HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion

Abstract

Kidney transplantation is the most successful treatment option for patients with end-stage renal disease, and chronic antibody-mediated rejection is the principal cause of allograft loss. Predictive factors for chronic rejection include high levels of HLA alloantibodies (particularly HLA class II) and activation of graft endothelial cells (ECs). The mechanistic basis for this association is unresolved. We used an experimental model of HLA-DR antibody stimulation of microvascular ECs to examine the mechanisms underlying the association between HLA class II antibodies, EC activation and allograft damage. Activation of ECs with the F(Ab 0 ) 2 fragment of HLA-DR antibody led to phosphorylation of Akt, ERK and MEK and increased IL-6 production by ECs cocultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an Akt-dependent manner. We previously showed that HLA-DR-expressing ECs induce polarization of Th17 and FoxP3 bright regulatory T cell (Treg) subsets. Preactivation of ECs with anti-HLA-DR antibody redirected EC allogenicity toward a proinflammatory response by decreasing amplification of functional Treg and by further increasing IL-6-dependent Th17 expansion. Alloimmunized patient serum containing relevant HLA-DR alloantibodies selectively bound and increased EC secretion of IL-6 in cocultures with PBMCs. These data contribute to understanding of potential mechanisms of antibody-mediated endothelial damage independent of complement activation and FcR-expressing effector cells.

Minimizing the risk of allo-sensitization to optimize the benefit of allogeneic cardiac-derived stem/progenitor cells

“…Alongside CDC and ADCC classical antibody-induced mechanisms, the relevance of antibody-induced HLA signaling in transplantation has been demonstrated1353. While HLA molecules are principally viewed as antigen presenting structures they are also bona fide signal transduction receptors54.…”

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

“…This is a significant gap in our knowledge, since numerous studies have found a strong relationship between DSAs against HLA-DQ and chronic rejection. Exposure of HLA-DR-expressing endothelial cells increased ERK and Akt phosphorylation (153), as well as activation of proinflammatory Th17 cells (154). More studies are needed to elucidate the effect of antibodies against HLA II on vascular endothelial cell signaling, and how they contribute to acute and chronic AMR.…”

Recent advances in allograft vasculopathy

“…Anti-HLA-DR antibodies can increase EC secretion of IL-6, thereby amplifying a pro-inflammatory response by enhancing T H 17 expansion diminishing functional regulatory T cell (T reg ) proliferation (55). While classically DSA targets have been anti-HLA antibodies, the presence of non-HLA antibodies is increasingly being recognized as correlated with chronic rejection and diminished long-term graft survival (56).…”