Induction of CD4+CD25+FOXP3+ Regulatory T Cells during Human Hookworm Infection Modulates Antigen-Mediated Lymphocyte Proliferation

Hookworm infection is considered one of the most important poverty-promoting neglected tropical diseases, infecting 576 to 740 million people worldwide, especially in the tropics and subtropics. These blood-feeding nematodes have a remarkable ability to downmodulate the host immune response, protecting themselves from elimination and minimizing severe host pathology. While several mechanisms may be involved in the immunomodulation by parasitic infection, experimental evidences have pointed toward the possible involvement of regulatory T cells (Tregs) in downregulating effector T-cell responses upon chronic infection. However, the role of Tregs cells in human hookworm infection is still poorly understood and has not been addressed yet. In the current study we observed an augmentation of circulating CD4+CD25+FOXP3+ regulatory T cells in hookworm-infected individuals compared with healthy non-infected donors. We have also demonstrated that infected individuals present higher levels of circulating Treg cells expressing CTLA-4, GITR, IL-10, TGF-β and IL-17. Moreover, we showed that hookworm crude antigen stimulation reduces the number of CD4+CD25+FOXP3+ T regulatory cells co-expressing IL-17 in infected individuals. Finally, PBMCs from infected individuals pulsed with excreted/secreted products or hookworm crude antigens presented an impaired cellular proliferation, which was partially augmented by the depletion of Treg cells. Our results suggest that Treg cells may play an important role in hookworm-induced immunosuppression, contributing to the longevity of hookworm survival in infected people

Time-resolved Imaging of Secondary Gamma Ray Emissions for in vivo Monitoring of Proton Therapy: Methodological and Experimental Feasibility Studies

Particle therapy (PT), including proton therapy, has important advantages compared to external beam photon therapy (section 1.1). This is because most of the therapeutic effect of a proton beam is localized at the endpoint, where most of its energy is imparted to the medium (Bragg peak), with nearly no dose deposited beyond that point. However, the highly localized dose deposition makes proton therapy more sensitive to (1) patient morphological alterations, including tumor progression / regression, (2) organ motion, (3) patient setup errors, (4) tissue lateral heterogeneities that render the results obtained with non-Monte-Carlo-based treatment planning algorithms unreliable to some degree, (5) beam characteristics utilized for treatment planning, and (6) the conversion of Hounsfield units (computed tomography data), to tissue density and stoichiometry. In addition, uncertainties in the mean excitation potential I, necessary to calculate the stopping power of the penetrating ions, further contribute to potential beam range inaccuracies. Given the aforementioned sources of treatment error, an imaging technique capable of providing feedback proportional to the quality of the treatment being delivered is highly desired and a very active field of research in proton therapy (section 1.2). Specifically, it is of utmost importance to develop an imaging technique capable of providing feedback with respect to the in vivo beam range, especially when highly-heterogeneous beam paths are crossed by a pencil beam. Such a imaging technique can make use of secondary gamma (γ) radiation emitted by the patient, as a result of nuclear interactions between the projectiles and the nuclei of the irradiated medium. These techniques are mainly divided into two categories, according to the type of secondary γ rays probed: (1) positron emission tomography (PET), which makes use of delayed emission, namely pairs of 511 keV annihilation photons, resulting from β+-decay; and (2) prompt gamma (PG) imaging, which makes use of the emission of single photons typically on a sub-nanosecond timescale

Optimization of the signal-to-background ratio in prompt gamma imaging using energy- and shifting time-of-flight discrimination: experiments with a scanning parallel-slit collimator

Much attention is currently being paid to imaging prompt gamma (PG) rays for in vivo proton range monitoring in proton therapy. PG imaging using a collimator is affected by neutron-related background. We study the effectiveness of background reduction experimentally, using a scanning parallel-slit PG collimator as a simplified model of a multislat PG camera. The analysis is focused on the falloff region of the PG intensity profile near the Bragg peak, which is the typical region of interest for proton range estimation. Background reduction was studied for different energy windows, with and without a shifting time-of-flight window that takes into account the proton velocity within the phantom. Practical methods are put forward that apply to cyclotron-based pencil beams. The parallel-slit collimator was placed in front of arrays of cerium-doped lutetium yttrium silicate-coupled digital silicon photomultipliers, used to measure energy and time spectra together with intensity profiles of prompt events emitted from a polymethylmethacrylate phantom irradiated with a 160-MeV proton pencil beam. The best signal-to-background ratio of ~1.6 was similar to that obtained previously with a knife-edge-slit collimator. However, the slope-over-noise ratio in the PG-profile falloff region, was ~1.2 higher for the present collimator, given its better resolution

Optimization of the signal-to-background ratio in prompt gamma imaging using energy- and shifting time-of-flight discrimination: experiments with a scanning parallel-slit collimator

Much attention is currently being paid to imaging prompt gamma (PG) rays for in vivo proton range monitoring in proton therapy. PG imaging using a collimator is affected by neutron-related background. We study the effectiveness of background reduction experimentally, using a scanning parallel-slit PG collimator as a simplified model of a multislat PG camera. The analysis is focused on the falloff region of the PG intensity profile near the Bragg peak, which is the typical region of interest for proton range estimation. Background reduction was studied for different energy windows, with and without a shifting time-of-flight window that takes into account the proton velocity within the phantom. Practical methods are put forward that apply to cyclotron-based pencil beams. The parallel-slit collimator was placed in front of arrays of cerium-doped lutetium yttrium silicate-coupled digital silicon photomultipliers, used to measure energy and time spectra together with intensity profiles of prompt events emitted from a polymethylmethacrylate phantom irradiated with a 160-MeV proton pencil beam. The best signal-to-background ratio of ~1.6 was similar to that obtained previously with a knife-edge-slit collimator. However, the slope-over-noise ratio in the PG-profile falloff region, was ~1.2 higher for the present collimator, given its better resolution.RST/Applied Radiation & IsotopesRST/Biomedical ImagingRST/Medical Physics & Technolog