• The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response.

      He, Jin-Shu; Meyer-Hermann, Michael; Xiangying, Deng; Zuan, Lim Yok; Jones, Leigh Ann; Ramakrishna, Lakshmi; de Vries, Victor C; Dolpady, Jayashree; Aina, Hoi; Joseph, Sabrina; et al. (2013-11-18)
      The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE(+) cells in memory responses is particularly unclear. IgE(+) B cell differentiation is characterized by a transient GC phase, a bias toward the plasma cell (PC) fate, and dependence on sequential switching for the production of high-affinity IgE. We show here that IgE(+) GC B cells are unfit to undergo the conventional GC differentiation program due to impaired B cell receptor function and increased apoptosis. IgE(+) GC cells fail to populate the GC light zone and are unable to contribute to the memory and long-lived PC compartments. Furthermore, we demonstrate that direct and sequential switching are linked to distinct B cell differentiation fates: direct switching generates IgE(+) GC cells, whereas sequential switching gives rise to IgE(+) PCs. We propose a comprehensive model for the generation and memory of IgE responses.
    • The molecular basis of synergism between carboplatin and ABT-737 therapy targeting ovarian carcinomas.

      Jain, Harsh Vardhan; Müller, A (2011-02-01)
      Resistance to standard chemotherapy (carboplatin + paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-x(L), whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-x(L) that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bcl-x(L) for survival. Numerical simulations predict the existence of a threshold of Bcl-x(L) below which these cells are unable to recover. Furthermore, co- plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists.