Selection and immunomagnetic purging of peripheral blood CD34+ cells for autologous transplantation in B-cell non-Hodgkin's lymphomas

Background: Clonogenic tumor cells in the hematopoietic progenitor cell harvest may contribute to relapse after high dose therapy for B-cell malignancies. Purging of the HPC harvest requires large amounts of anti-B-cell antibodies, whereas CD34-selection enriches self renewing HPC's but malignant cells are still detectable in many CD34+ fractions. Patients and methods: We examined the feasability and safety of a CD34-selection followed by purging with anti-B-cell antibodies in 11 patients with B-cell non-Hodgkin's lymphomas undergoing high-dose therapy with cyclophospha-mide, BCNU and etoposide with retransfusion of autologous HPC's. Results: A mean number of 340 × 108 mononuclear cells was used for CD34-selection and immunomagnetic purging. CD34+ cells were enriched from a mean of 1.7% (range 0.2%-4.5%) to a mean of 68% (range 49%-87%) with a mean recovery of 27% (range 15%-43%). The mean number of retransfused CD34+ cells was 1.2× 106/kg (range 0.6-2.2 ×106/kg) body weight with a median of 11 days (range 10-13 days) to neutrophil recovery of 0.5×109/1 and 17 days (range 13-25 days) to platelet recovery of 50 × 109/1. Mean number of intravenous antibiotics and inpatient days were 8 (range 0-14) and 22 (range 19-26) respectively. Major toxicity consisted in four septicemias. Conclusions: CD34-selected and purged HPC's are safe and mediate rapid hematological recovery after high dose therapy for B-cell non-Hodgkin's lymphoma

Nippostrongylus brasiliensis infection leads to the development of emphysema associated with the induction of alternatively activated macrophages

Chronic obstructive pulmonary disease (COPD) is the 5(th) most prevalent disease worldwide leading to severe morbidity and mortality in developed countries. The disease is strongly associated with smoking, and can be characterized by progressive and irreversible deterioration in lung function and destruction of the lung parenchyma. We show here that infection with the hookworm Nippostrongylus brasiliensis results in deterioration in lung function, destruction of alveoli and long-term airways hyperresponsiveness, consistent with COPD and emphysema. N. brasiliensis infection leads to chronic low level hemorrhaging in the lung and the presence of hemosiderin-laden macrophages in the absence of an overt inflammatory infiltrate. Microarray analysis of gene expression in diseased lungs and quantitative RT-PCR analysis of purified macrophages revealed a state of prolonged tissue injury and the presence of alternatively activated macrophages producing MMP-12. Taken together, these data show that lung tissue damage caused by hookworm infection can result in the development of COPD and emphysema

Noise Induced Coherence in Neural Networks

We investigate numerically the dynamics of large networks of $N$ globally pulse-coupled integrate and fire neurons in a noise-induced synchronized state. The powerspectrum of an individual element within the network is shown to exhibit in the thermodynamic limit ($N\to \infty$) a broadband peak and an additional delta-function peak that is absent from the powerspectrum of an isolated element. The powerspectrum of the mean output signal only exhibits the delta-function peak. These results are explained analytically in an exactly soluble oscillator model with global phase coupling.Comment: 4 pages ReVTeX and 3 postscript figure

T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17

Experimental autoimmune myocarditis (EAM) appears after infectious heart disease, the most common cause of dilated cardiomyopathy in humans. Here we report that mice lacking T-bet, a T-box transcription factor required for T helper (Th)1 cell differentiation and interferon (IFN)-γ production, develop severe autoimmune heart disease compared to T-bet−/− control mice. Experiments in T-bet−/− IL-4−/− and T-bet−/− IL-4Rα−/− mice, as well as transfer of heart-specific Th1 and Th2 cell lines, showed that autoimmune heart disease develops independently of Th1 or Th2 polarization. Analysis of T-bet−/− IL-12Rβ1−/− and T-bet−/− IL-12p35−/− mice then identified interleukin (IL)-23 as critical for EAM pathogenesis. In addition, T-bet−/− mice showed a marked increase in production of the IL-23–dependent cytokine IL-17 by heart-infiltrating lymphocytes, and in vivo IL-17 depletion markedly reduced EAM severity in T-bet−/− mice. Heart-infiltrating T-bet−/− CD8+ but not CD8− T cells secrete IFN-γ, which inhibits IL-17 production and protects against severe EAM. In contrast, T-bet−/− CD8+ lymphocytes completely lost their capacity to release IFN-γ within the heart. Collectively, these data show that severe IL-17–mediated EAM can develop in the absence of T-bet, and that T-bet can regulate autoimmunity via the control of nonspecific CD8+ T cell bystander functions in the inflamed target organ

IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo

Interleukin 21 (IL-21) is a member of the common gamma-chain family of cytokines, which influence a broad spectrum of immunologic responses. A number of studies have examined the function of IL-21, but its specific role in Th1/Th2-cell differentiation and related effector responses remains to be clarified. Thus, we generated IL-21R-deficient mice and have investigated the role of IL-21R signaling using a series of in vivo experimentally induced disease models. We first addressed the role of IL-21R signaling in Th2 immune responses by examining allergic airway inflammation, and Nippostrongylus brasiliensis and Heligmosomoides polygyrus antihelminth responses. In each of these systems, IL-21R signaling played a clear role in the development of Th2 responses. Comparatively, IL-21R signaling was not required for the containment of Leishmania major infection or the development of experimental autoimmune myocarditis, indicative of competent Th1 and Th17 responses, respectively. Adoptive transfer of T cells and analysis of IL-21R+/+/IL-21R-/- chimera mice revealed that IL-21R-signaling was central to Th2-cell survival or migration to peripheral tissues. Overall, our data show IL-21 plays a crucial role in supporting polarized Th2 responses in vivo, while appearing superfluous for Th1 and Th17 responses

