[Background] Despite a 50% decline in acute rejection over the past 10 years, antibody-mediated injury has been identified as perhaps the leading cause of chronic rejection in humans. Recently, we developed a novel model of de novo antibody production and antibody-mediated chronic rejection using transgenic mice expressing human CD52. It is now clear that previous pathogen exposures and resultant immune memory can influence the course of future immune responses to unrelated pathogens or transplanted antigen. As the factors determining alloantibody formation during chronic rejection remain poorly understood, in this study we examined the effects of pathogen infection on chronic antibody mediated rejection.
[Methods] NaÏve human CD52 Transgenic mice were infected with 1X105 PFU of MCMV. After 60-70 days infection, we transplanted C56BL/6 hearts to human CD52 transgenic CBA mice. Alemtuzumab (10Μg/dose) was given on day -2, -1, +2, and +4 of transplantation. Donor specific antibodies (DSA) and alloreactive B cells were measured with flow cytometry at 50 days after heart transplantation.
[Results] Allograft survivals were not different between two groups, naÏve/transplanted and infected/transplanted. Interestingly, pre-transplant chronic viral infection induced a 10 fold higher alloantibody titers when compared to naive un-infected mice (MFI, 2444±297.0 vs. 256.7±8.41; p<0.01). Post- transplant in mice undergoing chronic antibody mediated rejection, we observed an increase in DSA in infected/transplanted group when compared to uninfected/transplanted controls (Fold increase, 17.61±1.72 vs. 1.54±0.23; p<0.05) at 50 days after transplantation. Advanced flow cytometry methods were used to track allospecific B cells (anti H-2b reactive B cells). Consistent with increase DSA, there was an increase of alloreactive B cells in infected recipients. (%, 0.02293±0.005 vs. 0.003887 ± 0.002; p<0.01).
[Conclusion] As preexisting chronic or latent infections are prevalent in transplant recipients, the results of this study show that chronic viral infection can leads an increase of DSA during chronic antibody mediated rejection. The long-term goal is that the findings from these investigations may allow us not only to predict which patients are more at risk for alloantibody formation and graft destruction, but also to develop targeted treatment strategies that are currently lacking that could potentially improve long-term graft outcomes in patients who develop alloantibody after transplantation.
To cite this abstract in AMA style:Oh B, Ruhil R, Bulut O, Kwun J, Kirk A, Knechtle S, Iwakoshi N. Effects of Viral Infection on Chronic Anti-Mediated Rejection, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/effects-of-viral-infection-on-chronic-anti-mediated-rejection-the/. Accessed March 31, 2020.
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