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)

2'-Deoxycoformycin (dCF), a potent adenosine deaminase inhibitor, has been reported to display greater toxicity for T than for B lymphoblasts. Since this compound can block DNA replication and since this effect is mediated by the intracellular ATP/dATP balance, its possible effect on DNA ligase was investigated. dCF at relatively low concentrations (1 microM), in association with dATP (100 microM), is a strong inhibitor of DNA ligase in T blasts, whereas it has no significant effect in B blasts at this concentration. The AMP-ligase complex is the target of the observed inhibition because the combined presence of the inhibitor and dATP results in a more stable dAMP-ligase complex. Because of this observation and of the greater adenosine deaminase activity observed in T cells, the dATP mediated dCF inhibition of ligase might be the crucial replication target of T cell toxicity. These observations are discussed in terms of T immunodeficiencies including Graft Versus Host Disease and related syndromes.
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PMID:dATP-mediated inhibition of DNA ligase by 2'-deoxycoformycin in T and B cell leukemia. 278 73

The role of negative regulators or suppressors of the damage-associated molecular pattern-mediated (DAMP-mediated) stimulation of innate immune responses is being increasingly appreciated. However, the presence and function of suppressors of DAMP-mediated effects on T cells, and whether they can be targeted to mitigate T cell-dependent immunopathology remain unknown. Sialic acid-binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of DAMP-mediated responses in innate immune cells, but its T cell-autonomous role is unknown. Utilizing loss-of-function-based (genetic knockout) and gain-of-function-based (agonist) approaches, we demonstrate that in the presence of certain DAMPs, Siglec-G suppressed in vitro and in vivo T cell responses. We also demonstrate that its T cell-autonomous role is critical for modulating the severity of the T cell-mediated immunopathology, graft-versus-host disease (GVHD). Enhancing the Siglec-G signaling in donor T cells with its agonist, a CD24Fc fusion protein, ameliorated GVHD while preserving sufficient graft-versus-tumor (GVT) effects in vivo. Collectively, these data demonstrate that Siglec-G is a potentially novel negative regulator of T cell responses, which can be targeted to mitigate GVHD.
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PMID:Siglec-G represses DAMP-mediated effects on T cells. 2872