Chapter 2 B Lymphocytes in Cancer Immunology

Abstract The role of B lymphocytes in the pathogenesis and treatment of cancer has not received as much attention as the role of T cells. However, most patients with solid tumors harbor circulating antitumor antibodies and most tumors contain a population of infiltrating B cells implying an association between oncogenic events and B-cell activation. B-cell immunity can be beneficial by providing antibody-mediated protection from oncogenic viruses or a source of recombinant tumor-specific antibodies that can be used in combination with chemotherapeutic regimens. However, activation of B cells may also be detrimental to an effective antitumor response. Tumor-reactive antibodies and B cells often recognize antigens that are generated during the unscheduled apoptotic and necrotic death processes, which accompany tumor progression and may be involved in wound-healing processes that promote tumor growth and impair protective T-cell responses. Therefore, methods to eliminate autoreactive B cells, or switch them to a B effector-1 (Be-1) phenotype that amplifies Th1/Tc1-type T-cell responses, which are typically associated with effective antitumor responses, may improve the clinical outcomes of T-cell-mediated immunotherapies. Possible strategies include the administration of B-celldepleting monoclonal antibodies, use of targeted B-cell stimulatory agents such as Toll-like Receptor agonists, and adoptive transfer of large numbers of ex vivo generated tumor-reactive Be-1 cells

Association of Human Lymphocyte Antigens with Obstructive Airways Disease after Bone Marrow Transplantation

BACKGROUND: Obstructive airways disease (OAD) is a known complication of allogeneic bone marrow transplantation. The etiology of OAD is unknown but is probably multifactorial. The identification of a significant human lymphocyte antigen (HLA) association with the development of OAD might offer some insight into its pathogenesis and serve as a marker to identify prospectively patients at risk for developing OAD

Stem height and harvest management influence conservation biological control of wheat stem sawfly by endemic parasitoids.

The wheat stem sawfly (WSS; Cephus cinctus Norton (Hymenoptera: Cephidae)) is a serious pest of wheat (Triticum aestivum L.) in the Great Plains of North America. Two species of parasitoids, Bracon cephi Gahan and B. lissogaster Muesebeck, effectively attack C. cinctus; therefore, agronomic practices must strive to conserve these endemic parasitoids. Our objectives were 1) to establish distribution and within host infestation patterns of Bracon parasitoids, and 2) to study parasitoid responses to genetics, stubble height and straw management at harvest. Field surveys and harvest management studies were conducted in the southern Prairies of Canada and in Montana, USA. Harvest management consisted of 3 harvesting heights, 1) low, harvest near ground level to cut and thresh all material above the soil surface, 2) harvest stubble height = 15 cm, and 3) spikes only and two levels of straw management, 1) Chopped straw, or, 2) Not chopped. Most overwintering parasitoid cocoons (>80%) occurred in the bottom third (0 – 15 cm) of standing wheat stems, and the common harvest practice of chopping straw reduced adult parasitoid emergence. However, the incremental benefit of not chopping straw doesn’t justify elimination of the practice as residue management is critically important in conservation farming. Compared to a low cutting height, increasing harvesting heights to 15 cm, or higher to remove only the grain spikes, increased total emergence of Bracon cephi by 40% and 60%, respectively. Thus, the optimal conservation of wheat stem sawfly parasitoids can be achieved with easily-adopted practices on-farm without compromising sustainable production principles.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author

Risk and safety requirements for diagnostic and therapeutic procedures in allergology : World Allergy Organization Statement

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O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers

