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• W2022780178 abstract "TNFα and IL-10 are key cytokines active in the biology of posttransplant complications following bone marrow transplantation (BMT). It has been recognized since the early 1990s that inherent high and low producers of TNFα are present in the human population; however, working out the effect of this variation, if any, on the success of BMT is proving to be complicated. Early studies on microsatellite polymorphisms in the TNFα gene region identified a potential gene marker of these “producer” alleles, the TNFd microsatellite, which seemed to inform on TNFα production. Although these measurements suggested that the TNFd4 allele was linked to high TNFα production (1), measurements in heart transplant patients suggested allele d3 was the high producer, with the TNFd3 allele also being found to associate with acute rejection episodes following cardiac transplant (2). Initial studies on BMT patients appeared concordant with the cardiac studies, with the TNFd3 allele associating with occurrence of acute graft versus host disease (aGVHD) in one small UK study on sib-allo BMT and with poor overall survival in a U.S. transplant population (for all previous BMT studies, see references in the introduction in the paper by Bettens et al., in this issue). Subsequent reports however, cast doubts on these early findings on BMT, with the observation that allele d4 and not d3 was the GVHD risk allele in two independent BMT populations from the USA and Europe respectively. What is going on? Is this all a complex statistical artefact? The paper in this issue by Bettens et al. reports findings from yet another distinct European study cohort, and concludes that both alleles d3 and d4 may represent risk features for GVHD following BMT. This suggestion, of to least two risk alleles, not one, is also supported by more recent measurements on TNFα levels during preconditioning prior to BMT; serum TNFα levels have been observed to be higher for patients possessing either allele d3 or d4 (3). The results of studies on polymorphic microsatellites at the TNFα locus are in contrast with studies done with the more familiar single nucleotide polymorphisms (SNPs) at this locus. The A allele of the widely studied G-308A polymorphism has been associated with enhanced TNFα production and a wide range of pathologies including increased likelihood of organ rejection (for example, see recent review for cardiac transplant by Holweg et al. (4)). Studies with SNPs at the TNFα locus don’t show reproduce-able associations with GVHD in most BMT studies reported to date. Also, the –308A allele is not in linkage with either the TNFd3 or d4 alleles, but is in partial linkage with the less common microsatellite allele TNFd1 (1). The class III region in which the TNFα gene resides is one of the most “gene dense” regions of the human genome and consequently, the microsatellite marker TNFd doesn’t just inform on TNFα genetics. The TNFd microsatellite actually resides within an intron of an adjacent gene, originally termed LST1, and variants of other nearby genes including lymphotoxin α and β are present as shared, conserved haplotypes (1); although TNFα is the popular target, it isn’t necessarily the only candidate as culprit for these posttransplant effects. Bettens et al. also re-examined the microsatellite polymorphisms in the IL-10 gene promoter in their study. As in the case of the TNFα locus, previous studies have reported associations with both the highly informative microsatellite loci and with the more conventional SNPs. In their independent population, Bettens et al. found that IL-10 microsatellite alleles with greater numbers of bi-nucleotide repeats at the –1064 gene promoter locus associated with lower overall survival following MUD allo-BMT. A number of earlier studies found that these alleles associate with aGVHD following sib (HLA identical) allo BMT but not with survival. Reported studies on the SNPs at the IL-10 locus have produced mixed results, and although most opinion favors the model that “high producer IL-10 alleles protect from GVHD” following BMT, just about all possible allele associations have been suggested by one study or another. Direct comparison of the results of the different studies is tempting, but difficult. Could the same genetic influences be contributing to poor outcomes in different cohorts but in different ways, contributing to GVHD risk in some but manifesting as reduced survival in others? Or are these studies really just reflecting susceptibility to problems of patient heterogeneity, relatively modest study size and insufficient power. One challenge to comparing studies of this kind on BMT lies in the differences between different study cohorts. As each centre studies the patient groups available to them, the test groups differ in terms of age range, disease, type of transplant, prophylaxis etc. Consequently, we are rarely able to compare “like with like.” An additional complication to working out the IL-10 story may be the role of IL-10 in BMT. Although we all perceive IL-10 as an anti-inflammatory cytokine, it can have other effects, including stimulatory effects on NK cells (5); enhanced NK activity would produce cellular antigen release and a stimulatory effect. Could IL-10, and consequently IL-10 genetics, act differently in different BMT protocols? Clearly gene association studies investigating such complex players as the cytokines still have some way to go before we know exactly what is going on and whether or not the information generated has any clinical or strategic research value. However, the emergence of consistent trends from these studies is very encouraging … if a little head-stretching at times." @default.
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• W2022780178 date "2006-05-15" @default.
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• W2022780178 title "TNFα and IL-10 in Bone Marrow Transplantation: Does Genotype Matter?" @default.
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• W2022780178 doi "https://doi.org/10.1097/01.tp.0000208592.69452.c2" @default.
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