Activation of Dendritic Cells through the Interleukin 1 Receptor 1 Is Critical for the Induction of Autoimmune Myocarditis

Dilated cardiomyopathy, resulting from myocarditis, is the most common cause of heart failure in young patients. We here show that interleukin (IL)-1 receptor type 1–deficient (IL-1R1−/−) mice are protected from development of autoimmune myocarditis after immunization with α-myosin-peptide(614–629). CD4+ T cells from immunized IL-1R1−/− mice proliferated poorly and failed to transfer disease after injection into naive severe combined immunodeficiency (SCID) mice. In vitro stimulation experiments suggested that the function of IL-1R1−/−CD4+ T cells was not intrinsically defect, but their activation by dendritic cells was impaired in IL-1R1−/− mice. Accordingly, production of tumor necrosis factor (TNF)-α, IL-1, IL-6, and IL-12p70 was reduced in dendritic cells lacking the IL-1 receptor type 1. In fact, injection of immature, antigen-loaded IL-1R1+/+ but not IL-1R1−/− dendritic cells into IL-1R1−/− mice fully restored disease susceptibility by rendering IL-1R1−/− CD4+ T cells pathogenic. Thus, IL-1R1 triggering is required for efficient activation of dendritic cells, which is in turn a prerequisite for induction of autoreactive CD4+ T cells and autoimmunity

Selection and immunomagnetic purging of peripheral blood CD34+ cells for autologous transplantation in B-cell non-Hodgkin's lymphomas

Background: Clonogenic tumor cells in the hematopoietic progenitor cell harvest may contribute to relapse after high dose therapy for B-cell malignancies. Purging of the HPC harvest requires large amounts of anti-B-cell antibodies, whereas CD34-selection enriches self renewing HPC's but malignant cells are still detectable in many CD34+ fractions. Patients and methods: We examined the feasability and safety of a CD34-selection followed by purging with anti-B-cell antibodies in 11 patients with B-cell non-Hodgkin's lymphomas undergoing high-dose therapy with cyclophospha-mide, BCNU and etoposide with retransfusion of autologous HPC's. Results: A mean number of 340 × 108 mononuclear cells was used for CD34-selection and immunomagnetic purging. CD34+ cells were enriched from a mean of 1.7% (range 0.2%-4.5%) to a mean of 68% (range 49%-87%) with a mean recovery of 27% (range 15%-43%). The mean number of retransfused CD34+ cells was 1.2× 106/kg (range 0.6-2.2 ×106/kg) body weight with a median of 11 days (range 10-13 days) to neutrophil recovery of 0.5×109/1 and 17 days (range 13-25 days) to platelet recovery of 50 × 109/1. Mean number of intravenous antibiotics and inpatient days were 8 (range 0-14) and 22 (range 19-26) respectively. Major toxicity consisted in four septicemias. Conclusions: CD34-selected and purged HPC's are safe and mediate rapid hematological recovery after high dose therapy for B-cell non-Hodgkin's lymphoma

Collective dynamics of two-mode stochastic oscillators

We study a system of two-mode stochastic oscillators coupled through their collective output. As a function of a relevant parameter four qualitatively distinct regimes of collective behavior are observed. In an extended region of the parameter space the periodicity of the collective output is enhanced by the considered coupling. This system can be used as a new model to describe synchronization-like phenomena in systems of units with two or more oscillation modes. The model can also explain how periodic dynamics can be generated by coupling largely stochastic units. Similar systems could be responsible for the emergence of rhythmic behavior in complex biological or sociological systems.Comment: 4 pages, RevTex, 5 figure

Coherence Resonance and Noise-Induced Synchronization in Globally Coupled Hodgkin-Huxley Neurons

The coherence resonance (CR) of globally coupled Hodgkin-Huxley neurons is studied. When the neurons are set in the subthreshold regime near the firing threshold, the additive noise induces limit cycles. The coherence of the system is optimized by the noise. A bell-shaped curve is found for the peak height of power spectra of the spike train, being significantly different from a monotonic behavior for the single neuron. The coupling of the network can enhance CR in two different ways. In particular, when the coupling is strong enough, the synchronization of the system is induced and optimized by the noise. This synchronization leads to a high and wide plateau in the local measure of coherence curve. The local-noise-induced limit cycle can evolve to a refined spatiotemporal order through the dynamical optimization among the autonomous oscillation of an individual neuron, the coupling of the network, and the local noise.Comment: five pages, five figure

β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction

Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids (GCs) are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols because they exacerbated insulin resistance and suppressed β-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within β-cells ameliorated lipotoxic β-cell failure in transgenic mice overexpressing the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (MIP-HSD1tg/+ mice). Here, we tested the hypothesis that elevated β-cell 11beta-HSD1 protects against the β-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune β-cell destruction. MIP-HSD1tg/+ mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained β-cell survival, maintained β-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1tg/+ mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1tg/+ islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation