Glucocorticoid-Induced TNFR-Related Protein Stimulation Reverses Cardiac Allograft Acceptance Induced by CD40-CD40L Blockade

Abstract

CD40-CD40L blockade has potent immunosuppressive effects in cardiac allograft rejection but is less effective in the presence of inflammatory signals. To better understand the factors that mediate CD40-CD40L blockade-resistant rejection, we studied the effects of stimulation through glucocorticoid-induced TNFR-related protein (GITR), a costimulatory protein expressed by regulatory and effector T cells. Stimulation of CD40−/− or wild-type recipient mice treated with anti-CD40L mAb (WT+anti-CD40L) and with agonistic anti-GITR mAb resulted in cardiac allograft rejection. GITR stimulation did not induce rejection once long-term graft acceptance was established. In vitro, GITR stimulation increased proliferation of effector T cells and decreased regulatory T cell (Treg) differentiation in both treatment groups. GITR-stimulated CD40−/− recipients rejected their allografts more rapidly compared to GITR-stimulated WT+anti-CD40L recipients, and this rejection, characterized by a robust Th2 response and significant eosinophilic infiltrate, could be mediated by CD4+ T cells alone. In contrast, both CD4+ and CD8+ T cells were required to induce rejection in GITR-stimulated WT+anti-CD40L-treated recipients, and the pathology of rejection was less severe. Hence, early GITR stimulation could initiate graft rejection despite CD40 deficiency or anti-CD40L mAb treatment, though the recipient response was dependent on the mechanism of CD40-CD40L disruption.

CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study

“…The role of CD40 ligand in cardiovascular disease is also far from clear. However, there is an increasing body of evidence that connects the presence of CD40 ligand to heart-related problems such as vascular dysfunction/inflammation [33], coronary heart disease [34], and cardiac allograft rejection [35,36].…”

A Glimpse into Humoral Response and Related Therapeutic Approaches of Takayasu’s Arteritis

“…In our previous research, TAK patients exhibited decreased CD40 mRNA levels in peripheral blood mononuclear cells, relative to healthy individuals [ 91 ]. The data suggest the daily dose of glucocorticoids is inversely correlated with CD40 mRNA levels [ 92 ], suggesting that glucocorticoids may inhibit T cell activation through downregulating CD40. Consistently, gene co-expression networks have shown that compared with the active TAK group, inactive TAK groups have a reduced degree of CD40L and CD40 [ 91 ].…”