Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation (alloHCT), a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow (BM) derived T cells do not mediate severe GVHD because of their quantity and/or phenotype. During the course of experiments testing the impact of housing temperatures on GVHD, we discovered that this apparent resistance is a function of the relatively cool ambient housing temperature. Murine BM-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at IACUC mandated, cool standard temperatures (~22°C) are more resistant to developing GVHD than mice housed at thermoneutral temperatures (~30°C). We learned that the mechanism underlying this housing-dependent immunosuppression is associated with increased norepinephrine production and excessive signaling through β-adrenergic receptor (β-AR) signaling which is increased when mice are cold stressed. Treatment of mice housed at 22°C with a β2-adrenergic antagonist reverses the norepinephrine driven suppression of GVHD and yields similar disease to mice housed at 30°C. Conversely, administering a β2-adrenergic agonist decreases GVHD in mice housed at 30°C. In further mechanistic studies using β2-adrenergic receptor deficient (β2-AR−/−) mice, we found that it is host cell β2-AR signaling that is essential for decreasing GVHD. These data reveal how baseline levels of β-AR signaling can influence murine GVHD and point to the feasibility of manipulation of β2-AR signaling to ameliorate GVHD in the clinical setting.
A major question in plant biology concerns the specification and functional differentiation of cell types. This is in the context of constraints imposed by networks of cell walls that both adhere cells and contribute to the form and function of developing organs. Here, we report the identification of a glycan epitope that is specific to phloem sieve element cell walls in several systems. A monoclonal antibody, designated LM26, binds to the cell wall of phloem sieve elements in stems of Arabidopsis (Arabidopsis thaliana), Miscanthus x giganteus, and notably sugar beet (Beta vulgaris) roots where phloem identification is an important factor for the study of phloem unloading of Suc. Using microarrays of synthetic oligosaccharides, the LM26 epitope has been identified as a b-1,6-galactosyl substitution of b-1,4-galactan requiring more than three backbone residues for optimized recognition. This branched galactan structure has previously been identified in garlic (Allium sativum) bulbs in which the LM26 epitope is widespread throughout most cell walls including those of phloem cells. Garlic bulb cell wall material has been used to confirm the association of the LM26 epitope with cell wall pectic rhamnogalacturonan-I polysaccharides. In the phloem tissues of grass stems, the LM26 epitope has a complementary pattern to that of the LM5 linear b-1,4-galactan epitope, which is detected only in companion cell walls. Mechanical probing of transverse sections of M. x giganteus stems and leaves by atomic force microscopy indicates that phloem sieve element cell walls have a lower indentation modulus (indicative of higher elasticity) than companion cell walls.
Cancer remains the leading cause of death worldwide. Traditional treatments such as surgery, radiation, and chemotherapy have had limited efficacy, especially with late stage cancers. Cancer immunotherapy and targeted therapy have revolutionized how cancer is treated, especially in patients with late stage disease. In 2013 cancer immunotherapy was named the breakthrough of the year, partially due to the established efficacy of blockade of CTLA-4 and PD-1, both T cell coinhibitory molecules involved in tumor-induced immunosuppression. Though early trials promised success, toxicity and tolerance to immunotherapy have hindered long term successes. Optimizing the use of co-stimulatory and co-inhibitory pathways has the potential to increase the effectiveness of T cell-mediated antitumor immune response, leading to increased efficacy of cancer immunotherapy. This review will address major T cell co-stimulatory and co-inhibitory pathways and the role they play in regulating immune responses during cancer development and treatment.
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