Impact of Antifungal Compounds on Viability and Anti- Activity of Human Natural Killer Cells.

Despite the availability of new antifungal compounds, invasive aspergillosis carries high morbidity and mortality in hematopoietic stem cell transplant recipients. studies and animal models suggest that the adoptive transfer of natural killer (NK) cells might be a promising immunotherapeutic option in this setting. As it is unclear whether the viability and function of human NK cells are affected by common antifungal agents, we analyzed the interaction of various concentrations of amphotericin B deoxycholate (AmB-D), liposomal amphotericin B, caspofungin, fluconazole, voriconazole, and posaconazole with human NK cells.

Natural killer cells as a therapeutic tool for infectious diseases - current status and future perspectives.

Natural Killer (NK) cells are involved in the host immune response against infections due to viral, bacterial and fungal pathogens, all of which are a significant cause of morbidity and mortality in immunocompromised patients. Since the recovery of the immune system has a major impact on the outcome of an infectious complication, there is major interest in strengthening the host response in immunocompromised patients, either by using cytokines or growth factors or by adoptive cellular therapies transfusing immune cells such as granulocytes or pathogen-specific T-cells. To date, relatively little is known about the potential of adoptively transferring NK cells in immunocompromised patients with infectious complications, although the anti-cancer property of NK cells is already being investigated in the clinical setting.

Impact of human mesenchymal stromal cells on antifungal host response against .

Mesenchymal stromal cells (MSCs) are increasingly given as immunotherapy to hematopoietic stem cell transplant (HSCT) recipients with refractory graft-versus-host disease (GvHD). Whereas the immunosuppressive properties of MSCs seem to be beneficial in GvHD, there is, at the same time, major concern that MSCs increase the risk for infection. We therefore investigated the interplay of human MSCs with and the impact of MSCs on different arms of the anti- host response .

Natural Killer Cells in Antifungal Immunity.

Invasive fungal infections are still an important cause of morbidity and mortality in immunocompromised patients such as patients suffering from hematological malignancies or patients undergoing hematopoietic stem cell transplantion. In addition, other populations such as human immunodeficiency virus-patients are at higher risk for invasive fungal infection. Despite the availability of new antifungal compounds and better supportive care measures, the fatality rate of invasive fungal infection remained unacceptably high.

Lack of Effectiveness of Neutropenic Diet and Social Restrictions as Anti-Infective Measures in Children With Acute Myeloid Leukemia: An Analysis of the AML-BFM 2004 Trial.

Purpose: Although nonpharmacologic anti-infective measures are widely used in children treated for acute myeloid leukemia (AML), there is little evidence of their effectiveness.

Patients And Methods: We analyzed infectious complications in children during intensive treatment of AML according to the AML-BFM 2004 trial and surveyed sites on institutional standards regarding recommended restrictions of social contacts (six items), pets (five items), and food (eight items). A scoring system was developed with a restriction score for each item.

Immunotherapeutic strategies against mucormycosis in haematopoietic stem cell transplantation.

Mucormycoses remain a serious complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT). In these patients, mortality rates of mucormycosis reach up to 90%, which is due, at least in part, to the severe and prolonged immunosuppression after transplantation. Although prolonged neutropaenia is one of the most important risk factors for mucormycosis, other cell populations, such as CD4(+) T cells may also provide critical defence mechanisms against this infection.

Immunosuppressive compounds exhibit particular effects on functional properties of human anti-Aspergillus Th1 cells.

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at high risk for invasive aspergillosis. Whereas adoptive immunotherapy transferring donor-derived anti-Aspergillus TH1 cells has been shown to be beneficial for HSCT recipients suffering from invasive aspergillosis, little is known about the impact of commonly used immunosuppressants on the functional properties of anti-Aspergillus TH1 cells. Anti-Aspergillus TH1 cells were coincubated with different concentrations of methylprednisolone, cyclosporine (CsA), mycophenolic acid (MPA), the active component of mycophenolate mofetil, and rapamycin.

