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

The proinflammatory cytokine tumor necrosis factor-or (TNF-alpha) is strong ly implicated in graft-versus-host disease (GVHD) and other acute bone marr ow transplant (BMT) complications. The antiinflammatory interleukin-10 (IL- 10) antagonizes TNF-alpha and reduces GVHD. We previously showed associatio n of recipient TNF (TNFd) and IL-10 (IL-10(-1064)) gene polymorphisms with acute GVHD severity in matched sibling BMT using only cyclosporin A monothe rapy. The current study tested association of GVHD with TNFd and IL-10(-106 4/-1082) polymorphisms in a large cohort (144 matched sibling donor/recipie nt pairs) given both cyclosporine A (CyA) and methotrexate (MTX) prophylaxi s. Genotype results were correlated with acute and chronic GVHD and mortali ty. Patients homozygous for the TNFd microsatellite allele 3 had higher ear ly mortality: 23.7% of TNFd3/d3 homozygotes died before day 30, compared wi th 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 r ecipients possessing alleles 12 to 15 developed grade III to IV GVHD, versu s 3.92% of those with smaller alleles (P<.01). Other recipient or donor gen otypes tested did not significantly affect GVHD or mortality. We conclude t hat recipient TNFd and IL.10(-1064) polymorphisms associate with early mort ality and severe acute GVHD in matched sibling BMT with dual prophyaxis. Th is supports the hypothesis of genetic predisposition towards GVHD and other BMT complications other than histocompatibility antigen disparity. (C) 199 9 by The American Society of Hematology.