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The functional properties of myeloid dendritic cells (DCs) differ, depending on microenvironmental factors as well as on their stage of maturation. The main approaches for the selective enhancement of the tolerogenic properties of DCs include the induction of a pharmacological arrest of the DCs maturation and the genetical engineering of DCs expressing immunosuppressive molecules. Several immunosuppressive/anti-inflammatory agents have been discovered that potentially inhibit DC maturation and immunogenicity. Photopheresis (ECP) is an immunomodulatory therapy in which leucocytes are exposed to 8-methoxypsoralen (8-MOP) and ultraviolet (UV) A radiation (PUVA). The combination of ECP with immunosuppressive agents has demonstrated efficacy in the management of transplanted patients by reducing either the incidence of organ rejection or the pharmacological toxicity. In particular, we have observed in hepatitis C virus (HCV)-positive patients that the same combination has reduced the immunosuppressive burden and improved sustainability and efficacy of pre-emptive antiviral therapy after liver transplantation. Therefore, in our work we investigated the in vitroeffects of PUVA, combined with immunosuppressive drugs (IDs), on both in vitrohuman DC generation and maturation, in order to contribute to understanding the immunological mechanisms underlying this pharmacological combination. Monocyte PUVA-treatment was performed by using an in vitroexperimental protocol that we previously described. PUVA-treated or -untreated highly purified CD14+ cells were incubated with the association of the immunosuppressive drugs, used in the management of liver transplantation, at two different concentrations, in the presence of IL-4 and GM-CSF. The treatment with IDs at the highest concentration (corresponding to that used in clinical practice), alone or in association with PUVA, induced an immunosuppressive effect, by impairing both DC generation and maturation. Neither immunosuppressive drugs at the lowest concentration nor their combination with PUVA affected myeloid DC generation, but modified DC functions, strengthening the induction of a tolerogenic pattern. As this ID concentration was arbitrarily chosen, further experiments could highlight whether lower concentrations than those used in clinical practice would elicit the same effect on DCs and potentially improve their functional properties. This work describes an original experimental approach exploring the in vitromechanism of action of the combined procedure of PUVA with immunosuppressive drugs, used in liver transplantation, on DCs generation and function. Our results contribute to the knowledge of the mechanisms of action of this combined procedure on DCs, suggesting useful therapeutic implications for the in vivotherapy.

Transient hypogammaglobulinemia of infancy (THI) is a heterogenous disorder characterized by reduced serum IgG levels in early infancy. A putative diagnosis is initially made after exclusion of other causes of hypogammaglobulinemia while a definitive diagnosis of THI can only be made a posterioriin patients with normalization of IgG levels. The aim of this study is to characterize clinical and immunological features of children with an initial diagnosis of THI in correlation to natural outcome, and to assess predictive laboratory parameters of clinical evolution for this disorder. We prospectively analysed clinical and immunological characteristics of 77 THI children at initial diagnosis and of 57 patients at follow-up. Memory B cell subsets and in vitroimmunoglobulin production were evaluated. Seventy patients (91%) showed clinical symptoms. Patients suffered from infections (91%), allergies (47%) and autoimmune disease (4%). During follow-up 41/57 children (72%) normalized IgG values, mostly within 24 months of age (p<0.001), allowing the diagnosis of THI. The 16 children who did not normalize their IgG levels showed a higher frequency of severe infections and autoimmune disease (p<0.01). Moreover, they expressed a reduced frequency of IgM and switched memory B cells (p<0.01) and an inability to produce IgG in vitro(p<0.02). We conclude that most patients with an initial diagnosis of THI spontaneously recover within 24 months of age and have a benign clinical course, while a subgroup of children with undefined hypogammaglobulinemia share a clinical and immunological profile with other primary immunodeficiencies. Early recognition of children with hypogammaglobulinemia during infancy who are likely to suffer from permanent immunodeficiencies later in life would allow prompt and appropriate laboratory and clinical interventions.

The c-kit receptor (CD117) and its ligand stem cell factor (SCF) play an important role in the development, differentiation, and survival of normal and malignant hematopoietic cells. The aim of this work is to review the cellular distribution of this receptor and the effect of SCF on the hematopoietic system, particularly among lymphoid lineage, either in normal or malignant cell progenitors. We examined reports and results in the field and articles or abstracts published in journals covered by MEDLINE. Additionally, we evaluated CD117 expression on fresh blast cells of 376 newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL) that were referred to centers affiliated with the Italian Association for Pediatric Hematology and Oncology (AIEOP). In view of our data, approximately 11% of ALL are CD117 positive. In particular, this receptor can be expressed in 10% and 11.5% of T-lineage and B-lineage ALL, respectively. Its expression is associated with an intermediate/mature phenotype in T-lineage ALL, whereas in B-lineage ALL, the majority of the positive cases are classified as early B ALL. The effect of SCF on malignant hematopoiesis and its potential clinical uses are reviewed.