Clinical-scale generation of multi-specific anti-fungal T cells targeting Candida, Aspergillus and mucormycetes.

Background Aims: Invasive fungal infections, in particular, infections caused by Candida, Aspergillus and mucormycetes, are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. Adoptive transfer of donor-derived anti-fungal T cells shows promise to restore immunity and to offer a cure. Because T cells recognize only specific epitopes, the low rate of patients in which the causal fungal pathogen can be identified and the considerable number of patients with co-infection with several genera or species of fungi significantly limit the application of adoptive immunotherapy.

Immunotherapy of invasive fungal infection in hematopoietic stem cell transplant recipients.

Despite the availability of new antifungal compounds, invasive fungal infection remains a significant cause of morbidity and mortality in children and adults undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT recipients suffer from a long lasting defect of different arms of the immune system, which increases the risk for and deteriorates the prognosis of invasive fungal infections. In turn, advances in understanding these immune deficits have resulted in promising strategies to enhance or restore critical immune functions in allogeneic HSCT recipients.

Natural killer cells and antifungal host response.

As a result of improved experimental methodologies and a better understanding of the immune system, there is increasing insight into the antifungal activity of natural killer (NK) cells. Murine and human NK cells are able to damage fungi of different genera and species in vitro, and they exert both direct and indirect antifungal activity through cytotoxic molecules such as perforin and through cytokines and interferons, respectively. On the other hand, recent data suggest that fungi exhibit immunosuppressive effects on NK cells.

Immunotherapy in invasive fungal infection--focus on invasive aspergillosis.

Despite the availability of new antifungal compounds, morbidity and mortality of invasive aspergillosis are still unacceptably high, in particular in immunocompromised patients such as patients with hematological malignancies or allogeneic hematopoietic stem cell or solid organ transplant recipients. Over the last decades, our knowledge of the immunopathogenesis of invasive aspergillosis has greatly advanced. This, in turn, provided critical information to augment host immunity against fungal pathogens.

Rhizopus oryzae hyphae are damaged by human natural killer (NK) cells, but suppress NK cell mediated immunity.

Mucormycosis has a high mortality and is increasingly diagnosed in hematopoietic stem cell transplant (HSCT) recipients. In this setting, there is a growing interest to restore host defense to combat infections by adoptively transferring donor-derived immunocompetent cells. Natural killer (NK) cells exhibit antitumor and antiinfective activity, but the interaction with Mucormycetes is unknown.

Characterization of the cellular immune responses to Rhizopus oryzae with potential impact on immunotherapeutic strategies in hematopoietic stem cell transplantation.

Infections due to mucormycetes have a poor outcome, in particular in allogeneic hematopoietic stem cell transplantation (HSCT). In order to evaluate the cellular host response against mucormycetes, we enriched and cultivated anti-Rhizopus oryzae T cells from healthy individuals. These cells were characterized as memory/effector T(H)1 cells, they proliferated upon restimulation, they exhibited cross-reactivity to some but not all Mucorales species tested, and they increased the activity of phagocytes.

Immunotherapy against invasive fungal diseases in stem cell transplant recipients.

Despite the availability of new antifungal compounds, morbidity and mortality of invasive fungal disease in allogeneic hematopoietic stem cell recipients are still unacceptably high. Over the past decade, one could witness an exciting improvement of the understanding of the molecular pathogenesis and of the complexity of host antifungal immune responses. This, in turn, provides critical information to augment host immunity against fungal pathogens.

Challenges and prospects of adoptive immunotherapy in prevention and treatment of opportunistic mycoses in hematologic transplant recipients.

Invasive fungal infections remain a serious and life-threatening complication in patients undergoing hematopoietic stem cell transplantation. Since it became clear that lymphocytes, in particular lymphocytes from the T helper 1 (T(H)1) subset, play a critical secondary defense against fungal pathogens, the adoptive transfer of functionally active antifungal T(H)1 cells might be an attractive option to restore adaptive antifungal immune effector mechanisms. Major advances have been made in the generation and characterization of antifungal T cells, which are active against medical important fungi such as Aspergillus spp and Candida spp.

