| Popis: |
A crucial unsolved problem for all vaccines is the inhibition by maternal antibodies. Maternal antibodies confer protection against infections early in life. Over time, titers of maternal antibodies decline to non-protective titers that still inhibit vaccination. Generally, the generation of neutralizing antibodies is most significantly inhibited while T cell responses are not affected by maternal antibodies. Although this problem arises for many pathogens, no effective immunization strategy for vaccination in the presence of maternal antibodies has been defined because the underlying mechanism of interference was not known. The cotton rat is the only rodent in which measles virus replicates in the respiratory tract and lymphoid organs after intranasal inoculation. Using the cotton rat model of measles virus (MV) vaccination, we have been able to study the mechanism of maternal antibody inhibition and vaccination strategies in the presence of maternal antibodies.In the absence of experimental data and based on antibody feedback study, it has been suggested that epitope masking is one of the mechanism explaining the inhibition by maternal antibodies. However, we found that maternal antibodies inhibit B cell responses through cross-linking of the B cell receptor (BCR) with Fc gamma IIB receptor (FcgRIIB). This inhibition can be partially overcome by injection of MV-specific monoclonal IgM antibody. IgM stimulates the B cell through cross-linking the BCR via complement protein and antigen to the complement receptor 2 (CR2) signaling complex.To fully stimulate B cells in the presence of maternal antibodies, B cells require an extra stimulus to differentiate into antibody-secreting plasma cells. In order to provide such a stimulus, we generated a recombinant Newcastle disease virus (NDV) expressing the MV hemagglutinin (NDV-H). In contrast to MV, NDV-H induced high levels of type I interferon in plasmacytoid dendritic cells (pDCs) and in lung tissue. In cotton rats immunized with NDV-H, the induction of neutralizing antibodies was partially restored in the presence of maternal antibodies. These data indicated that type I interferon is an additional stimulus for B cell activation in the presence of maternal antibodies. Complete B cell activation resulting in secretion of neutralizing antibodies is the ultimate goal of vaccination in the presence of maternal antibodies. Co-stimulation of Toll-like receptor (TLR)-3 and TLR-9 with their respective agonists, Poly I:C (Polyinosinic polycytidylic acid, TLR-3 agonist) and ODN 2216 (CpG oligodeoxynucleotides 2216, TLR-9 agonist), induced synergistically higher type I interferon than that of NDV-H induced. In cotton rats, co-immunization of ODN 2216 and Poly I:C with MV vaccine induced normal B cell proliferation and neutralizing antibody response in the presence of maternal antibodies. These data support that type I interferon is crucial and sufficient to stimulate normal B cell responses in the presence of maternal antibodies. In addition, we have shown that CD21 functions as an interferon alpha receptor. In aggregate our data demonstrate that the shift in the balance of negative and positive signals by interferon alpha towards B cell stimulation is crucial in overcoming maternal antibody inhibition. |
