Influence of Donor and Recipient Gender on Telomere Maintenance after Umbilical Cord Blood Cell Transplantation: A Study by the Gruppo Italiano Trapianto Di Midollo Osseo.

Physiologic loss of telomerase activity in adult life determines progressive telomere length (TL) shortening. Inflammation and oxidative damage are established causes of TL loss; moreover, males have shorter telomeres compared with females. Despite these notions, mechanisms regulating TL maintenance are poorly defined. Because umbilical cord blood (UCB) cells harbor very long telomeres, not yet exposed to environmental damages, UCB transplantation (UCBT) provides a unique experimental setting to study determinants of TL in humans. TL dynamics were analyzed on peripheral blood mononuclear cells (MNCs) from 36 patients (median age, 42 years) undergoing UCBT. TL was studied at a median of 20 months after UCBT. A significantly longer TL (mean, 8698 bp; range, 6521 to 11,960) was documented in UCBT recipients compared with age-matched healthy control subjects (mean, 7396 bp; range, 4375 to 11,108; P < .01). Among variables potentially influencing TL maintenance, including recipient features, graft type, transplant procedure, and engraftment kinetics, only donor-recipient gender combination was associated with TL, with the longest TL in women receiving male UCB (mean, 10,063 bp; range, 8381 to 11,960). To further investigate this trend, telomerase activation was assessed in vitro. Experiments showed that telomerase subunits were preferentially upregulated in male-derived bone marrow MNCs exposed ex vivo to estradiol as compared with female MNCs. This implies an increased sensitivity of male-derived MNCs to telomerase activation induced by estradiol. The results suggest that extrinsic and modifiable factors such as hormonal status and female milieu could be major determinants of TL in humans, providing the rationale for investigating hormonal-based approaches to counteract telomere erosion and aging-related diseases.

Fecal but not serum calprotectin is a potential marker of GVHD after stem cell transplantation.

Gastrointestinal graft-versus-host disease (GvHD) represents a life-threatening complication after stem cell transplantation. Differential diagnosis between gut GvHD and other causes of diarrhea after HSCT is still subjected to endoscopy and histological findings. The research for a reliable biomarker for gut GvHD might allow an early diagnosis of this condition and a consequent prompt treatment that could reduce unfavorable outcomes. Recently, fecal calprotectin was reported as reliable marker of gut involvement. We would evaluate if serum instead of fecal calprotectin could be considered a possible biomarker of gut GvHD. Serum calprotectin was measured in a cohort of 54 patients submitted to allogeneic stem cell transplantation using ELISA assay. For a subset of 21 patients, calprotectin serum levels were compared with fecal calprotectin detection. Contrary to fecal calprotectin, we found only a trend to high level of serum calprotectin for GvHD development and gut involvement, but statistical difference was not reached. Fecal but not serum calprotectin could be considered as possible biomarker for gut GvHD.

HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation.

Life-threatening graft-versus-host disease (GVHD) limits the use of HLA-C-mismatched unrelated donors in transplantation. Clinicians lack criteria for donor selection when HLA-C-mismatched donors are a patient's only option for cure. We examined the role for HLA-C expression levels to identify permissible HLA-C mismatches. The median fluorescence intensity, a proxy of HLA-C expression, was assigned to each HLA-C allotype in 1975 patients and their HLA-C-mismatched unrelated transplant donors. The association of outcome with the level of expression of patients' and donors' HLA-C allotypes was evaluated in multivariable models. Increasing expression level of the patient's mismatched HLA-C allotype was associated with increased risks of grades III to IV acute GVHD, nonrelapse mortality, and mortality. Increasing expression level among HLA-C mismatches with residue 116 or residue 77/80 mismatching was associated with increased nonrelapse mortality. The immunogenicity of HLA-C mismatches in unrelated donor transplantation is influenced by the expression level of the patient's mismatched HLA-C allotype. HLA-C expression levels provide new information on mismatches that should be avoided and extend understanding of HLA-C-mediated immune responses in human disease.