Human natural killer cells exhibit direct activity against Aspergillus fumigatus hyphae, but not against resting conidia.

Because natural killer (NK) cells kill tumor cells and combat infections, there is growing interest in adoptively transferring NK cells to hematopoietic stem cell recipients. Unfortunately, in humans, the activity of NK cells against Aspergillus species, the major cause of invasive fungal infection in stem cell recipients, are poorly characterized. Our results show that unstimulated and interleukin-2 prestimulated human NK cells kill Aspergillus fumigatus hyphae but do not affect resting conidia.

Adoptive antifungal T cell immunotherapy--into the clinic?

The morbidity and mortality rates of invasive fungal infection in allogeneic stem cell recipients are still unacceptably high and have not been significantly improved by alternative antifungal strategies to date. Over the last few years, rapid methods for the clinical-scale generation of functionally active and well characterized antifungal T(H)1 cells have become available. In addition, current data on the use of donor-derived virus-specific T cells in allogeneic stem cell transplantation suggest that the risk of severe adverse events, in particular the risk of graft-versus-host disease, is negligible.

IL-2-driven regulation of NK cell receptors with regard to the distribution of CD16+ and CD16- subpopulations and in vivo influence after haploidentical NK cell infusion.

To characterize natural killer (NK) cell subpopulations during activation, we analyzed the NK cell receptor repertoire and functionality of purified clinical scale CD56CD3 donor NK cells during stimulation with 1000 U/mL interleukin (IL)-2 for up to 14 days. In a phase I/II trial, we investigated the efficacy and feasibility of nonidentical NK cell infusion in patients with neuroblastoma after haploidentical stem cell transplantation. After IL-2 stimulation, large differences in the distribution of CD16 and CD16 subpopulations were found in 12 donors.

Cultivated anti-Aspergillus T(H)1 cells.

Invasive aspergillosis remains a serious complication in patients undergoing allogeneic stem cell transplantation. Since it became clear that lymphocytes provide a critical secondary defense against fungi, adoptive transfer of functionally active anti-Aspergillus T cells might be an option to restore adaptive immune effector mechanisms. Using the interferon (IFN)-gamma secretion assay, we isolated human activated T cells upon stimulation with a cellular extract of Aspergillus fumigatus.

Enumeration of functionally active anti-Aspergillus T-cells in human peripheral blood.

Invasive aspergillosis remains a life-threatening complication in patients undergoing allogeneic stem cell transplantation (SCT). Since CD4(+) T-cells provide a critical secondary defense against Aspergillus spp., the quantification of "functional" anti-Aspergillus T-cells might be important in the clinical care of allogeneic transplant patients.

Changes in host defence induced by malignancies and antineoplastic treatment: implication for immunotherapeutic strategies.

Changes of the immune system can be a consequence of an underlying malignancy or induced by antineoplastic treatment. Both influence the risk for infectious complications and relapse. Over the past decade, there have been a series of major developments in the laboratory assessment of immune dysfunction, particularly as it relates to the complex interactions of the distinct components of the immune system.

Age-matched lymphocyte subpopulation reference values in childhood and adolescence: application of exponential regression analysis.

Background: Normal values of lymphocyte subpopulations for healthy children and adults have been published in defined age groups exclusively, which results in difficult data interpretation for patients close to the limit of contiguous age group ranges. In addition, normal values for a number of lymphocyte subpopulations have not been established to date.

Objective: The aim of this study was to develop a model which provides continuous age-dependent reference values.

Generation and characterization of anti-Candida T cells as potential immunotherapy in patients with Candida infection after allogeneic hematopoietic stem-cell transplant.

Because lymphocytes play a major role in the host response to Candida infection, adoptive transfer of anti-Candida T cells might be a therapeutic option in patients undergoing allogeneic hematopoietic stem-cell transplant (alloHSCT) who have invasive Candida infection. Using the interferon (IFN)- gamma secretion assay, we isolated human anti-Candida T cells after stimulation with a cellular extract of C. albicans.