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VIP Protects Corneas
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PGI2 Inhibition of BMDCs
Prostacyclin (PGI2) has anti-inflammatory actions in virus- or OVA-induced allergic responses. However, the cell responsible and the molecular mechanisms involved have not been determined. Zhou et al. (p. 702
) found induced expression of the PGI2 receptor IP on mouse bone marrow-derived dendritic cells (BMDCs) differentiated in vitro with GM-CSF. Each of the three PGI2 analogues suppressed LPS-induced release of proinflammatory cytokines and increased production of anti-inflammatory IL-10. The cytokine suppression by the analogues was not abrogated by addition of anti-IL-10 Ab, and LPS-induced production of cytokines and chemokines by IP–/– BMDCs was not affected by the PGI2 analogues. Intracellular cAMP levels were increased severalfold in IP+/+, but not in IP–/–, BMDCs treated with LPS plus an analogue; preincubation of the treated cells with an inhibitor of a cAMP-dependent protein kinase increased production of some cytokines severalfold, although the final levels were still less than vehicle-treated cells. BMDCs purified from mice transgenic for a luciferase-tagged NF-
B gene exhibited less luciferase activity after treatment with LPS and PGI2 analogues than controls; preincubation of the cells with the protein kinase inhibitor increased luciferase activity. Treatment of wild-type, but not IP–/–, DCs with an analogue plus LPS resulted in decreased surface expression of CD86, CD40, and MHC class II molecules. DCs from mice transgenic for an OVA-specific TCR given an analogue in the presence of LPS and OVA were less able to stimulate proliferation of syngeneic CD4+ T cells. The authors demonstrate that PGI2 analogues signal through the IP receptor on mouse BMDCs to limit an anti-inflammatory response to stimulation.
Immunizing against Yersinia pestis
Aerosol delivery of Yersinia pestis, the causative agent of bubonic and pneumonic plague, presents a bioterrorist threat. Although there are effective Y. pestis vaccines using the major capsule protein (F1-Ag) or virulence Ag (V-Ag) or a fusion protein of the two Ags, problems with delivery of the Ags compromise their efficacy. Yang et al. (p. 1059 ) engineered a chimeric attenuated Salmonella typhimurium vaccine vector to produce V-Ag under control of a chimeric promoter plus F1-Ag from its own operon. Analyses on subcellular components of the vector showed expression of V-Ag in spheroplasmic and outer membrane fractions similar to its location in Y. pestis. Mice injected and boosted with the chimeric vector produced serum IgG Abs against both proteins that were equivalent to responses seen with vectors producing only one of the Ags; mucosal IgA Ab titers were lower than either Ag alone. The chimeric vector induced a mixed Th cell response. Survival of mice orally immunized and boosted s.c. with the chimeric vector was 87.5% after challenge with a strain of Y. pestis that induced bubonic plague or a strain of Y. pestis that induced pneumonic plague. Immunization with control vectors expressing one of the two Ags conferred lower levels of protection. This study indicates that an orally administered live recombinant Salmonella vaccine independently expressing two Y. pestis Ags provides a high level of protection against both bubonic and pneumonic plague.
Fc
RIIB in Autoimmunity
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RIIB is considered to influence the progression of B cells to memory cells. FcRIIB has reduced expression on autoimmune GC B cells. To determine the role of FcRIIB in negative selection in the GC/memory pathway, Rahman et al. (p. 897
) developed two FcRIIB-deficient lines of mice transgenic for BCRs that differed in a single amino acid in the CDR2 region and resulted in weak (HKI65 with wild-type sequence) or strong (HKIR with mutation) autoreactivity. Primary B cell development and tolerance were unaffected by lack of FcRIIB. CFSE-labeled splenocytes from each strain had similar proliferation profiles after adoptive transfer into nonirradiated C57BL/6 (B6) syngeneic mice immunized with the specific Ag before or after transfer. Recipients had more Ab-producing Ag-forming cells (AFCs) and Ag-specific serum Abs compared with controls; the AFCs were located in spleen bridging channels by immunohistochemistry. Whereas HKIR cells given to Ag-immunized B6 recipients entered GCs, the number of cells per GC was reduced at days 4 and 5 posttransfer and boosting compared with HKI65 cells. Similar results were obtained when FcRIIB–/– cells were transferred. Laser capture microdissection on AFC clusters from recipient B6 spleens indicated a low frequency of mutations in either FcRIIB–/– AFCs as did analyses of purified recipient GC B cells. Secondary AFCs were 2-fold higher in recipients of FcRIIB–/– HKI65 cells vs HKI65 controls but 4-fold lower in recipients of FcRIIB–/– HKIR vs FcRIIB–/– HKI65 splenocytes. AFCs were reduced in recipients of HKIR with or without FcRIIB. The authors conclude that FcRIIB acts as a modifier of autoimmunity by regulating the magnitude of the AFC response but does not influence negative selection of autoreactive B cells in the GC/memory pathway. T Cell Lineage Commitment
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DC-Targeted Vaccine
Vaccines that rely upon dendritic cells (DCs) to elicit immune responses are being tested clinically to treat cancer or viral infections. However, those vaccines often require manipulation of DCs in vitro. In an effort to target Ags to DCs in vivo, Lasarte et al. (p. 748
) engineered a fusion protein encoding the type III repeat extra domain A (EDA) from fibronectin that binds and activates TLR4 plus the OVA CD8+ T cell epitope SIINFEKL. Recombinant fusion protein EDA-SIINFEKL bound to cells expressing TLR4, promoted NF-B activation, and stimulated bone marrow-derived DCs (BMDCs) to produce proinflammatory cytokines and express surface markers of maturation. Injection of the fusion protein into mice induced maturation of BMDCs in vivo. In vitro, BMDCs incubated with the fusion protein induced higher IFN- production from T cells transfected with an OVA peptide-specific TCR than BMDCs exposed to EDA or the OVA peptide alone. Lack of effect of various inhibitors suggested that the fusion peptide was processed by the MHC class I cytosolic pathway. Mice immunized with EDA-SIINFEKL developed a strong OVA-specific CTL response, and 40% of animals injected with OVA-expressing tumor cells remained tumor-free. Mice immunized with the OVA peptide alone did not develop a CTL response, and all succumbed to tumors. A recombinant protein consisting of EDA fused with full-length OVA induced BMDCs to elicit a stronger OVA-specific CTL response in vitro and in vivo than EDA-SIINFEKL. The authors demonstrate a new strategy invoking EDA recognition of TLR4 to deliver Ags to DCs to stimulate a potent antitumor response.
Preventing Premature Birth
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, IL-1
, and IL-6 levels in amniotic fluids. PDE4 activity represented half of total cAMP-PDE activity in uterine and decidua-placental tissues, but PDE4 activity in only the decidua-placental tissues increased with LPS stimulation. Nuclear translocation of NF-B p65 within the LPS-treated decidual cap was noted in maternal cells at 2 h, in fetal cells at 4 h, and in fetal glycogen trophoblasts at 6 h poststimulation; nuclear localization was not seen in tissues from LPS-treated animals given rolipram. Recruitment of mesometrial NK cells by LPS treatment did not occur in inhibitor-treated mice. The authors show that the PDE4 inhibitor rolipram blocks intrauterine inflammation in vivo, prevents preterm delivery, and reduces fetal death if administered within 2 h of LPS injection into the murine uterus. Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
RIIB Regulates Autoreactive Primary Antibody-Forming Cell, but Not Germinal Center B Cell, Activity
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