1,720,997 research outputs found
Vulnerability of a vaccine-induced anti-tumor B-cell response to soluble protein antigen in the absence of T cell help
No full text
DNA gene fusion vaccines against cancer
No full textThe ability of DNA vaccination to induce effective immune responses has been shown in a range of preclinical disease models. However, the potency of DNA vaccines must be further improved for their use in patients. DNA fusion vaccine strategies, whereby target antigens are genetically linked to immuno-enhancing molecules, are currently being explored. The ease of DNA manipulation has allowed incorporation of a wide variety of molecules able to promote antigen uptake, processing and presentation by professional antigen-presenting cells, to provide critical CD4 T-cell help and to activate more effective immune effector pathways. These strategies are particularly important for cancer vaccines to increase their immunogenicity and to overcome tolerance
DNA vaccination: a potential weapon against infection and cancer
No full textDNA vaccination is a novel approach for inducing immunity against target antigens. It provides a direct link between identification of genes encoding these antigens and incorporation of the gene sequences into a vaccine vehicle. Identification of candidate genes is proceeding very rapidly both for infectious organisms and for cancer cells. One advantage is that DNA appears to activate all pathways of immunity, especially cytotoxic T-cell responses, which have been difficult to induce with protein vaccines. For viruses, including those which have caused problems for blood transfusion, DNA vaccination could be used for prevention. However, for chronic infection, or for cancer, vaccination will be performed in a therapeutic setting. For this situation, it is probable that immune-activating sequences will have to be included in the vaccine. The ease of manipulation of gene sequences, together with the increasing knowledge of the operation of the immune system, means that we now have the tools to take vaccines into the next exciting stage of development
Isotype switch variants reveal clonally related subpopulations in diffuse large B-cell lymphoma.
No full textPrimary diffuse large B-cell lymphomas (DLBCLs) are aggressive tumors accounting for approximately 40% of B-cell malignancies. The immunoglobulin (Ig) variable region genes have undergone rearrangement and are commonly somatically mutated. The majority show intraclonal variation which indicates that somatic mutation has continued after transformation. Typically, cells of DLBCLs express Ig of a single isotype, but there may be accompanying cells that express alternative isotypes. To probe the status of the isotype switch process in DLBCL, 4 cases of tumor-derived constant region transcripts of all isotypes were investigated. Following the identification of the VDJ sequences, the presence of the major isotype expected from immunohistochemical analysis was confirmed at the RNA level. Another 3-4 alternative isotypes were revealed in all cases, some of which could also be detected by immunohistochemistry. All cases were somatically mutated with an intraclonal variation. In 2 cases there were clearly distinct patterns of somatic mutation between isotypes, which was consistent with independent evolution of the tumor subpopulations. There was apparent clustering of mutational patterns into either an IgMD/IgG3/IgA set or an IgG1/IgA set, indicating that the switch to IgA can occur by different routes. Alternative isotype expression is evident in DLBCL at both the RNA and protein levels. The pattern of mutation indicates that switching is occurring in subpopulations of the tumor after malignant transformation. The findings support the concept that isotype switch events may be a feature of DLBCL
Chronic lymphocytic leukemia: revelations from the B-cell receptor
No full textThe finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia
Recognition of auto- and exoantigens by V4-34 gene encoded antibodies
No full textThe antigenic specificities of 24 V4-34-encoded monoclonal antibodies were compared with the amino acid sequence. The specificities were divided into three categories, red blood cells, B lymphocytes and auto/exoantigens. Six anti-I monoclonal antibodies, with multiple substitutions in their VH region, did not bind B lymphocytes or auto/exoantigens. Reactivity to these two antigens segregated with the 16 anti-i monoclonal antibodies, which were derived from the near germline V4-34 gene. All anti-i monoclonal antibodies bound B lymphocytes, albeit with varying intensities. B-cell binding correlated with basic amino acids in the VH-CDR3. Reactivity to auto/exoantigens was demonstrated only by a subset anti-i monoclonal antibodies and did not correlate with B-lymphocyte or i-antigen binding. These anti-ssDNA reactive monoclonal antibodies had basic amino acids in the VH-CDR3, strongly supporting the suggested role of arginine in DNA binding. However, an arginine-rich CDR3 was not enough to ensure DNA reactivity, since six other anti-i monoclonal antibodies that fulfilled this criteria did not bind ssDNA. Thus it is possible that the anti-DNA reactivity of V4-34-encoded monoclonal antibodies is mediated by the classic antigen-binding groove generated by the CDRs of the heavy/light chains. In contrast, anti-B-cell/i-antigen reactivity is mediated, unconventionally, by the V4-34 protein with a dominant influence of the VH-CDR3
- …
