) or small bowel transplantation (20). The prevention of acute lethal GVHD by FK-506 represents a distinct therapeutic advantage for this agent.…”

Section: Discussionmentioning

confidence: 99%

The Use of Fk-506 for Small Intestine Allotransplantation Inhibition of Acute Rejection and Prevention of Fatal Graft-Versus-Host Disease

et al. 1990

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Small intestine allotransplantation in humans is not yet feasible due to the failure of the current methods of immunosuppression. FK-506, a powerful new immunosuppressive agent that is synergistic with cyclosporine, allows long-term survival of recipients of cardiac, renal, and hepatic allografts. This study compares the effects of FK-506 and cyclosporine on host survival, graft rejection, and graft-versus-host-disease in a rat small intestine transplantation model. Transplants between strongly histoincompatible ACI and Lewis (LEW) strain rats, and their F 1 progeny are performed so that graft rejection alone is genetically permitted (F 1 →LEW) or GVHD alone permitted (LEW→F 1 ) or that both immunologic processes are allowed to occur simultaneously (ACI→LEW). Specific doses of FK-506 result in prolonged graft and host survival in all genetic combinations tested. Furthermore, graft rejection is prevented (ACI→LEW model) or inhibited (rejection only model) and lethal acute GVHD is eliminated. Even at very high doses, cyclosporine did not prevent graft rejection or lethal GVHD, nor did it allow long-term survival of the intestinal graft or the host. Animals receiving low doses of cyclosporine have outcomes similar to the untreated control groups. No toxicity specific to FK-506 is noted, but earlier studies by other investigators suggest otherwise.Small intestine allotransplantation (SIA) * that results in the establishment of grafts capable of absorbing nutrients and supporting human life has not yet been achieved, despite the demonstration of its technical feasibility 30 years ago (1). The limiting obstacle in all SIA models examined to date remains the failure of traditional methods of immunosuppression, including cyclosporine, to prevent rejection. Since the introduction of CsA, some progress in long-term survival following SIA in rats and larger animals has been reported (2-6). Recently, 6-month survival has been achieved following human small intestine allotransplantation (7) as well as multivisceral organ transplantation, which included the entire small intestine and most of the colon (8). However, failures are more common than temporary successes. This is particularly distressing in light of the fact that the number of patients who would potentially benefit from SIA and who have been otherwise relegated to total parenteral nutrition or worse is significant (9). It is clear that future improvements of SIA will depend upon the development of more-specific and less-toxic forms of immunosuppression. FK -506 is a powerful new immunosuppressant that has recently been demonstrated to successfully inhibit hepatic (10), renal (11), and cardiac (12) rejection in animal models.The purpose of the present study was to compare the effects of FK-506 and CsA on host survival, graft rejection, and graft-versus-host disease in a rat small intestine transplantation model. MATERIALS AND METHODS AnimalsMale Lewis (LEW) (RTl 1 ), ACI (RT1 a ) strains, and (ACI×LEW)F 1 hybrid rats weighing 200-300 g were purchased from Har...

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Section: Discussionmentioning

confidence: 99%

The Use of Fk-506 for Small Intestine Allotransplantation Inhibition of Acute Rejection and Prevention of Fatal Graft-Versus-Host Disease

et al. 1990

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“…1,8 While cyclosporin is most often implicated as the cause of this syndrome in bone marrow and in solid organ transplant recipients, 4,9 a number of other risk factors have also been described. The observation that TA-TMA may occur in autologous blood stem cell transplant recipients suggests that high-dose chemotherapy alone may be responsible for some cases of this disorder.…”

Section: Incidence and Risk Factors For Ta-tmamentioning

confidence: 99%

“…1 Recent work has led to an improvement in our understanding of the pathophysiology of this disorder, while new experimental models of thrombotic microangiopathies give reason to hope that effective treatment may one day become available.…”

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confidence: 99%

Transplantation-associated thrombotic microangiopathy: twenty-two years later

Daly

Xenocostas

Lipton

2002

Bone Marrow Transplant

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Summary:A syndrome of microangiopathic hemolytic anemia, renal dysfunction and neurological abnormalities was first noted in bone marrow transplant recipients 22 years ago. Now known as transplantation-associated thrombotic microangiopathy (TA-TMA) to distinguish it from other thrombotic microangiopathies, this disorder responds poorly to conventional treatments for thrombotic thrombocytopenic purpura. In this review, we discuss the incidence and risk factors for TA-TMA and describe a pathophysiologic model of the disorder based on results obtained from laboratory models of the thrombotic microangiopathies. We conclude by suggesting possible approaches to the early diagnosis and treatment of TA-TMA based on this model that may warrant testing in future clinical trials.

