Interleukin-1 alpha genotype and outcome of unrelated donor haematopoietic stem cell transplantation for chronic myeloid leukaemia

Autor: Parinda A. Mehta, Margaret L. MacMillan, Stella M. Davies, Tiffany Zamzow, James Elliott, Mary Eapen, Michelle D. Combs, Effie W. Petersdorf, Richard Aplenc, Daniel J. Weisdorf, Sharavi Gandham, John P. Klein
Rok vydání: 2007
Předmět:
Zdroj: British Journal of Haematology. 137:152-157
ISSN: 1365-2141
0007-1048
DOI: 10.1111/j.1365-2141.2007.06552.x
Popis: Allogeneic haematopoietic stem cell transplantation (HSCT) offers a potential cure for a variety of malignant and non-malignant conditions. However, regimen-related toxicity, graft-versus-host disease (GVHD), and opportunistic infections (Kernan et al, 1993) still remain the major cause of morbidity and mortality after unrelated donor (URD) allogeneic HSCT. In addition to identifying patients and transplant-related prognostic factors, identifying favourable factors in the donor may aid in donor selection and may improve outcomes after HSCT. Non-human leucocyte antigen (HLA) genetic polymorphism has been shown to influence risk of GVHD and HSCT mortality. Middleton et al (1998) showed that the homozygous d3 genotype of the tumour necrosis factor (TNF)-α microsatellite, and the presence of IL10 alleles with greater numbers of dinucleotide repeats were preferentially associated with grade III/IV GVHD in sibling transplant recipients. In studies of 993 recipients of matched sibling donor transplant, Lin et al (2003, 2005 showed that interleukin 10 (IL-10) genotype of the recipient and IL-10 receptor genotype of the donor modified the risk of GVHD. Associations between IL-6 and interferon-gamma genotype and susceptibility to GVHD have also been shown in sibling donor HSCT recipients (Cavet et al, 2001; Socie et al, 2001). Data addressing this issue in the unrelated donor HSCT setting are scarce, however Keen et al (2004) have reported association of TNF-α and IL-10 genotypes with toxicity after unrelated donor transplant. Taken together, these data suggest that non-HLA genetic variation influences risk of GVHD and HSCT mortality, and that it might be possible to predict HSCT outcome from a profile of donor or recipient risk factors, including cytokine polymorphisms. Interleukin-1 is a pro-inflammatory cytokine implicated in the initiation and maintenance of GVHD and the immune response to infection (Ferrara & Deeg, 1991). The IL-1 gene family includes three members [IL1A (IL-1α), IL1B (IL-1β) and IL1N alias IL1RA (IL-1 receptor agonist; IL-1RA)] that mediate immune and inflammatory responses through two specific cell surface receptors. IL-1α and IL-1β are agonists and IL-1RA is a competitive receptor antagonist. A cytosine (C) to thymine (T) transition at position −889 in the IL1A promoter is believed to influence gene transcription. The T/T genotype creates the consensus site for a novel transcription factor (Skn-1) and is associated with a significant increase in promoter activity compared with the C/C genotype. Three previous studies have examined IL-1 polymorphism and outcome of sibling donor bone marrow transplantation. Cullup et al (2001) studied IL1B and IL1N polymorphism and showed modest evidence for an association between donor IL-1RA genotype and incidence of acute GVHD. In a larger study, Lin et al (2000) reported little association between donor or recipient IL-1β and IL-1RA genotypes and frequency of GVHD. Cullup et al (2003) have also reported the association of IL1A −889 polymorphism in the donor genotype with the occurrence of chronic GVHD. Neither of these studies investigated IL1A polymorphism or examined URD HSCT recipients. A previous single institution report of 90 recipients of unrelated donor HCT showed improved survival at 1 year if at least one IL1A T allele was present in the donor. Lower TRM was seen if both donor and recipient possessed the IL1A T allele (MacMillan et al, 2003). While these data showed a striking reduction in TRM associated with IL-1 genotype, numbers were small and these studies were performed in a heterogeneous patient population. In this study, we sought to replicate these findings in a larger and more uniform population.
Databáze: OpenAIRE
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