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Recipient tumor necrosis factor-alpha and interleukin-10 gene polymorphisms associate with early mortality and acute graft-versus-host disease severity in HLA-matched sibling bone marrow transplants

Lookup NU author(s): Dr Jennifer Cavet, Dr Peter Middleton, Professor Anne Dickinson


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The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is strongly implicated in graft-versus-host disease (GVHD) and other acute bone marrow transplant (BMT) complications. The antiinflammatory interleukin-10 (IL-10) antagonizes TNF-alpha and reduces GVHD. We previously showed association of recipient TNF (TNFd) and IL-10 (IL-10(-1064)) gene polymorphisms with acute GVHD severity in matched sibling BMT using only cyclosporin A monotherapy. The current study tested association of GVHD with TNFd and IL-10(-1064/-1082) polymorphisms in a large cohort (144 matched sibling donor/recipient pairs) given both cyclosporine A (CyA) and methotrexate (MTX) prophylaxis. Genotype results were correlated with acute and chronic GVHD and mortality. Patients homozygous for the TNFd microsatellite allele 3 had higher early mortality: 23.7% of TNFd3/d3 homozygotes died before day 30, compared with 6.80% of non-d3/d3 recipients (P=.013). Recipients possessing longer IL-10-1064 microsatellite alleles developed more severe acute GVHD: 22.3% of recipients possessing alleles 12 to 15 developed grade III to IV GVHD, versus 3.92% of those with smaller alleles (P<.01). Other recipient or donor genotypes tested did not significantly affect GVHD or mortality. We conclude that recipient TNFd and IL-10(-1064) polymorphisms associate with early mortality and severe acute GVHD in matched sibling BMT with dual prophyaxis. This supports the hypothesis of genetic predisposition towards GVHD and other BMT complications other than histocompatibility antigen disparity. (C) 1999 by The American Society of Hematology.

Publication metadata

Author(s): Cavet J, Middleton PG, Segall M, Noreen H, Davies SM, Dickinson AM

Publication type: Article

Publication status: Published

Journal: Blood

Year: 1999

Volume: 94

Issue: 11

Pages: 3941-3946

Print publication date: 01/12/1999

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology