Belatacept (CTLA4-Ig) Shows Minimal Suppression of CMV-Specific Memory T Cell (CMV-T) and Antibody (CMV-Ab) in CMV Sero (+) Kidney Transplant Recipients (Tx Pts).

Abstract

Background: Belatacept-treated (Rx) pts are at high risk for viral infections and their complications. We also observed an increased rate of CMV viremia in kidney Tx pts with Belatacept-Rx. However, the infection was mild in sero (+) pts. Clearance of CMV infection depends on CMV-T and CMV-Ab levels in CMV sero (+) pts. CD28 co-signaling is not required for memory T cell activation, but accelerates the activation. CD28 expression on plasma cells was recently shown, suggesting a possible role in maintenance of plasma cell function including viral-Ab production. Here we examine the effect of CD28 signaling blockade on CMV-T and CMV-Ab levels in vitro and in kidney Tx pts with Belatacept-Rx. Methods: CMV sero (+) blood from 18 normals and 20 pts treated with Belatacept + MMF + steroids for median 10M were submitted for CMV-T-cytokine flow cytometry (CFC) & anti-CMV-IgG ELISA. In some experiments, CMV-T-CFC was performed w/ or w/o anti-CD28 Ab co-stimulator, or w/ or w/o Belatacept. A peptide mixture from CMV pp65 & CMV lysate were used for CMV-CD8+ (CMV-Tc) & CD4+ T (CMV-Th) detection, respectively. The results were expressed as IFNγ+ cell% in each cell population and CMV-T >0.2% was considered+. Results: CMV-Tc levels w/ or w/o anti-CD28 Ab in the CFC were similar (2.2±2.4% vs. 2.9±3.1%), while CMV-Th was slightly lower w/o the Ab than w/ (0.9±0.8% vs. 1.0±1.0%, p=0.2). When Belatacept (0-1000mg/ml) was added to the CMV-T-CFC, no change was observed in CMV-Tc (4.2 vs. 4.2% at 0 vs. 1000mg/ml) and CMV-Th (1.2 vs. 1.2%). Positivity for CMV-Tc or CMV-Th was detected even after 10M Belatacept treatment in all 9 pts with available CMV-T results (Tc+/Th+: 7/9 [78%], Tc+/Th-: 1/9 11%], Tc-/Th+: 1/9 [11%]), which is a similar trend in 18 CMV sero (+) normals (Tc+/Th+: 15/18 [83%], Tc+/Th-: 1/18 [6%], Tc-/Th+: 2/18 [11%]). Anti-CMV-IgG levels in these pts did not change even after 10M Rx (Index: 3.8±1.1 vs. 3.5±1.1) Conclusions: The effect of CD28 blockade on CMV-T is minimal, and CMV-Tc, CMV-Th activity and anti-CMV-IgG levels are intact even after 10M Belatacept-Rx in CMV sero (+) pts. These results may explain the mild CMV infection in CMV sero (+) kidney Tx pts treated with Belatacept. DISCLOSURES:Jordan, S.: Grant/Research Support, Genentech Roche, CSL-Behring grant support.