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)

Allogenic bone marrow transplantation (BMT) was carried out on a 3-year-old white caucasian girl with Niemann-Pick disease (NPD) type B. The donor was her unaffected brother. The patient was neurologically normal at the time of transplantation. Engraftment was based on cytogenetic studies and increased leukocyte acid sphingomyelinase (ASM) activity. However, liver biopsies taken up to 33 months post transplantation showed only a moderate reduction in stored sphingomyelin and no significant increase in ASM activity. The post-transplantation period was complicated by severe graft-versus-host disease and a respiratory arrest. By 6 years of age, neurological involvement was observed, including bilateral cherry red spots. The proband is now severely mentally and physically disabled. Liver cirrhosis has continued to progress despite the BMT, and haematemesis due to portal hypertension occurred at 17 years of age. However, pulmonary infiltration regressed after BMT and there has been no clinical evidence of pulmonary insufficiency.
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PMID:Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant. 1473 82

Niemann-Pick disease type A (NP-A; OMIM 257200) is an autosomal recessive lysosomal storage disorder caused by deficiency of acid sphingomyelinase and resulting in accumulation of sphingomyelin, unesterified cholesterol, and other complex lipids in many tissues. It is characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course culminating in death by 3 years of age. There is no known effective treatment. We report the case of a prenatally diagnosed girl who underwent cord blood stem cell transplantation (CBSCT) at 3 months of age. She was neurologically intact at the time of CBSCT. Hepatosplenomegaly, was detected at 6 weeks of age; the splenomegaly resolved following CBSCT. Recovery was complicated by graft-versus-host disease. She subsequently developed and continues to show marked global developmental delay, generalized hypotonia, and signs of neurological regression, despite continued engraftment. Bilateral cherry red spots were detected at 10 months of age, 7 months post-CBSCT. Although she is doing better than her affected brother, she shows little overall benefit from CBSCT.
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PMID:Unsuccessful treatment attempt: cord blood stem cell transplantation in a patient with Niemann-Pick disease type A. 1796 Apr 92

Alloreactive donor cytolytic T lymphocytes play a critical role in pathophysiology of acute graft-versus-host disease (GVHD). As GVHD progression involves tumor necrosis factor superfamily receptor activation, and as apoptotic signaling for some tumor necrosis factor superfamily receptors might involve acid sphingomyelinase (ASMase)-mediated ceramide generation, we hypothesized that ASMase deletion would ameliorate GVHD. Using clinically relevant mouse models of acute GVHD in which allogeneic bone marrow and T cells were transplanted into asmase+/+ and asmase(-/-) hosts, we identify host ASMase as critical for full-blown GVHD. Lack of host ASMase reduced the acute inflammatory phase of GVHD, attenuating cytokine storm, CD8+ T-cell proliferation/activation, and apoptosis of relevant graft-versus-host target cells (hepatocytes, intestinal, and skin cells). Organ injury was diminished in asmase(-/-) hosts, and morbidity and mortality improved at 90 days after transplantation. Resistance to cytolytic T lymphocyte-induced apoptosis was found at the target cell membrane if hepatocytes lack ASMase, as hepatocyte apoptosis required target cell ceramide generation for formation of ceramide-rich macrodomains, sites concentrating proapoptotic Fas. These studies indicate a requirement for target cell ASMase in evolution of GVHD in liver, small intestines, and skin and provide potential new targets for disease management.
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PMID:Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease. 2007 75

The activity of acid sphingomyelinase (aSMase) was previously reported to be involved in glucocorticoid-induced cell death (GICD) of T lymphocytes. This mechanism in turn is believed to contribute to the therapeutic efficacy of glucocorticoids (GCs) in the treatment of inflammatory diseases. In this study, we reassessed the role of aSMase in GICD by using aSMase knockout mice. The absence of aSMase largely abolished the partial protection that effector memory CD4(+) T cells in wild-type mice possess against GICD. Reduced IL-2 secretion by aSMase-deficient CD4(+) T cells suggested that a lack of this important survival factor might be the cause of these cells' enhanced susceptibility to GICD. Indeed, addition of IL-2 restored the protection against GICD, whereas neutralization of IL-2 abrogated the otherwise protective effect seen in wild-type effector memory CD4(+) T cells. The therapeutic implications of the altered sensitivity of aSMase-deficient T cells to GICD were assessed in models of inflammatory disorders; namely, experimental autoimmune encephalomyelitis and acute graft-versus-host disease. Surprisingly, GC treatment was equally efficient in both models in terms of ameliorating the diseases, regardless of the genotype of the T cells. Thus, our data reveal a hitherto unrecognized contribution of aSMase to the sensitivity of effector memory CD4(+) T cells to GICD and call into question the traditionally attributed importance of GICD of T cells to the treatment of inflammatory diseases by GCs.
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PMID:Acid sphingomyelinase is required for protection of effector memory T cells against glucocorticoid-induced cell death. 2194 86