Cytochemical and immunologic analysis of cells obtained from two patients with chronic myeloid leukemia (CML) during blast crisis reveals markers suggestive of an immature lymphoid phenotype. Peripheral blood mononuclear cells from both patients generated spontaneous lymphoblastoid colonies in methylcellulose, a phenomenon observed in T cell acute lymphoblastic leukemias and T cell non- Hodgkin's lymphomas but not in any other type of leukemia. Colonies derived from one patient were composed predominantly of OKT3+ cells (89%), whereas those from the second patient displayed 42% OKT3+ and OKT6+ cells. In the second patient's colonies, each of five mitoses contained the Philadelphia chromosome (Ph1) and two of five displayed the same additional karyotypic abnormalities as the blast crisis cells. Cells obtained from the two patients during remission still gave rise to spontaneous T cell colonies (greater than 85% OKT3+) and Ph1 was detected in 33% and 60% of the metaphases, respectively. However, when colony growth was induced by an interleukin 2-containing conditioned medium, less than 5% of mitoses were Ph1-positive. These data suggest that: (1) the T cell lineage might be involved in CML; (2) a subset of T cells may remain unaffected by the leukemic process, as demonstrated by the virtual absence of Ph1 in induced T cell colonies; and (3) the spontaneous colony assay seems to select for the growth of malignant T cells.

The rarity of acute lymphoblastic leukemia in association with hypereosinophilia justifies the communication of this new case; as the eosinophilia preceded the diagnosis, our case emphasizes observation and checking them regularly.

An in vitro B cell colony assay system was used to evaluate B cell growth from peripheral blood precursors in common acute lymphoblastic leukemia (CALL) patients in remission during maintenance therapy and in normal controls. Major differences between the two groups were found in the phenotypic and morphologic features of pooled colony cells. In both cases, the cells were E-. Controls' cells were surface immunoglobulin (sIg)-positive, and some (mean, 25%) expressed la determinants. By Wright-Giemsa staining, they appeared as plasmacytoid cells. In contrast, patients' cells had predominantly a lymphoblastoid appearance, fewer cells had developed sIg, and a large fraction (mean, 43%) were Ia-positive. Moreover, the CALL antigen (CALLA) was expressed by a mean of 18% (range, 2% to 72%) of the patients' colony cells, whereas CALLA was never found in control colonies. Thus, cells with immature features persist in the colonies of CALL patients. Secondary colonies could be generated from the patients' cultured cells, indicating their self-renewal capacity. CALLA + cells were also present in the secondary colonies. Finally, cytogenetic studies showed that a fraction of the patients' colony cells had karyotypic abnormalities similar to that of the original lymphoblasts. It is believed that in CALL patients this B cell assay permits the clonal expansion of residual circulating cells linked to malignant clones that are not detectable by classic hematologic and cytologic methods.

In this study we evaluated whether isolated human (HI), porcine (PI) and bovine (BI) islets, either fresh (Fr) or cultured for 4 weeks (4w) affect cytokine release from human lymphomononuclear cells (LMC) differently. We prepared LMC from peripheral blood by density gradient purification and co-cultured 1×106 LMC for 24 h with 100 hand-picked islets, either within 48 h of isolation or after culture for 4 weeks. Soluble interleukin-2 receptor (IL-2R), interferon-gamma (IFN), interleukin-4 (IL-4) and interleukin-10 (IL-10) were measured by sandwich enzyme-linked immunoadsorbent assay. Compared with controls (Ctrl, LMC without islets), Fr-HI, Fr-PI and Fr-BI caused a similar increase of IL-2R and IFN release, whereas 4w-HI and 4w-BI did not lead to any significant production of these two cytokines. IL-10 concentrations increased with Fr-PI and Fr-BI, but not with Fr-HI, and no major effect of the 4-week culture was seen. IL-4 levels were below the detection limit of the method used in these experiments. Thus, fresh allo- and xeno-islets caused a similar increase of the release of cytokines known to be markers of Th1 activation, whereas the release of IL-10, a marker of Th2 activation, increased with xeno-, but not with allo-islets; culturing the islets for 4 weeks decreased Th1, but not Th2 activation.

This document provides information about a clinical trial for the treatment of acute immune thrombocytopenic purpura (ITP) in children. The trial aims to enroll 102 participants between the ages of 1 and 18 and will focus on patients who have been diagnosed with acute ITP based on clinical manifestations and laboratory investigations. The trial will investigate the use of corticosteroids, specifically methylprednisolone therapy, in the treatment of ITP in children. The primary contact for the study is Shereen Hassan Abd-Elrady, and the principal investigator is Azza Ahmed El-Tayab. [Extracted from the article]

Byline: Bian. Shi, Junfeng. Chu, Qilong. Gao, Tongde. Tian Aims: Several studies suggested that promoter methylation of human mutL homolog 1 (hMLH1) was associated with the risk of colorectal cancer [...]