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Articles by A Kallies
Total Records ( 3 ) for A Kallies
  K D`Costa , D Emslie , D Metcalf , G. K Smyth , A Karnowski , A Kallies , S. L Nutt and L. M. Corcoran

Multiple myeloma (MM) and plasmacytomas are cancers of antibody-secreting cells (ASCs). PRDM1/BLIMP1 is an essential regulator of ASC development. Histologic evidence shows that 100% of MM expresses PRDM1/BLIMP1, indicating that PRDM1/BLIMP1 is important for the development or persistence of MM. In contrast, some diffuse large B-cell lymphomas (DLBCLs) lose PRDM1 expression, suggesting that PRDM1 may act as a tumor suppressor in DLBCL. Thus, the role of PRDM1/BLIMP1 in transformation of mature B cells is unclear. We have used a plasmacytoma-prone transgenic mouse model to study the effect of Blimp1 loss on plasmacytoma prevalence, latency, and phenotype. Two possible outcomes could be envisaged: loss of Blimp1 might decrease plasmacytoma prevalence, through reduction of plasma cells, and so the number of susceptible transformation targets. Alternatively, Blimp1 may participate in the transformation process itself. Our results support the latter scenario, showing that decreasing Blimp1 dosage does not change plasma cell number in nontransgenic mice in vivo, but it significantly reduces plasmacytoma prevalence in transgenic mice. Loss of functional Blimp1 completely prevents plasmacytoma formation in this tumor model. These observations suggest that Blimp1 is limiting for plasma cell transformation and thus has potential as a target for new therapies to combat MM.

  D Zotos , J. M Coquet , Y Zhang , A Light , K D'Costa , A Kallies , L. M Corcoran , D. I Godfrey , K. M Toellner , M. J Smyth , S. L Nutt and D. M. Tarlinton

Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.

  H Lauterbach , B Bathke , S Gilles , C Traidl Hoffmann , C. A Luber , G Fejer , M. A Freudenberg , G. M Davey , D Vremec , A Kallies , L Wu , K Shortman , P Chaplin , M Suter , M O'Keeffe and H. Hochrein

Polyinosinic:polycytidylic acid (poly IC), a double-stranded RNA, is an effective adjuvant in vivo. IFN-s (also termed IL-28/29) are potent immunomodulatory and antiviral cytokines. We demonstrate that poly IC injection in vivo induces large amounts of IFN-, which depended on hematopoietic cells and the presence of TLR3 (Toll-like receptor 3), IRF3 (IFN regulatory factor 3), IRF7, IFN-I receptor, Fms-related tyrosine kinase 3 ligand (FL), and IRF8 but not on MyD88 (myeloid differentiation factor 88), Rig-like helicases, or lymphocytes. Upon poly IC injection in vivo, the IFN- production by splenocytes segregated with cells phenotypically resembling CD8+ conventional dendritic cells (DCs [cDCs]). In vitro experiments revealed that CD8+ cDCs were the major producers of IFN- in response to poly IC, whereas both CD8+ cDCs and plasmacytoid DCs produced large amounts of IFN- in response to HSV-1 or parapoxvirus. The nature of the stimulus and the cytokine milieu determined whether CD8+ cDCs produced IFN- or IL-12p70. Human DCs expressing BDCA3 (CD141), which is considered to be the human counterpart of murine CD8+ DCs, also produced large amounts of IFN- upon poly IC stimulation. Thus, IFN- production in response to poly IC is a novel function of mouse CD8+ cDCs and their human equivalents.

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