As severe dengue disease is associated with a second infection wi

As severe dengue disease is associated with a second infection with a heterologous serotype of DENV, it would be of interest to determine the magnitude, quality, serotype specificity and enhancing activity of antibodies generated following a second infection with other serotypes and strains of DENV. There is variability in the infection rate and immunological responses detected in BLT-NSG mice. We were unable to find

a correlation between the degree of reconstitution of hCD45+ cells in the blood before infection Caspase inhibitor and the ability of BLT-NSG mice to become productively infected (data not shown). Robust IgM immune responses also did not correlate with viral titres in these mice. Another limitation of the BLT-NSG model

is variable and low DENV-specific IgG responses, which may reflect multiple deficiencies in this model. The inability of mouse cytokines such as B-lymphocyte-stimulating factor to signal effectively to human B cells in the xenogeneic environment may account for poor B-cell development.26,32 Generation of B-lymphocyte-stimulating factor-transgenic NSG mice is currently underway and should enhance both human B-cell and T-cell immune function in humanized mice. Human IgG concentrations in the serum are on average lower in BLT-NSG mice compared with human adults.33,34 Inadequate T-cell help and lack of human follicular dendritic cell engraftment may also contribute to ineffective class switching in these mice. Providing adequate human HLA expression as well as supporting CT99021 in vitro B-cell maturation by addition of human stromal cells with follicular dendritic cell engraftment differentiation capacity should lead to improved humoral responses. We have begun to phenotype human B cells in engrafted BLT-NSG mice and speculate that poor IgG production may be related to high frequencies of immature B cells in the periphery, as Thymidylate synthase has been

shown by other groups.35,36 Biswas et al.37 indicate that 50% of the human B cells in the periphery, but not in the bone marrow, also express the CD5 antigen, which is found only infrequently on mature follicular B cells in humans. Immunization with recombinant viral envelope antigens (HIV-gp140 and West Nile virus envelope proteins) stimulated production of antigen-specific human antibodies to West Nile virus and HIV gp140 that were predominantly of the IgM isotype. Transgenic expression of human-specific molecules and cytokines should better recapitulate immune responses observed in immunocompetent individuals.11,24 In conclusion, we have demonstrated improved DENV-specific adaptive immune responses in BLT-NSG mice. There are still some limitations with current models and further improvement in human engraftment and DENV-specific immune responses are required before these models can be used routinely and reproducibly in vaccine development.

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