Angelo Andreini

Role for Interferon‐γ in the Immunomodulatory Activity of Human Bone Marrow Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) inhibit the proliferation of HLA‐unrelated T lymphocytes to allogeneic stimulation, but the mechanisms responsible for this activity are not fully understood. We show here that MSCs suppress the proliferation of both CD4+ and CD8+ T lymphocytes, as well as of natural killer (NK) cells, whereas they do not have an effect on the proliferation of B lymphocytes. The antiproliferative effect of MSCs was not associated with any effect on the expression of cell‐activation markers, induction of cell apoptosis, or mimicry/enhancement of T regulatory cell activity. The suppressive activity of MSCs was not contact‐dependent and required the presence of interferon (IFN)‐γ produced by activated T cells and NK cells. Accordingly, even activated B cells became susceptible to the suppressive activity of MSCs in the presence of exogenously added IFN‐γ. The suppressive effect of IFN‐γ was related to its ability to stimulate the production by MSCs of indoleamine 2,3‐dioxygenase activity, which in turn inhibited the proliferation of activated T or NK cells. These findings suggest that the beneficial effect on graft‐versus‐host disease induced by in vivo coinfusion with the graft of MSCs may be due to the activation of the immunomodulatory properties of MSCs by T cell– derived IFN‐γ.

Predictors of anxiety and depression in hematopoietic stem cell transplant patients during protective isolation.

To examine in a sample of hematopoietic stem cell transplant patients assessed throughout protective isolation (i) levels of anxiety and depression and (ii) pre‐isolation factors (socio‐demographics, biomedical variables and personality traits), which might predict higher levels of anxiety and depression during isolation.

A proliferation-inducing ligand (APRIL) serum levels predict time to first treatment in patients affected by B-cell chronic lymphocytic leukemia.

Purpose:  A proliferation‐inducing ligand (APRIL), a tumor necrosis factor superfamily member involved in B‐lymphocytes differentiation and survival, plays a role in protecting B‐Cell Chronic lymphocytic leukemia (B‐CLL) cells from apoptosis. Having observed that APRIL serum (sAPRIL) levels were higher in B‐CLL patients with CLL at diagnosis as compared to healthy donors (14.61 ± 32.65 vs. 4.19 ± 3.42 ng/mL; P < 0.001), we tested the correlation existing in these patients between sAPRIL, clinical–biological parameters and disease progression. Experimental design: sAPRIL levels were measured by ELISA in 130 patients with B‐CLL at diagnosis and in 25 healthy donors. Results: sAPRIL levels did not correlate with gender, age, clinical stage, blood cell counts, β2‐microglobulin (β2M) levels, ZAP‐70 and CD38 expression. Using median sAPRIL natural logarithm (ln) as cutoff, we distinguished two groups of patients (APRILLOW and APRILHIGH) who were comparable with regard to clinical–biological parameters and overall survival, but different with regard to time to the first treatment (TTFT; P = 0.035). According to univariate analysis, high lymphocyte count, high β2M, Binet stage B–C, ZAP‐70 expression and ln(sAPRIL) above median were associated with earlier TTFT. Advanced clinical stage, high β2M, ZAP‐70 expression and ln(sAPRIL) above median remained independently predictive of shorter TTFT at multivariate analysis. Moreover, sAPRIL increased its prognostic significance when patients were stratified according to independent favorable clinical–biological characteristics (low β2M, stage A and lack of ZAP‐70 expression). Conclusions: sAPRIL is a novel indicator of shorter TTFT in B‐CLL and a predictor of progression especially in patients otherwise considered at low risk according to validated prognostic factors.

The National Institutes of Health criteria for classification and scoring of chronic graft versus host disease: long-term follow-up of a single center series

Abstract We assessed the retrospective applicability and prognostic value of the National Institutes of Health (NIH) classification of chronic graft versus host disease (cGVHD) in 159 consecutive patients after allogeneic hematopoietic stem cell transplant (HSCT). Seventy-four patients (46.5%) were affected by late-acute GVHD (n = 19; 25.7%), classic cGVHD (n = 44; 59.4%) and overlap syndrome (n = 11; 14.9%). Overall, patients with NIH-defined cGVHD (i.e. classic cGVHD and overlap syndrome) had better 10-year overall survival (OS) as compared to patients without GVHD (76.9% vs. 47.4%, p = 0.0002) or with late-acute GVHD (47.4%, p = 0.001). Relapse mortality (RM) was lower in patients with NIH-defined cGVHD than in patients without GVHD (14.5% vs. 38.7%, p = 0.001), but comparable to that of late-acute type (19.4%, p = 0.31). Non-relapse mortality (NRM) was lower in patients with NIH-defined cGVHD as compared to late-acute GVHD (10.0% vs. 41.1%, p = 0.0005), as well as patients without GVHD (22.2%, p = 0.045). At multivariate analysis, NIH-defined cGVHD remained independently predictive for lower RM, but not for NRM. Thus, the new NIH classification identifies two subtypes of GVHD (late-acute and chronic) with different long-term outcomes and impact on RM and NRM.

Chronic graft versus host disease is associated with erectile dysfunction in allogeneic hematopoietic stem cell transplant patients: a single-center experience

Angelo Andreini , Nicola Zampieri , Claudio Costantini, Giovanni Malerba, Costanza Bruno, Gianluca Salvagno, Giuseppe Francia, Michele Gottardi, Michela Rimondini, Isacco Ferrarini, Giuseppe Lippi, Achille Ambrosetti, Fabio Benedetti and Cristina Tecchio Department of Medicine, Section of Hematology and Bone Marrow Transplant Unit, University of Verona, Verona, Italy; Department of Surgery, Pediatrics and Gynecology, Section of Pediatric Surgery, University of Verona, Verona, Italy; Department of Neuroscience, Biomedicine and Movement Science, Section of Biology and Genetics, University of Verona, Verona, Italy; Department of Diagnostics and Public Health, Section of Radiology, University of Verona, Verona, Italy; Department of Neuroscience, Biomedicine and Movement Science, Section of Clinical Biochemistry, University of Verona, Verona, Italy; Department of Medicine, Section of Endocrinology, University of Verona, Verona, Italy; Hematology Unit, Ospedale C a Foncello, Treviso, Italy; Department of Neuroscience, Biomedicine and Movement Science, Section of Clinical Psychology, University of Verona, Verona, Italy

Haploidentical hematopoietic stem cell transplantation in a myelofibrosis patient with primary graft failure

The prognosis of patients affected by myelofibrosis (MF) is usually dismal and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only cure. The number of HSCTs in MF patients has recently increased. However, a major obstacle is still represented by primary graft failure (PGF). Currently there are no definitive guidelines for the treatment of PGF and a second HSCT can be performed only when an allogeneic donor is rapidly available. Herein we report on a MF patient with PGF after an unrelated HSCT, who was rescued by a non-myeloablative, unmanipulated, haploidentical HSCT that resulted in persistent engraftment and bone-marrow fibrosis regression, but not in a long-term disease control. Based on this experience we briefly review the role of different conditioning regimens and hematopoietic stem cell sources in the setting of HSCT for MF patients with PGF. The role of haploidentical donors in MF patients lacking HLAmatched relatives is also discussed.