Beneficial effect of the CXCL12-3'A variant for patients undergoing hematopoietic stem cell transplantation from unrelated donors.

The present study aimed to assess the impact of the CXCL12 gene polymorphism (rs1801157) on clinical outcome of hematopoietic stem cell transplantation from unrelated donors. Toxic complications were less frequent among patients transplanted from donors carrying the CXCL12-3'-A allele (42/79 vs. 105/151, p=0.014 and 24/79 vs. 73/151, p=0.009, for grade II-IV and III-IV, respectively). Logistic regression analyses confirmed a role of donor A allele (OR=0.509, p=0.022 and OR=0.473, p=0.013 for grade II-IV and III-IV toxicity). In addition, age of recipients (OR=0.980, p=0.036 and OR=0.981, p=0.040, respectively) was independently protective while female to male transplantation and HLA compatibility were not significant. The incidence of aGvHD (grades I-IV) was lower in patients having A allele (52/119 vs. 113/204, p=0.043) and AA homozygous genotype (6/25 vs. 159/298, p=0.005). Independent associations of both genetic markers with a decreased risk of aGvHD were also seen in multivariate analyses (A allele: OR=0.591, p=0.030; AA homozygosity: OR=0.257, p=0.006) in which HLA compatibility seemed to play less protective role (p<0.1) while recipient age and donor-recipient gender relation were not significant. Moreover, CXCL12-3'-A-positive patients were less prone to early HHV-6 reactivation (2/34 vs. 19/69, p=0.026). The presence of the CXCL12-3'-A variant was found to facilitate outcome of unrelated HSCT.

Interferon gamma 13-CA-repeat homozygous genotype and a low proportion of CD4(+) lymphocytes are independent risk factors for cytomegalovirus reactivation with a high number of copies in hematopoietic stem cell transplantation recipients.

Cytomegalovirus (CMV) reactivation was analyzed in 92 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) in relation to the proportion of CD4(+) lymphocytes in blood and a microsatellite polymorphism within the first intron of the interferon-gamma (IFNG) gene. CMV reactivation was found in 50% of the HSCT recipients; in 30% of these individuals, the level of CMV copies exceeded 100 per 10(5) peripheral blood (PB) cells on at least one occasion during the 100-day post-HSCT observation period. This high CMV copy level was most frequently found between 31 and 60 days post-HSCT (P = .021). Patients with > or = 100 CMV copies/10(5) cells were characterized by poorer overall survival (OS) compared with those lacking CMV copies or having < 100 CMV copies/10(5) cells (P = .04), and they suffered from severe post-HSCT complications, including acute graft-versus-host disease (aGVHD) and relapse. Thus, patients with > or = 100 CMV copies/10(5) cells were designated as having clinically significant CMV reactivation. Patients with < 10% CD4(+) lymphocytes had a higher number of CMV DNA copies than those with higher proportions of CD4(+) lymphocytes (0.62 vs 0.21, P = .001; mean +/- SEM, 4422 +/- 1667 vs 937 +/- 662 CMV copies/10(5) cells, P < .001, for the proportion of cases with reactivation and numbers of copies, respectively). Similarly, patients carrying 2 IFNG 13-CA-repeat alleles (homozygotes) had more frequent CMV reactivation (0.50 vs 0.26; P = .039) and a higher CMV load (4111 +/- 1699 vs 950+/-591 CMV copies/10(5) cells; P = .041) compared with those with other IFNG microsatellite allele constellations. Multivariate analysis demonstrated that the IFNG 13-CA-repeat homozygous genotype (odds ratio [OR] = 0.221; P = .044), a low proportion of CD4(+) lymphocytes (OR = 0.276; P = .050), and a lack of optimal (10/10 alleles) donor-recipient HLA match (OR = 15.19; P = .006) were independent risk factors for CMV reactivation with a high number of copies.

CCR5 deletion mutation and its association with the risk of developing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AND OBJECTIVES: Recently published data have suggested a potential role of CC chemokine receptor-5 (CCR5) in a mouse model of graft-versus-host disease (GvHD). It has also been described that a 32-nucleotide deletion within the CCR5 gene (CCR5Delta32) leads to complete loss of functional CCR5 in subjects homozygous for this mutation and decreased expression in heterozygous individuals. We analyzed CCR5 genotypes and their relationship to transplant outcome. DESIGN AND METHODS: A total of 349 individuals, comprising 186 recipients and 163 donors of allogeneic hematopoietic stem cell transplants, were typed for CCR5 polymorphisms. RESULTS: Recipients carrying the CCR5Delta32 allele developed acute GvHD (grades I-IV) less frequently than did patients lacking the CCR5 deletion mutation (11/35 vs. 76/151, p=0.033). This association was still valid after correcting for other known variables (recipient age, donor-recipient gender relation, type of donor, conditioning regimen, diagnosis, stem cell source and GvHD prophylaxis) by logistic regression (OD=0.391, p=0.023). Transplantation from a donor other than a matched sibling (OD=2.007, p=0.028), recipient age (OD=2.117, p=0.041) and myeloablative conditioning regimen (OD=2.235, p=0.014) were found to be factors associated with an increased risk of GvHD. Moreover, acute GvHD symptoms were not observed in any of the recipients carrying the CCR5Delta32 allele transplanted from donors with this deletion mutation (0/11 vs. 70/151, p=0.002). INTERPRETATION AND CONCLUSION: The presence of the CCR5Delta32 allele in recipients constituted an independent and protective factor associated with a decreased risk of GvHD. This protective effect of the CCR5 deletion mutation was particularly marked in patients transplanted from donors also carrying the CCR5Delta32 allele.