Memory T cells and the endothelium in allograft rejection

Organ transplantation has become increasingly important as a treatment for many human diseases. Despite the dramatic improvements in immunosuppression in recent years, acute and chronic rejection remain significant problems. It has become increasingly evident that the presence of T cell memory correlates with both acute and chronic rejection episodes. Endothelial cells (EC) have been shown to preferentially activate memory T cells and, as the lining of every transplanted organ, they are in a unique position to provide signals to alloreactive memory T cells. EC activation of memory T cells depends in part on the costimulatory molecule LFA-3 in addition to other signals. The nature of these other signals is not well understood. In this dissertation I further explore the mechanisms by which EC activate memory T cells and investigate the role that these mechanisms play in a model of memory T cell mediated allograft rejection.Several newly described costimulatory pathways, ICOS-ICOSL, 4-1BB-41BBL, and OX40-OX40L, have recently been recognized as important players in the generation and function of memory T cells. EC can express all three of the ligands from these pathways and also increase expression in response to the cytokine tumor necrosis factor (TNF) and in co-cultures with T cells. Furthermore, blockade of these pathways using monoclonal antibodies in co-cultures causes reductions in T cell production of IFN-gamma and IL-2 as well as decreased T cell proliferation.To examine the contribution of memory T cells to allograft rejection in vivo, I describe a chimeric model of human skin grafted onto SCID mice that are adoptively transferred with various subsets of human T cells. In this model, rejection of the human skin by the transferred T cells is mediated by memory T cells alone. Using this model, the effect of different costimulatory pathways on allograft rejection is tested. Interestingly, blockade of any of the three costimulatory pathways can diminish the T cell response to the allograft. The role of the B7-CD28 pathway is also examined and found to partially contribute to the memory T cell response.Finally, using observations that memory T cells can be further divided into two functionally distinct subsets known as central and effector memory T cells, the response of these two subsets to EC is explored. Central memory T cells respond to EC by producing IL-2 while effector memory T cells generate IFN-gamma. The basis for this difference may be due to the differential expression and sensitivity of the two subsets to costimulatoryn by CD27 and CD28. Further, in the chimeric human-SCID model effector memory T cells alone can mediate allograft rejection while central memory T cells cannot.Our results strongly support the idea that the EC capacity to activate memory T cells and its subsets depends in part on the CD28-B7 pathway and memory T cell specific costimulatory molecules. Furthermore, targeting CD28 or these molecules in vivo can attenuate allograft rejection mediated by memory T cells

Targeting Innate Immunity to Enhance the Efficacy of Radiation Therapy

Radiation continues to play a major role in the treatment of almost every cancer type. Traditional radiation studies focused on its ability to damage DNA, but recent evidence has demonstrated that a key mechanism driving the efficacy of radiation in vivo is the immune response triggered in irradiated tissue. Innate immune cells including macrophages, dendritic cells, and natural killer cells are key mediators of the radiation-induced immune response. They regulate the sensing of radiation-mediated damage and subsequent radiation-induced inflammation. Given the importance of innate immune cells as determinants of the post-radiation anti-tumor immune response, much research has been devoted to identify ways to both enhance the innate immune response and prevent their ability to suppress ongoing immune responses. In this review, we will discuss how the innate immune system shapes anti-tumor immunity following radiation and highlight key strategies directed at the innate immune response to enhance the efficacy of radiation

Survival Impact of Adjuvant Therapy in Salivary Gland Cancers following Resection and Neck Dissection

Objective To evaluate the impact of postoperative radiotherapy (PORT) and chemotherapy on survival in salivary gland cancer (SGC) treated with curative-intent local resection and neck dissection. Study Design Retrospective population-based cohort study. Setting National Cancer Database. Subjects and Methods Patients with SGC who were undergoing surgery were identified from the National Cancer Database between 2004 and 2013. Neck dissection removing a minimum of 10 lymph nodes was required. Because PORT violated the proportional hazards assumption, this variable was treated as a time-dependent covariate. Results Overall, 4145 cases met inclusion criteria (median follow-up, 54 months). PORT was associated with improved overall survival in multivariable analysis, both 9 months (HR, 0.75; 95% CI, 0.66-0.86; P <.001). In propensity score-matched cohorts, 5-year overall survival was 67.1% and 60.6% with PORT and observation, respectively (P <.001). Similar results were observed in landmark analysis of patients surviving at least 6 months following diagnosis. Adjuvant chemotherapy was not associated with improved survival (HR, 1.15; 95% CI, 0.99-1.34; P = .06). Conclusion PORT, but not chemotherapy, is associated with improved survival among patients with SGC for whom neck dissection was deemed necessary. These results are not applicable to low-risk SGCs not requiring neck dissection.Peer reviewe

