Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease--friends or foes?

Mesenchymal stromal cells (MSCs) are multipotent cells, which exhibit broad immunosuppressive activities. Moreover, they may be administered irrespectively of human leukocyte antigen (HLA) compatibility, without inducing life-threatening immunological reactions, as they express no HLA class II and limited HLA class I antigens under resting conditions. These characteristics have made MSC an appealing candidate for cell therapy after hematopoietic stem cell transplantation (HSCT), for example, for treatment of graft-versus-host disease (GvHD) or for graft rejection prevention/treatment in allogeneic HSCT recipients. Unfortunately, information regarding the effect of MSC infusion on the host response to infectious agents is scarce, and study results on infectious complications in patients receiving MSC are conflicting. The present review focuses on the available data from in vitro studies and animal models regarding the interaction of MSC with bacterial, viral and fungal pathogens. In a clinical part, we present the current information on infectious complications in allogeneic HSCT recipients who had received MSCs as prophylaxis or treatment of GvHD disease.

No effect of antifungal compounds on functional properties of human antifungal T-helper type 1 cells.

Despite the availability of new antifungal compounds, invasive fungal disease is associated with a high mortality in hematopoietic stem cell transplant (HSCT) recipients. A growing body of evidence suggests that T lymphocytes from the T-helper type 1 (TH 1) play an important role in the antifungal host defense, and preliminary data indicate a potential benefit of infusing donor-derived antifungal TH 1 cells to HSCT patients suffering from invasive fungal disease. Unfortunately, it is unclear to date whether the function of these cells is affected by concomitantly administered antifungal agents. We therefore analyzed the effects of various concentrations of commonly used antifungal compounds such as amphotericin B, caspofungin, fluconazole, voriconazole, and posaconazole on the functional properties of cultivated human antifungal TH 1 cells. None of the antifungal compounds tested significantly influenced the secretion of interferon-γ and tumor necrosis factor-α, and only posaconazole at high concentrations slightly decreased proliferation of antifungal TH 1 cells. Our data indicate that the antifungal agents tested do not significantly affect the functional properties of antifungal TH 1 cells and can therefore be concomitantly administered.

Liposomal amphotericin B twice weekly as antifungal prophylaxis in paediatric haematological malignancy patients.

Data on antifungal prophylaxis in paediatric cancer patients at high risk for invasive fungal disease (IFD) are scant. Intermittent administration of liposomal amphotericin B (LAMB) has been shown to be safe and effective in adult patients with haematological malignancies. We prospectively evaluated the safety and efficacy of prophylactic LAMB at a dosage of 2.5 mg/kg twice weekly in children at high risk for IFD. Efficacy was compared with that in a historical control group of patients with similar demographic characteristics not receiving LAMB prophylaxis. A total of 46 high-risk patients (24 boys; mean age, 7.7 years) with 187 episodes of antifungal prophylaxis were analysed. The median duration of neutropenia (<500/µL) was 10 days. LAMB was discontinued in four patients because of acute allergic reactions. Median values for creatinine and liver enzymes at end of treatment did not differ significantly from those at baseline. Hypokalaemia (<3.0 mmol/L) occurred with 13.5% of the prophylactic episodes, but was usually mild and always reversible. No proven/probable IFD occurred in patients receiving LAMB prophylaxis. In comparison, five proven and two probable IFDs were observed in 45 historical controls not receiving LAMB prophylaxis (p 0.01). LAMB prophylaxis had no impact on the use of empirical antifungal therapy. Systemic antifungal prophylaxis with LAMB 2.5 mg/kg twice weekly is feasible and safe, and seems to be an effective approach for antifungal prophylaxis in high-risk paediatric cancer patients.

Clinical-scale generation of human anti-Aspergillus T cells for adoptive immunotherapy.

Invasive aspergillosis is a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic SCT. There is a growing body of evidence that T cells are important in the host defense against Aspergillus, and adoptively transferred anti-Aspergillus T-helper 1 (T(H)) 1 cells might reduce infectious mortality in hematopoietic transplant recipients. Here we present for the first time a simple and rapid method for the clinical-scale generation of functionally active anti-Aspergillus T cells according to good manufacturing practice conditions. A total of 1.1 x 10(9) WBCs derived from a leukapheresis product were incubated with Aspergillus antigens. Stimulated cells were selected by means of the IFN-gamma secretion assay and expanded. In three independent experiments, a median number of 2 x 10(7) CD3+CD4+cells (range, 0.9-3.2 x 10(7)) were obtained within 13 days. The cultured CD3+CD4+ cells exhibited almost exclusively a memory activated T-helper cell phenotype. Upon restimulation, the generated T cells produced IFN-gamma, but no IL-4 or IL-10, indicating a T(H)1-cell population. Additionally, the cells proliferated upon restimulation and showed reduced alloreactivity compared to unselected CD4+ cells. This method of generating is suitable for future prospective trials designed to evaluate the effect of adoptive immunotherapy in hematopoietic transplant recipients with invasive aspergillosis.

Piperacillin-tazobactam in pediatric cancer patients younger than 25 months: a retrospective multicenter survey.

Piperacillin-Tazobactam (Pip-Taz) is an evidence-based empirical treatment of febrile neutropenia in adolescents and adults. No data are available in pediatric cancer patients <25 months of age. In this retrospective, multicenter data survey, the analysis focuses on safety, tolerance, and efficacy. The daily dose administered was 240 mg/kg given in three equally divided doses. Data on 156 Pip-Taz treatment courses in 69 children <25 months from five pediatric cancer treatment centers (2001-2005) were analyzed. The median duration of treatment with Pip-Taz was 5 days (range, 1-23 days; 1-12 Pip-Taz courses per patient). Pip-Taz was started on the first day of fever in 90% of all courses, in 6% in the first 72 h, and in 4% as second- or third-line agent. Forty-five percent of all patients were neutropenic. In all patients, the outcome was favorable independent whether Pip-Taz was given as monotherapy (42 courses; 27%) or in combination. Overall, Pip-Taz was well tolerated and discontinued due to adverse events in only two patients who experienced non-life-threatening allergic reactions (skin rash and wheezing). The results of this study are preliminary due to the methodological limitations of a retrospective survey. Taking this bias into consideration, Pip-Taz appears to be a safe, and feasible alternative in pediatric cancer patients with febrile neutropenia <25 months of age suggesting that the inclusion of children of all age groups in future prospective controlled studies evaluating Pip-Taz is justified.