Allosensitization following left ventricular assist device (LVAD) implantation is dependent on CD40-CD40 ligand interactions

Abstract

LVAD implantation is associated with in vivo T cell activation, induction of B cell hyperreactivity, and a high prevalence of anti-HLA antibodies. We have previously shown that exposure to polyurethane derived from the LVAD diaphragm induces activation of human T cells via an NFAT-dependent mechanism. Since B cell activation and antibody production requires T cell expression of the NFAT-dependent molecule CD40 ligand, we examined the effects of LVAD biomaterial on CD40-dependent pathways of B cell activation. Culture with medium containing LVAD biomaterial increased T cell expression of CD40 ligand by a mean of 2.6-fold (p<0.01), and resulted in B cell activation as defined by >2-fold increase in surface expression of CD86 (p<0.01). Pre-incubation with either cyclosporine (CsA) or mAB to the IL-2 receptor inhibited induction of both T cell surface CD40L expression and B cell CD86 expression, indicating that these events were calcineurin and IL-2 dependent. Furthermore, addition of a mAb to CD40 ligand was able to completely reverse the state of B cell activation following exposure to the LVAD polyurethane. To relate these findings to LVAD implantation in humans, T cell production of CD40 ligand was measured by RT-PCR of mRNA from explanted LVAD surfaces and by ELISA from sera of LVAD recipients, heart failure controls and normal volunteers. CD40 ligand mRNA was detected in all samples obtained from explanted LVADs. Moreover, whereas CD40 ligand serum levels were undetectable in either healthy volunteers or heart failure controls, they were significantly elevated in sensitized LVAD recipients (8.5ng/ml) compared with unsensitized LVAD recipients (0.5 ng/ml) (p<0.001). Together, these results indicate that T cell activation by LVAD-derived biomaterial causes NFAT translocation and induction of CD40 ligand, resulting in B cell activation via triggering of CD40. Inhibition of T cell activation by calcineurin-binding agents such as cyclosporine or blockage of the CD40-CD40 ligand interaction may successfully prevent allosensitization accompanying LVAD implantation.