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The success of hematopoietic stem cell transplantation (HSCT) lies with the ability of the engrafting immune system to remove residual leukemia cells via a graft-versus-leukemia effect (GvL), caused either spontaneously post-HSCT or via donor lymphocyte infusion. GvL effects can also be initiated by allogenic mismatched natural killer cells, antigen-specific T cells, and activated dendritic cells of leukemic origin. The history and further application of this GvL effect and the main mechanisms will be discussed and reviewed in this chapter.

Summary:We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patient's genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10 ؊1064 and IFN-␥ genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12. and poly-A polymorphisms are in linkage disequilibrium with each other. It is proposed that these polymorphisms exert their effects through enhanced transcription of the VDR gene or through altered mRNA stability. 5,6 The role of vitamin D3 and of the VDR in bone metabolism and turnover is well established. Homozygosity for the closely linked bb and aa genotypes of the BsmI and ApaI RFLPs in intron 8 is associated with increased femoral and vertebral bone density. 3,4,7 Reduced bone loss associated with liver transplantation is less frequent in transplant patients who possess the BsmI and ApaI aa and bb genotypes for VDR. 8 Polymorphism at the ATG initiation codon (FokI site) has been associated with genetic determination of final height in Japanese subjects, with heterozygotes at this locus achieving a greater final height than homozygotes for either allele, 1 and with heritable variation in bone mineral density. 9 Polymorphism at both the FokI and TaqI sites has been associated with variation in intervertebral disc degeneration in males. 10

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