The breadth and strength of HLA specific antibodies (HSA) have a significant impact on waiting times for transplantation and the presence of HSA prior to transplantation is correlated with higher rates of AMR and graft loss after transplantation. Irrespective of the timing of HSA analysis, changes in the dynamics of HSA has important clinical implications, and underscores the importance of understanding the mechanisms involved in controlling HSA levels. In the current study we studied the role of viral infection in the maintenance of alloantibody in a sensitized murine model.
Methods/results: C57BL/6 mice received fully mismatched skin graft from Balb/c mice. Upon stabilization of serum alloantibody (7 week post-transplant), mice were infected with acute LCMV virus (2×105 pfu/mice I.P). Interestingly infected sensitized mice showed 2-4 fold increases in alloantibody over baseline sensitization levels 2 week post-infection. Importantly this increase level of alloantibody was maintained for greater than 10 weeks post-infection. We next examined the effect of viral infection on alloreactive B cells in sensitized mice. Advanced flow cytometry analysis of alloreactive B cells revealed a significantly higher number of alloreactive B cells in infected sensitized mice (CD19+IgD-H2d+, 6-8 fold increase) in comparision to uninfected sensitized controls. The majority of alloreactive B cells were IgG+, GL7-, CD38+ supporting the activation memory B cells by viral infection in sensitized recipients The sustained level of increased alloantibody and alloreactive B cell activation was accompanied with alloreactive plasmablast differentiation in the spleen and the establishment of long lived alloreactive plasma cells (5-7 folds higher) in the bone marrow when measured by ELISPOT and flow cytometry.
Conclusion: Our preliminary studies in a sensitized murine model revealed that acute viral infection results in a significant polyclonal activation of B cells and hypergammaglobulinemia. Within this polyclonal activation, clones of alloreactive memory B cells expand and differentiate to alloantibody producing long lived plasma cells resulting in increased level of sensitization. Thus, we propose that inflammation induced hypergammaglobulinemic responses regulate HLA antibody levels in sensitized patients. Understanding the mechanisms responsible for an increase in the breadth or level of HSA is critical to the continued successful management and transplantation of sensitized patients.
To cite this abstract in AMA style:Ruhil R, Bulut O, Talebagha S, Oh B, Lu V, Knechtle S, Iwakoshi N. Regulation of Serological Alloreactive Memory by Pathogen Infection, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/regulation-of-serological-alloreactive-memory-by-pathogen-infection-the/. Accessed May 6, 2021.
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