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“…The main method of post-transplant immunosuppression after HLA-identical sibling bone marrow transplantation has been the administration of immunosuppressive agents, including methotrexate (MTX), cyclosporine (CS), and glucocorticosteroids. [1][2][3] Early clinical trials were characterized by high transplantation-related mortality, of up to 42% of patients, especially those given CS or MTX alone. 1,2,4-11 Over half of the cases of transplantationrelated mortality were due to interstitial pneumonitis, with or without documented cytomegalovirus (CMV) disease.…”

mentioning

confidence: 99%

“…[1][2][3] Early clinical trials were characterized by high transplantation-related mortality, of up to 42% of patients, especially those given CS or MTX alone. 1,2,[4][5][6][7][8][9][10][11] Over half of the cases of transplantationrelated mortality were due to interstitial pneumonitis, with or without documented cytomegalovirus (CMV) disease. Post-transplant immunosuppression utilizing combinations of immunosuppressive agents showed a lower incidence of acute graft-versus-host disease (GVHD) and transplantation-related deaths.…”

mentioning

confidence: 99%

Cyclosporine alone vs cyclosporine plus methotrexate for post-transplant immunosuppression after HLA-identical sibling bone marrow transplantation: a randomized prospective study

Lee

Choi

Lee

et al. 2004

Bone Marrow Transplant

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Summary:The role of methotrexate (MTX), given with cyclosporine (CS), after HLA-identical sibling bone marrow transplantation needs to be defined. In all, 80 patients with hematologic malignancies were enrolled in a prospective randomized trial. All were given BuCy conditioning. The 40 patients in the CS arm received CS 3 mg/kg/day intravenously, with subsequent oral dosing. Patients in the CS þ MTX arm received, in addition to CS, MTX intravenously, 15 mg/m 2 on day 1, and 10 mg/m 2 on days 3, 6, and 11. Transplantation-related mortality was low in both groups of patients (13 vs 11% for CS vs CS þ MTX groups, P ¼ 0.94). The CS group had a significantly higher frequency of chronic graft-versus-host disease (56 vs 32%, P ¼ 0.05). After a median follow-up of 22.1 months (5.1-47.8 months), three of 30 vs 10 of 28 patients with acute leukemia/myelodysplastic syndrome (MDS) in CS group vs CS þ MTX group relapsed (P ¼ 0.01) yielding better overall survival for patients with acute leukemia/MDS treated with CS (P ¼ 0.02). After HLAidentical sibling bone marrow transplantation, immunosuppression with CS, with or without MTX, resulted in similarly low transplantation-related mortality. In acute leukemia/MDS, decreased relapse with patient survival prolongation was observed in the CS group. The main method of post-transplant immunosuppression after HLA-identical sibling bone marrow transplantation has been the administration of immunosuppressive agents, including methotrexate (MTX), cyclosporine (CS), and glucocorticosteroids. [1][2][3] Early clinical trials were characterized by high transplantation-related mortality, of up to 42% of patients, especially those given CS or MTX alone. 1,2,4-11 Over half of the cases of transplantationrelated mortality were due to interstitial pneumonitis, with or without documented cytomegalovirus (CMV) disease. Post-transplant immunosuppression utilizing combinations of immunosuppressive agents showed a lower incidence of acute graft-versus-host disease (GVHD) and transplantation-related deaths. 3,6-11 Although combination therapy is widely accepted for post-transplant immunosuppression in various settings of allogeneic hematopoietic cell transplantation, including HLA-identical sibling bone marrow transplantation, 12 the optimum regimen for post-transplant immunosuppression in the latter requires further investigation, primarily because recent improvements in the management of patients with GVHD and resulting infectious complications, such as CMV, have been shown to significantly decrease the incidence of transplantationrelated mortality after allogeneic hematopoietic cell transplantation. 13 In addition, several studies have reported increased relapse rates of underlying leukemia resulting from combined immunosuppression after HLA-identical sibling bone marrow transplantation. 7,14 These findings indicate that, in HLA-identical sibling bone marrow transplantation, where the genetic disparity between the donor and the patient is relatively small, optimum posttransplant immunosuppression s...

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Cyclosporin a to Prevent Graft-Versus-Host Disease in Man After Allogeneic Bone-Marrow Transplantation

Cited by 384 publications

References 8 publications

The Use of Fk-506 for Small Intestine Allotransplantation Inhibition of Acute Rejection and Prevention of Fatal Graft-Versus-Host Disease

The Use of Fk-506 for Small Intestine Allotransplantation Inhibition of Acute Rejection and Prevention of Fatal Graft-Versus-Host Disease

Transplantation-associated thrombotic microangiopathy: twenty-two years later

Cyclosporine alone vs cyclosporine plus methotrexate for post-transplant immunosuppression after HLA-identical sibling bone marrow transplantation: a randomized prospective study

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