FOXP3؉ regulatory T cells. Furthermore, we demonstrate that in addition to their action on the adaptive immune system, MSCs, through HLA-G5, affect innate immunity by inhibiting both NK cell-mediated cytolysis and interferon-␥ secretion. Our results provide evidence that HLA-G5 secreted by MSCs is critical to the suppressive functions of MSCs and should contribute to improving clinical therapeutic trials that use MSCs to prevent GvHD. STEM CELLS 2008;26:212-222 Disclosure of potential conflicts of interest is found at the end of this article.

y These authors contributed equally to this work. Persistent ATG-induced CD4þ T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one-year later in 97 incident RTR À62 patients receiving ATG and 35 receiving anti-CD25 mAb (a-CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34 þ hematopoietic progenitor cells (CD34 þ HPC) and lymphoid (l-HPC) and myeloid (m-HPC) progenitor ratio; (iii) T cell phenotype; and (iv) measurement of T cell relative telomere length (RTL) and telomerase activity (RTA). Clinical correlates were analyzed with a 3 year follow-up. Thymic output significantly decreased oneyear posttransplant in ATG-treated patients. ATG was associated with a significant decrease in l-HPC/m-HPC ratio. Late stage differentiated CD57 þ /CD28 À T cells increased in ATG-treated patients. One-year posttransplant T cell RTL and RTA were consequently lower in ATG-treated patients. ATG is associated with accelerated immune senescence. Increased frequency of late differentiated CD4 þ T cell frequency at transplantation tended to be predictive of a higher risk of subsequent opportunistic infections and of acute rejection only in ATG-treated patients but this needs confirmation. Considering pretransplant immune profile may help to select those patients who may benefit from ATG to prevent severe infections and acute rejection.

No abstract

Adult bone marrow-derived mesenchymal stem cells (MSCs) are multipotential cells capable of regenerating injured tissues. In addition to their multipotency, MSCs inhibit natural killer cell cytotoxicity and T-lymphocyte alloproliferation. Several immunosuppressive mechanisms have been described, including indoleamine 2, 3, -dioxygenase-induced depletion of tryptophan from the lymphocyte environment, and the secretion of prostaglandin E2 and other immunosuppressive factors. Here, we review data supporting a new MSC immunoregulation pathway, in which the key molecule is the human leukocyte antigen-G protein. This nonclassical human leukocyte antigen-class I molecule was initially found on trophoblasts, where it contributes to tolerance at the materno-fetal interface. Because trophoblasts are also able to express indoleamine 2, 3, -dioxygenase and prostaglandin E2, MSC immunomodulatory properties are similar to those of trophoblasts. These mechanisms should be explored in relation to induction of tolerance to alloantigens for the prevention of graft rejection after transplantation.

CKD was associated with premature immune ageing. Each of these alterations increased the risk of specific age-related diseases, such as RTL and death, thymic function and infections and terminally differentiated CD8+ T-cell expansion and CEs.

Some data suggest that cytomegalovirus (CMV) may be involved in atherogenesis. However, there are few data suggesting that CMV may contribute to posttransplantation atherosclerosis. We studied a cohort of 570 consecutive renal transplant recipients. The impact of CMV on atherosclerotic events was analyzed with respect to other known main cardiovascular risk factors. The mean follow-up duration (± SD) was 87 ± 31 months. A total of 357 patients were considered to be CMV exposed, and 213 were considered to be CMV naive. Cox regression analysis revealed that CMV exposure (hazard ratio [HR], 1.80 [95% confidence interval {CI}, 1.06-3.05]; P = .030) was an independent risk factor for atherosclerotic events. A total of 213 patients remained CMV negative during follow-up, 225 CMV-positive patients had no replication after transplantation, and 132 CMV-positive patients experienced CMV replication after transplantation. Atherosclerotic event rates were 8.5%, 13.3%, and 18.2%, respectively (P = .034). Cox regression analysis revealed that patients with posttransplantation CMV replication had an increased risk of atherosclerotic events (HR, 2.06 [95% CI, 1.03-4.15]; P = .042) and death (HR, 1.76 [95% CI, 1.08-2.89]; P = .024). There was also a trend toward an increased risk of atherosclerotic events in CMV-positive patients without posttransplantation replication (HR, 1.62 [95% CI, .91-3.05]; P = .098). Both pretransplantation CMV exposure and posttransplantation CMV replication contribute to the increased risk of cardiovascular disease in transplant recipients.

Previous studies have shown that DNA can be transferred from dying engineered cells to neighboring cells through the phagocytosis of apoptotic bodies, which leads to cellular transformation. Here, we provide evidence of an uptake of apoptotic-derived cervical cancer cells by human mesenchymal cells. Interestingly, HeLa (HPV 18+) or Ca Ski (HPV16+) cells, harboring integrated high-risk HPV DNA but not C-33 A cells (HPV-), were able to transform the recipient cells. Human primary fibroblasts engulfed the apoptotic bodies effectively within 30 minutes after co-cultivation. This mechanism is active and involves the actin cytoskeleton. In situ hybridization of transformed fibroblasts revealed the presence of HPV DNA in the nucleus of a subset of phagocytosing cells. These cells expressed the HPV16/18 E6 gene, which contributes to the disruption of the p53/p21 pathway, and the cells exhibited a tumorigenic phenotype, including an increased proliferation rate, polyploidy and anchorage independence growth. Such horizontal transfer of viral oncogenes to surrounding cells that lack receptors for HPV could facilitate the persistence of the virus, the main risk factor for cervical cancer development. This process might contribute to HPV-associated disease progression in vivo.

International audienc