In the past decade, aberrant O-GlcNAcylation has emerged as a new hallmark of cancer. O-GlcNAcylation is a post-translational modification that results when the amino-sugar β-D-N-acetylglucosamine (GlcNAc) is made in the hexosamine biosynthesis pathway (HBP) and covalently attached to serine and threonine residues in intracellular proteins by the glycosyltransferase O-GlcNAc transferase (OGT). O-GlcNAc moieties reflect the metabolic state of a cell and are removed by O-GlcNAcase (OGA). O-GlcNAcylation affects signaling pathways and protein expression by cross-talk with kinases and proteasomes and changes gene expression by altering protein interactions, localization, and complex formation. The HBP and O-GlcNAcylation are also recognized to mediate survival of cells in harsh conditions. Consequently, O-GlcNAcylation can affect many of the cellular processes that are relevant for cancer and is generally thought to promote tumor growth, disease progression, and immune escape. However, recent studies suggest a more nuanced view with O-GlcNAcylation acting as a tumor promoter or suppressor depending on the stage of disease or the genetic abnormalities, proliferative status, and state of the p53 axis in the cancer cell. Clinically relevant HBP and OGA inhibitors are already available and OGT inhibitors are in development to modulate O-GlcNAcylation as a potentially novel cancer treatment. Here recent studies that implicate O-GlcNAcylation in oncogenic properties of blood cancers are reviewed, focusing on chronic lymphocytic leukemia and effects on signal transduction and stress resistance in the cancer microenvironment. Therapeutic strategies for targeting the HBP and O-GlcNAcylation are also discussed.</jats:p

Effect of Statins in the Watch and Wait Phase of Chronic Lymphocytic Leukemia

ABSTRACT Background It is an unclear how cholesterol‐lowering statin drugs affect progression of chronic lymphocytic leukemia (CLL). Methods Clinical records of 57 CLL patients were examined to determine how initiating statins in the “watch and wait” phase of management affected disease progression. Results After 6.4 ± 0.6 months, when average low‐density lipoprotein cholesterol levels had been lowered from 3.58 ± 0.11 mM to 2.1 ± 0.06 mM, blood levels of CLL cells and beta‐2‐microglobulin (β2M) increased significantly, accompanied by significant decreases in platelets. Following statin institution, rates of change of blood lymphocytes and β2M increased from 1.55 ± 0.39 × 106 to 3.4 ± 0.68 × 106 cells/mL/month (n = 43) and 0.035 ± 0.011 to 0.055 ± 0.007 μg/mL/month (n = 40), respectively. Conventional first‐line CLL treatment was ultimately required in 37 patients. Conclusions These observations suggest that statins as single agent do not slow and may even modestly stimulate progression of CLL

A novel NOD.SCID mouse model suggests CD200-mediated regulation may be important for both growth and therapy of CLL (165.36)

Abstract Chronic lymphocytic leukemia is characterized by the accumulation of malignant CD5+CD19+ B cells that, like anergic B cells, typically fail to engraft in immunocompromised murine hosts. CD200, a type I transmembrane molecule with potent immunoregulatory functions, is known to be overexpressed on CLL cells. Using a CD200 sandwich-ELISA, we have identified a soluble form of CD200 (sCD200), whose expression is increased by &amp;gt;5-fold in the serum of CLL patients compared to healthy controls. Further analysis of sCD200 levels in CLL patient serum showed a correlation between sCD200 levels and Rai disease stage. Infusion of sCD200hi CLL serum into NOD.SCIDIL-2γ-/- mice receiving 1x108 CLL splenocytes enhanced engraftment of CLL cells, which were detectable in both the spleen and peritoneum of animals, in comparison to mice receiving sCD200lo normal serum. Enhanced engraftment using CLL serum was abrogated by depletion of sCD200 from the serum. When given at 21 days post-CLL splenocyte infusion, anti-CD200mAb was as effective as Rituximab in eliminating engrafted CLL. In vivo T cell depletion with anti-CD3mAb also suppressed CLL engraftment, despite ongoing CLL serum infusion, suggesting that T cells are important to maintain CLL survival and growth. Our studies show that infusion of sCD200hi CLL serum into NOD.SCID mice allows development of a novel xenograft model for CLL, and further suggest that anti-CD200 mAb may have value in treatment of disease.</jats:p