The Revised TESS Input Catalog and Candidate Target List

We describe the catalogs assembled and the algorithms used to populate the revised TESS Input Catalog (TIC), based on the incorporation of the Gaia second data release. We also describe a revised ranking system for prioritizing stars for 2-minute cadence observations, and assemble a revised Candidate Target List (CTL) using that ranking. The TIC is available on the Mikulski Archive for Space Telescopes (MAST) server, and an enhanced CTL is available through the Filtergraph data visualization portal system at the URL http://filtergraph.vanderbilt.edu/tess_ctl.Comment: 30 pages, 16 figures, submitted to AAS Journals; provided to the community in advance of publication in conjunction with public release of the TIC/CTL on 28 May 201

Spatial Mapping of Myeloid Cells and Macrophages by Multiplexed Tissue Staining

An array of phenotypically diverse myeloid cells and macrophages (MC&amp;M) resides in the tumor microenvironment, requiring multiplexed detection systems for visualization. Here we report an automated, multiplexed staining approach, named PLEXODY, that consists of five MC&amp;M-related fluorescently-tagged antibodies (anti - CD68, - CD163, - CD206, - CD11b, and - CD11c), and three chromogenic antibodies, reactive with high- and low-molecular weight cytokeratins and CD3, highlighting tumor regions, benign glands and T cells. The staining prototype and image analysis methods which include a pixel/area-based quantification were developed using tissues from inflamed colon and tonsil and revealed a unique tissue-specific composition of 14 MC&amp;M-associated pixel classes. As a proof-of-principle, PLEXODY was applied to three cases of pancreatic, prostate and renal cancers. Across digital images from these cancer types we observed 10 MC&amp;M-associated pixel classes at frequencies greater than 3%. Cases revealed higher frequencies of single positive compared to multi-color pixels and a high abundance of CD68+/CD163+ and CD68+/CD163+/CD206+ pixels. Significantly more CD68+ and CD163+ vs. CD11b+ and CD11c+ pixels were in direct contact with tumor cells and T cells. While the greatest percentage (~70%) of CD68+ and CD163+ pixels was 0–20 microns away from tumor and T cell borders, CD11b+ and CD11c+ pixels were detected up to 240 microns away from tumor/T cell masks. Together, these data demonstrate significant differences in densities and spatial organization of MC&amp;M-associated pixel classes, but surprising similarities between the three cancer types

Heritability of Macular Pigment: A Twin Study

PURPOSE. Several studies have reported higher levels of macular pigment (MP) in association with reduced risk for age-related macular degeneration (ARMD), a disease to which there is a genetic predisposition. A classic twin study was performed to determine the heritability of MP in the healthy eye. METHODS. One hundred fifty twin pairs (76 monozygotic [MZ] and 74 dizygotic [DZ]), aged 18 to 50 years, participated. MP optical density was measured psychophysically with heterochromatic flicker photometry (HFP) and also with an imaging method involving fundus autofluorescence (AF). The covariance of MP within MZ and DZ twin pairs was compared, and genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in MP. RESULTS. The mean MP optical density, measured using HFP, was 0.43 Ϯ 0.21. Using AF, the mean MP optical density, measured at 1°eccentricity, was 0.28 Ϯ 0.11. MP optical densities correlated more highly in MZ twins than in DZ twins, according to both HFP (MZ: 0.65; DZ: 0.24) and AF (MZ: 0.83; DZ: 0.50). A model combining additive genetic and unique environmental effects provided the best fit and resulted in MP heritability estimates of 0.67 (95% CI, 0.52-0.77) and 0.85 (95% CI, 0.78 -0.90) for HFP and AF readings, respectively. CONCLUSIONS. This classic twin study demonstrates that genetic background is an important determinant of MP optical density, reflected in heritability estimates of 0.67 and 0.85 for HFP and AF measures, respectively. (Invest Ophthalmol Vis Sci. 2005; 46:4430 -4436

The ocean sampling day consortium.

Ocean Sampling Day was initiated by the EU-funded Micro B3 (Marine Microbial Biodiversity, Bioinformatics, Biotechnology) project to obtain a snapshot of the marine microbial biodiversity and function of the world's oceans. It is a simultaneous global mega-sequencing campaign aiming to generate the largest standardized microbial data set in a single day. This will be achievable only through the coordinated efforts of an Ocean Sampling Day Consortium, supportive partnerships and networks between sites. This commentary outlines the establishment, function and aims of the Consortium and describes our vision for a sustainable study of marine microbial communities and their embedded functional traits

The ocean sampling day consortium

Ocean Sampling Day was initiated by the EU-funded Micro B3 (Marine Microbial Biodiversity, Bioinformatics, Biotechnology) project to obtain a snapshot of the marine microbial biodiversity and function of the world’s oceans. It is a simultaneous global mega-sequencing campaign aiming to generate the largest standardized microbial data set in a single day. This will be achievable only through the coordinated efforts of an Ocean Sampling Day Consortium, supportive partnerships and networks between sites. This commentary outlines the establishment, function and aims of the Consortium and describes our vision for a sustainable study of marine microbial communities and their embedded functional traits