Circulating γδ T cells in young/adult and old patients with cutaneous primary melanoma

BACKGROUND: In a previous study we demonstrated the existence of numerical and functional alterations of γδ T cells in healthy elderly. Recently, we analysed the involvement of γδ T lymphocytes in malignant melanoma, describing a lower frequency of circulating γδ T cells, an altered pattern of cytokine production, and an impaired in vitro expansion of these cells in primary cutaneous melanoma patients. METHODS: In this study we investigated the existence of numerical and functional alterations of circulating γδ T cells in young/adult and old melanoma patients, comparing the data obtained with age-matched healthy subjects. RESULTS: We demonstrated that the number of circulating γδ(+ )T cells was significantly and similarly reduced in young/adult and old melanoma patients and in old healthy subjects in comparison with young healthy donors. The decrease was due to a reduction of Vδ2 T cells whereas the number of Vδ1 T cells was not affected. A higher percentage of γδ(+ )T cells producing TNF-α was found in old healthy donors, whereas a reduced number of TNF-α-producing γδ(+ )T cells was present in melanoma patients independently by age. No significant difference was observed in IFN-γ production. After a 10-day in vitro culture, both the percentage and the expansion index of γδ T cells, and in particular of Vδ2 subset, were significantly and similarly reduced both in young/adult and old melanoma patients, and in healthy aged people, in comparison with young/adult healthy subjects. CONCLUSIONS: Our study demonstrates that the numerical and functional impairment of γδ T cells found in melanoma patients is not correlated with age and that it has characteristics very similar to the alterations of γδ T cells found in old healthy subjects. We suggest that a similar impairment of γδ T cell population may be related to the increased susceptibility to tumors present in the elderly as well as in the pathogenesis of malignant melanoma

Late-Onset Hepatic Veno-Occlusive Disease after Allografting: Report of Two Cases with Atypical Clinical Features Successfully Treated with Defibrotide

Hepatic Veno-occlusive disease (VOD) is a potentially severe complication of hematopoietic stem cell transplantation (HSCT). Here we report two patients receiving an allogeneic HSCT  who developed late onset VOD with atypical clinical features. The two  patients presented with only few risk factors, namely, advanced acute leukemia, a myeloablative busulphan-containing regimen and received grafts from an unrelated donor. The first patient did not experience painful hepatomegaly and weight gain and both  patients showed only a mild elevation in total serum bilirubin level. Most importantly, the two patients developed clinical signs beyond day 21 post-HSCT. Hepatic transjugular biopsy confirmed the diagnosis of VOD. Intravenous defibrotide was promptly started leading to a marked clinical improvement. Based on our experience, liver biopsy may represent a useful diagnostic tool when the clinical features of VOD are ambiguous. Early therapeutic intervention with defibrotide  represents a crucial issue for the successful outcome of patients with VOD

Numerical and functional changes of hematopoietic progenitor cells during aging\ud

Aging is associated with changes of hematopoietic stem cells (HSCs), but it has not been established whether these changes are determined intrinsically or caused by the aging of their environment. The aim of this study was to evaluate through cross-transplantation models the effect of aging on the number of Lin-c-kit+ hematopoietic progenitor cells, on their ability to differentiate towards a lymphocyte phenotype, and on the role of the microenvironment in hematopoietic differentiation. The absolute number of purified Lin-c-kit+ cells from bone marrow was significantly\ud lower in aged than in young mice. When transplanted in young recipients, Lin-c-kit+ hematopoietic\ud progenitor cells from aged mice showed a reduced differentiation capacity in T cells and NK cells,\ud compared to Lin-c-kit+ cells from young animals. The role of microenvironment in Lin-c-kit+ hematopoietic progenitor cells differentiation was evaluated by injecting young Lin-c-kit+ cells in young or aged recipients, the latter transplanted or not with a young thymus. In these onditions, the differentiation of Lin-c-kit+ cells from young mice in T and NK cells was less efficient in aged than\ud in young recipients, independently of thymus grafting in aged recipients. Besides to quantitative defects also qualitative alterations were present Lin-c-kit+ cells from aged mice, as evidenced by the fact that the injection of Lin-c-kit+ cells from aged donors in young recipients, differentiated in CD4+ T cells, which retained an IL-4 production in-between young and old control values. In\ud conclusion, we have demonstrated that aging is associated with numerical and functional alterations of Lin-c-kit+ hematopoietic progenitor cells as well as with an altered microenvironment which is required for Lin-c-kit+ cells differentiation towards a lymphocyte phenotype.\u

VARS2 and TARS2 Mutations in Patients with Mitochondrial Encephalomyopathies

By way of whole-exome sequencing, we identified a homozygous missense mutation in VARS2 in one subject with microcephaly and epilepsy associated with isolated deficiency of the mitochondrial respiratory chain (MRC) complex I and compound heterozygous mutations in TARS2 in two siblings presenting with axial hypotonia and severe psychomotor delay associated with multiple MRC defects. The nucleotide variants segregated within the families, were absent in Single Nucleotide Polymorphism (SNP) databases and are predicted to be deleterious. The amount of VARS2 and TARS2 proteins and valyl-tRNA and threonyl-tRNA levels were decreased in samples of afflicted patients according to the genetic defect. Expression of the corresponding wildtype transcripts in immortalized mutant fibroblasts rescued the biochemical impairment of mitochondrial respiration and yeast modeling of the VARS2 mutation confirmed its pathogenic role. Taken together, these data demonstrate the role of the identified mutations for these mitochondriopathies. Our study reports the first mutations in the VARS2 and TARS2 genes, which encode two mitochondrial aminoacyl-tRNA synthetases, as causes of clinically distinct, early-onset mitochondrial encephalopathies