Date: Monday, May 4, 2015
Session Time: 4:00pm-5:30pm
Presentation Time: 4:24pm-4:36pm
Location: Room 122-AB
Belatacept, a B7-specific fusion protein, blocks CD28-B7 costimulation and prevents kidney allograft rejection. However, it is ineffective in a sizable minority of patients. Although T cell receptor and CD28 engagement is known to initiate T cell activation, many human antigen-experienced T cells lose CD28, and can be activated independent of CD28 signals. We posit that these cells are central drivers of costimulation blockade resistant rejection (CoBRR) and propose that CoBRR might relate to an accumulation of CD28- T cells resulting from viral antigen exposure. Here we demonstrate that infection with Polyomavirus (a BK virus analog), murine CMV (a human CMV analog), and gammaherpes virus (an EBV analog) can induce CD28 down-regulation in murine T effector memory cells. Using mixed lymphocyte reactions assays, we show that these murine analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic, costimulation blockade resistant, alloreactive response against MHC-mismatched tissue without prior alloantigen exposure. Further analysis reveals that gammherpesvirus-induced oligoclonal T cell expansion is required for the increased alloreactivity. Finally, preliminary data of mice with MHC-mismatched heterotopic heart transplants suggest that virally infected mice exhibit histologically worse acute cellular rejection relative to uninfected mice. Taken together, virus exposure results in reduced expression of CD28, the target of costimulation blockade therapy. These viruses also contribute to increased alloreactivity both in vitro and in vivo. Thus, CD28 downregulation following viral infection may play a seminal role in driving CoBRR. These findings have significant clinical implications. Further elucidation of this phenomenon may ultimately enable clinicians to stratify transplant candidates based on their viral serologies and tailor their immunosuppression regimens accordingly.
To cite this abstract in AMA style:Mou D, Espinosa J, Stempora L, Kwun J, Iwakoshi N, Kirk A. Virus Induced CD28 Down-Regulation as a Potential Driver of Costimulation Blockade Resistant Rejection [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/virus-induced-cd28-down-regulation-as-a-potential-driver-of-costimulation-blockade-resistant-rejection/. Accessed May 27, 2020.
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