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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3943-3948
Cytokine Gene Polymorphisms Associating With Severe Acute
Graft-Versus-Host Disease in HLA-Identical Sibling Transplants
Peter G. Middleton,
Penelope R.A. Taylor,
Graham Jackson,
Stephen
J. Proctor, and
Anne M. Dickinson
From the Leukaemia Research Fund (LRF) Laboratory, Catherine Cookson
Building, The Medical School, Framlington Place, Newcastle upon Tyne,
UK; and the Department of Haematology and University Department of
Haematology, School of Clinical Laboratory Sciences, Royal Victoria
Infirmary, Queen Victoria Road, Newcastle upon Tyne, UK.
It is now well known that the initial phase of graft-versus-host
disease (GVHD) involves cytokine release during preconditioning of the
recipient of an allogeneic bone marrow transplant (BMT). Tumor necrosis
factor  (TNF), in particular, has been implicated in pathological
damage and is released pretransplant due to irradiation and cytotoxic
preconditioning regimens. Interleukin-10 (IL-10), a natural
immunosuppressant of TNF , may be involved in downregulation of
these responses, which may be an individual patient-specific effect. In
this study, we determined the genotype for polymorphisms associated
with TNF and IL-10 in 80 potential allo-BMT recipients and
correlated the genotype with the severity of GVHD in 49 patients for
whom clinical data relating to GVHD was available. The widely studied
TNF  308 polymorphism does not show any significant
associations, but the d3 homozygous allele of the TNFd microsatellite
is preferentially associated with grade III/IV GVHD (7 of 11 patients)
compared with its occurrence in 8 of 38 patients with grade 0/II GVHD
(P = .006). Alleles of the IL-10 1064 promoter
region microsatellite polymorphism that possess greater numbers of
dinucleotide (CA) repeats also significantly associate with more severe
GVHD. This region has been demonstrated to be important in the
regulation of the IL-10 promoter. Eighteen of 38 patients with grade
0-II GVHD possessed alleles with greater numbers (12 or more) of
dinucleotide repeats, compared with 9 of 11 cases with grade III-IV
GVHD (P < .02). Of the 38 patients with grade 0-II GVHD, 3 of
38 had a both TNFd3/d3 and IL-10 (12-15) genotype,
compared with 6 of 11 patients with grade III-IV GVHD (P < .001). There was no association of either the TNFd or IL-10 microsatellite polymorphisms with mortality (P = .43 and .51, respectively). Our results suggest that patient cytokine gene polymorphism genotypes may influence GVHD outcome by affecting cytokine
activation during the pretransplant conditioning regimens, and these
results are the first to suggest a genetic predisposition to this
important transplant-related complication.
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