Background: The appearance of alloantibody can initiate the onset of rapid and destructive antibody-mediated rejection (AMR) or have no demonstrable acute effects. The factors determining the promotion and end result of alloantibody formation remain poorly understood. Our preliminary data reveals that pathogen-induced hypergammaglobulinemia results in de novo alloantibody production. To better understand the viral determinants that control this potentially harmful alloantibody production, in this study we compared widely replicating viruses with a tendency to persist (non-cytopathic) to poorly replicating (cytopathic) viral strains.

Methods/Results: NaÏve C57BL/6 mice were infected with non-cytopathic (acute LCMV Armstrong 2×105 pfu, chronic MCMV 1×105 pfu) and cytopathic (vaccinia 1x106pfu, polyoma 1x106pfu)virus infection. Alloantibody was measured by flow crossmatch and anti-H2d ELISA. Advanced flow cytometric methods were used to track allospecific B cells (H2d reactive cell, CD19+IgD-H2d+). Consistent with previous results from our lab, within the hypergammaglobulimic response (5-8 fold higher total IgG) generated by LCMV and MCMV infection, there was formation of de novo alloantibody (2-4 folds higher) in naÏve mice. Allospecific B cells were induced by both LCMV and MCMV infection, and were measured by flow cytometry analysis of splenocytes at 12 days post infection (0.020 +/- 0.009 % of total B cells, n=5). In contrast, infection with vaccinia and polyoma virus did not induce hypergammaglobulinemia. As expected, there was complete absence of de novo alloantibody formation. Consistent with the absence of alloantibody, both polyoma and vaccinia failed to induce alloreactive B cell development.

Conclusion: In this study we show that high amounts of viral antigens produced by widely replicating viruses induced polyclonal B cell activation leads to humoral allosensitization. Our data give a predictive reasoning to the alloreactive humoral immune response generated in transplanted/waiting list patient after viral infection depending on the nature of infection (non-cytopathic vs cytopathic, CMV vs. polyoma). Clearly, a better understanding of the association between pathogen infection, hypergammaglobulinemic and alloantibody production is needed. Ultimately, we propose that pathogen induced hypergammaglobulinemic responses may establish the likelihood of a detrimental donor-specific antibody (DSA) response and determine the ultimate clinical import of an alloantibody response.

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