Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 10(13) genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 10(12) gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.

T regulatory cells (Tregs) play a key role in modulating T cell responses. Clinical trials showed that Tregs modulate graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, their ability to mediate anti-leukemic activity (graft-versus-leukemia [GvL]) is largely unknown. Enforced interleukin-10 (IL-10) expression converts human CD4+ T cells into T regulatory type 1 (Tr1)-like (CD4IL-10) cells that suppress effector T cells in vitro and xenoGvHD in humanized mouse models. In the present study, we show that CD4IL-10 cells mediate anti-leukemic effects in vitro and in vivo in a human leukocyte antigen (HLA) class I-dependent but antigen-independent manner. The cytotoxicity mediated by CD4IL-10 cells is granzyme B (GzB) dependent, is specific for CD13+ target cells, and requires CD54 and CD112 expression on primary leukemic target blasts. CD4IL-10 cells adoptively transferred in humanized mouse models directly mediate anti-tumor and anti-leukemic effects. In addition, when co-transferred with peripheral blood mononuclear cells (PBMCs), CD4IL-10 cells contribute to the GvL activity but suppress xenoGvHD mediated by the PBMCs. These findings provide for the first time a strong rationale for CD4IL-10 cell immunotherapy to prevent GvHD and promote GvL in allo-HSCT for myeloid malignancies.

The dorsal hippocampus is crucial for mammalian spatial memory, but its exact role in item memory is still hotly debated. Recent evidence in humans suggested that the hippocampus might be selectively involved in item short-term memory to deal with an increasing memory load. In this study, we sought to test this hypothesis. To this aim we developed a novel behavioral procedure to study object memory load in mice by progressively increasing the stimulus set size in the spontaneous object recognition task. Using this procedure, we demonstrated that naive mice have a memory span, which is the number of elements they can remember for a short-time interval, of about six objects. Then, we showed that excitotoxic selective lesions of the dorsal hippocampus did not impair novel object discrimination in the condition of low memory load. In contrast, the same lesion impaired novel object discrimination in the high memory load condition, and reduced the object memory span to four objects. These results have important heuristic and clinical implications because they open new perspective toward the understanding of the role of the hippocampus in item memory and in memory span deficits occurring in human pathologies, such as Alzheimer's disease and schizophrenia.[Supplemental material is available for this article.]The dorsal hippocampus-HP (the CA fields, dentate gyrus, and subicular complex) is generally crucial for mammalian memory, but its exact role in memory formation is still hotly debated around a conspicuous number of rival theories. Although, in the early 1980s, Olton and colleagues (Wible et al. 1992;Wan et al. 1994) showed that HP lesions produced an impairment on both spatial and nonspatial memory independently on the retention time interval, converging evidence presented a dichotomous view between spatial and item memory (Brown and Aggleton 2001), and between short-term (STM) and long-term (LTM) memory (Shrager et al. 2008), regarding the role of the HP. Brown and Aggleton (2001) proposed that the HP is essential for associational, multi-item, re-collective aspects of recognition memory, but has little or no involvement for single item recognition, which would be mediated by the perirhinal cortex. Squire and colleagues (Broadbent et al. 2004), in contrast, suggested that the HP is selectively involved in LTM, and not in STM or working memory (WM), independently of the nature of the information.Studies in rodents unequivocally demonstrated that HP lesions impair memory consolidation of newly acquired spatial information, and quite consistently affect spatial STM, thus suggesting that the HP is involved in spatial memory

Disclosure of potential conflicts of interest: M. Arock has patents through CNRS (Centre national de la recherche scientifique) and ENS (Ecole normale sup erieure de Cachan) Cachan for human mast cell lines, preparations, and uses (WO 2013064639 A1). U. Raap has received research support and payment for lectures from Novartis Pharma. K. Hartmann has consultant arrangements with Novartis; has received payment for lectures from Abbvie, Biogen, and Novartis; and has received a research grant from Novartis. The rest of the authors declare that they have no relevant conflicts of interest. Almeida J, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients.