Maria Theresa Krauth

Allergen-specific immunotherapy with a monophosphoryl lipid A-adjuvanted vaccine: reduced seasonally boosted immunoglobulin E production and inhibition of basophil histamine release by therapy-induced blocking antibodies.

Background Allergen‐specific immunotherapy represents a causal form of treatment for IgE‐mediated allergies. The allergen extract‐based analyses of immunotherapy‐induced effects yielded highly controversial results regarding a beneficial role of therapy‐induced IgG antibodies.

Expression of the target receptor CD33 in CD34+/CD38-/CD123+ AML stem cells.

Background  CD33 (Siglec‐3) is becoming increasingly important as a target of antibody‐mediated therapy in acute myeloid leukaemia (AML). In normal myelopoiesis, expression of CD33 is restricted to advanced stages of differentiation, whereas primitive stem cells do not express CD33. In the present study, we asked whether leukaemic stem cells in patients with AML express CD33.

Identification of mTOR as a novel bifunctional target in chronic myeloid leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells

The mammalian target of rapamycin (mTOR) has recently been described to be constitutively activated in Bcr‐Abl‐transformed cells and to mediate rapamycin‐induced inhibition of growth in respective cell lines. We have recently shown that rapamycin down‐regulates expression of vascular endothelial growth factor (VEGF), a mediator of leukemia‐associated angiogenesis, in primary CML cells. In the present study, we analyzed growth‐inhibitory in vitro and in vivo effects of rapamycin on primary CML cells and asked whether rapamycin‐induced suppression of VEGF in leukemic cells is related to growth inhibition. Rapamycin dose dependently inhibited growth of primary CML cells obtained from patients with imatinib‐responsive or imatinib‐resistant disease as well as growth of Bcr‐Abl‐transformed imatinib‐resistant cell lines. Moreover, we observed potent cytoreductive effects of rapamycin in a patient with imatinib‐resistant Bcr‐Abl+ leukemia. The growth‐inhibitory effects of rapamycin on CML cells were found to be associated with G1 cell cycle arrest and with induction of apoptosis. In all cell types tested, rapamycin was found to down‐regulate expression of VEGF. However, exogenously added VEGF did not counteract the rapamycin‐induced decrease in proliferation. In conclusion, rapamycin inhibits growth of CML cells in vitro and in vivo and, in addition, down‐regulates expression of VEGF. Both effects may contribute to the antileukemic activity of the drug in CML.

Characterization of Der p 21, a new important allergen derived from the gut of house dust mites.

Background:  The house dust mite (HDM) Dermatophagoides pteronyssinus is a major allergen source eliciting allergic asthma. The aim of the study was to identify new important HDM allergens associated with allergic asthma.

On the way to targeted therapy of mast cell neoplasms: identification of molecular targets in neoplastic mast cells and evaluation of arising treatment concepts

Several emerging treatment concepts for myeloid neoplasms are based on novel drugs targeting cell surface antigens, signalling pathways, or critical effector molecules. Systemic mastocytosis is a haematopoietic neoplasm that behaves as an indolent myeloproliferative disease in most patients, but can also present as aggressive disease or even as an acute leukaemia. In patients with aggressive disease or mast cell leukaemia, the response to conventional therapy is poor in most cases, and the prognosis is grave. Therefore, a number of attempts have been made to define novel treatment strategies for these patients. One promising approach may be to identify novel targets and to develop targeted drug therapies. In this article, we support the notion that neoplastic mast cells indeed express a number of potential molecular targets including immunoreactive CD antigens, the microphthalmia transcription factor (MITF), and members of the Bcl‐2 family. In addition, the tyrosine kinase receptor KIT and downstream signalling pathways have been proposed as targets of a specific pharmacological intervention. A particular challenge is the disease‐related D816V‐mutated variant of KIT, which is resistant against diverse tyrosine kinase inhibitors including STI571, but may be sensitive to more recently developed targeted compounds. The therapeutic potential of target‐specific approaches in malignant mast cell disorders should be evaluated in forthcoming clinical trials in the near future.

Midostaurin (PKC412) inhibits immunoglobulin E-dependent activation and mediator release in human blood basophils and mast cells

Background KIT tyrosine kinase inhibitors (TKI), such as nilotinib or midostaurin (PKC412), are increasingly used in clinical trials to counteract neoplastic cell growth in patients with aggressive mast cell (MC) disorders. However, these patients suffer not only from MC infiltration and consecutive organ damage but also from MC mediator‐related symptoms.

Detection of differentiation- and activation-linked cell surface antigens on cultured mast cell progenitors.

Background:  Mast cells (MC) are multifunctional effector cells of the immune system. They derive from uncommitted CD34+ hemopoietic progenitor cells (HPC). Depending on the stage of maturation and the environment, MC variably express differentiation‐ and activation‐linked antigens. Little is known, however, about the regulation of expression of such antigens in immature human MC.

Effects of various statins on cytokine-dependent growth and IgE-dependent release of histamine in human mast cells

Background:  Statins are inhibitors of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase, a key enzyme in mevalonic acid (MVA)‐dependent signaling. Recent data suggest that statins exhibit profound inhibitory effects on growth and function of various immune cells. In the present study, we examined the in vitro effects of five different statins on primary human mast cells (MCs), MC progenitors, and the human MC line HMC‐1.

Targeting of mTOR is associated with decreased growth and decreased VEGF expression in acute myeloid leukaemia cells.

Background  The mammalian target of rapamycin (mTOR) has recently been implicated in leukaemic cell growth, tumour‐associated angiogenesis and expression of vascular endothelial growth factor (VEGF). We examined whether mTOR plays a role as regulator of growth and VEGF‐expression in acute myeloid leukaemia (AML). Three mTOR‐targeting drugs, rapamycin, everolimus (RAD001) and CCI‐779, were applied. The effects of these drugs on growth, survival, apoptosis and VEGF expression in primary AML cells and various AML cell lines were examined.

Targeting of Hsp32 in solid tumors and leukemias: a novel approach to optimize anticancer therapy.

Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related anti-apoptotic molecule, that has been implicated in enhanced survival of neoplastic cells and in drug-resistance. We here show that Hsp32 is expressed in most solid tumors and hematopoietic neoplasms and may be employed as a new therapeutic target as evidenced by experiments using specific siRNA and a Hsp32-targeting pharmacologic inhibitor. This Hsp-32 targeting drug, SMA-ZnPP, was found to inhibit the proliferation of neoplastic cells with IC(50) values ranging between 1 and 50 microM. In addition, SMA-ZnPP induced apoptosis in all neoplastic cells examined. Furthermore, SMA-ZnPP was found to synergize with other targeted and conventional drugs in producing growth-inhibition. Resulting synergistic effects were observed in all tumor and leukemia cells examined. Interestingly, several of the drug partners, when applied as single agents, induced the expression of Hsp32 in neoplastic cells, suggesting that synergistic effects resulted from SMA-ZnPP-induced ablation of a Hsp32-mediated survival-pathway that is otherwise used by tumor cells to escape drug-induced apoptosis. Together, Hsp32 is an important survival factor and target in solid tumors and hematopoietic neoplasms, and may be used to optimize anticancer therapy by combining conventional or targeted drugs with Hsp32-inhibitors. Based on these data, it seems desirable to explore the value of Hsp32-targeting drugs as anti-cancer agents in clinical trials.