ABSTRACT
Optimal local treatment for nodal oligorecurrent prostate cancer is unknown. The randomized phase 2 PEACE V-STORM trial will explore the best treatment approach in this setting. Early results on the acute toxicity profile are projected to be published in quarter 3, 2021.
Subject(s)
Prostatic Neoplasms , Salvage Therapy , Humans , Male , Prostatic Neoplasms/therapyABSTRACT
The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of an as yet unidentified mutant gene, Yaa (Y-linked autoimmune acceleration). In view of a possible role of marginal zone (MZ) B cells in murine SLE, we have explored whether the expression of the Yaa mutation affects the differentiation of MZ and follicular B cells, thereby implicating the acceleration of the disease. In this study, we show that both BXSB and C57BL/6 Yaa mice, including two different substrains of BXSB Yaa males that are protected from SLE, displayed an impaired development of MZ B cells early in life. Studies in bone marrow chimeras revealed that the loss of MZ B cells resulted from a defect intrinsic to B cells expressing the Yaa mutation. The lack of selective expansion of MZ B cells in diseased BXSB Yaa males strongly argues against a major role of MZ B cells in the generation of pathogenic autoantibodies in the BXSB model of SLE. Furthermore, a comparative analysis with mice deficient in CD22 or expressing an IgM anti-trinitrophenyl/DNA transgene suggests that the hyperreactive phenotype of Yaa B cells, as judged by a markedly increased spontaneous IgM secretion, is likely to contribute to the enhanced maturation toward follicular B cells and the block in the MZ B cell generation.
Subject(s)
B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/pathology , Lupus Nephritis/genetics , Lupus Nephritis/immunology , Mutation , Y Chromosome/genetics , Y Chromosome/immunology , Animals , Antigens, T-Independent/administration & dosage , Antigens, T-Independent/immunology , B-Lymphocyte Subsets/metabolism , Cell Differentiation/genetics , Cell Differentiation/immunology , Cells, Cultured , Down-Regulation/genetics , Down-Regulation/immunology , Gene Expression Regulation/immunology , Immunoglobulin M/biosynthesis , Immunoglobulin M/genetics , Injections, Intravenous , Kruppel-Like Transcription Factors , Lupus Nephritis/pathology , Lymphocyte Count , Lymphopenia/genetics , Lymphopenia/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Mice, Transgenic , Receptors, Complement 3d/biosynthesis , Spleen/immunology , Spleen/metabolism , Spleen/pathology , Stem Cells/immunology , Stem Cells/pathology , Transcription Factors/biosynthesis , Transcription Factors/deficiency , Transcription Factors/genetics , Transgenes/immunology , Trinitrobenzenes/immunologyABSTRACT
Incubation of Burkitt lymphoma-derived Raji cells at physiological temperature with submicromolar concentrations of humanized anti-CD20 antibody rituximab (RTX) redistributes CD20 to liquid-ordered, plasma membrane rafts. This accumulation of the CD20 tetraspan protein in rafts does not change the existing lipid and phosphoprotein composition but makes sphingolipids and the Src regulator Cbp/PAG (Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomain) transmembrane phosphoprotein more resistant to n-octyl-beta-pyranoside, a detergent that dissociates sphingolipid clusters. On the contrary, sphingolipids and Cbp/PAG are not protected by the presence of CD20 against the disruptive effects of methyl-beta-cyclodextrin, a cyclic carbohydrate that removes membrane cholesterol. After accumulation of CD20, the activity of the raft-associated Lyn kinase is down-regulated without apparent alteration of its relationship to substrates. Moreover, in rafts of lymphoblastoid cells that express lower amounts of Cbp/PAG, RTX redistributes CD20 to rafts but does not modulate the raft-associated protein tyrosine kinase activity, suggesting that the presence of Cbp/PAG protein in rafts is necessary for RTX to exert its transmembrane "signaling effects." Lastly, redistribution of CD20 in rafts renders the glycosylphosphatidyl inositol (GPI)-linked CD55 C'-defense protein hypersensitive to glycosylphosphatidyl inositol-specific phospholipases. By redistributing CD20 to rafts, RTX modifies their stability and organization and modulates the associated signaling pathways and C' defense capacity.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antigens, CD20/metabolism , Antineoplastic Agents/pharmacology , Lymphoma, B-Cell/metabolism , Membrane Microdomains/metabolism , beta-Cyclodextrins , Antibodies, Monoclonal, Murine-Derived , CD55 Antigens/metabolism , Cyclodextrins/chemistry , Glucosides/chemistry , Humans , Lymphoma, B-Cell/drug therapy , Membrane Lipids/metabolism , Membrane Microdomains/drug effects , Membrane Proteins/metabolism , Phospholipase D/metabolism , Phosphoproteins/metabolism , Rituximab , Type C Phospholipases/metabolism , src-Family Kinases/metabolismABSTRACT
CD22 is a B cell-restricted transmembrane protein that apparently controls signal transduction thresholds initiated through the B cell Ag receptor (BCR) in response to Ag. However, it is still poorly understood how the expression of CD22 is regulated in B cells after their activation. Here we show that the expression levels of CD22 in conventional B-2 cells are markedly down-regulated after cross-linking of BCR with anti-IgM mAb but are up-regulated after stimulation with LPS, anti-CD40 mAb, or IL-4. In contrast, treatment with anti-IgM mAb barely modulated the expression levels of CD22 in CD5(+) B-1 cells, consistent with a weak Ca(2+) response in anti-IgM-treated CD5(+) B-1 cells. Moreover, in CD22-deficient mice, anti-IgM treatment did not trigger enhanced Ca(2+) influx in CD5(+) B-1 cells, unlike CD22-deficient splenic B-2 cells, suggesting a relatively limited role of CD22 in BCR signaling in B-1 cells. In contrast, CD22 levels were markedly down-regulated on wild-type B-1 cells in response to LPS or unmethylated CpG-containing oligodeoxynucleotides. These data indicate that the expression and function of CD22 are differentially regulated in B-1 and conventional B-2 cells, which are apparently implicated in innate and adaptive immunity, respectively.
