Dendritic Cell Function in Transplantation Arteriosclerosis

Rationale: Heme oxygenase (HO)1 is an important modulator of physiological function with cytoprotective properties. Although HO1 has previously been associated with an improved survival of the vascular allograft in rat models in response to pharmaceutical induction of HO1 the exact mechanism by which HO1 exerts it protective function remains to be elucidated. Objective: We sought to define the role of HO1 in dendritic cells (DCs) function that governs the alloimmune response underlying the development of transplantation associated vasculopathy. Methods and Results: Loss of HO1 in DCs or by small interfering RNA silencing resulted in major histocompat-ibility complex class II (MHCII) upregulation by CIITA-driven transcriptional regulation and by STAT1 (signal transducers and activators of transcription 1) phosphorylation. As a result, increased MHCII alloantigen presentation by HO1 ؊/؊ DCs directed the primary T-cell response preferentially toward a CD4 ؉ T-cell, rather than a CD8 ؉ T-cell reaction. In a murine model for transplantation arteriosclerosis, adoptive transfer of HO1 ؊/؊ DCs before allograft transplantation was indeed associated with pronounced intragraft CD4 ؉ T-cell infiltration and increased IgG deposition, suggestive of an accelerated development of vasculopathy toward the chronic phase. The role of HO1 in DC-mediated T cell activation was further validated by inhibition of endogenous HO1 in allograft recipients. Inhibition of HO1 in DCs aggravated transplant arteriosclerosis development, by increasing intima hyperplasia, and by activation of a CD4 ؉ T cells allograft response, mediated by MHCII upregulation. Conclusions: These findings demonstrate that HO1 plays an important role in the genetic regulation of the vascular alloimmune response elicited by DCs. A rterial intimal hyperplasia subsequent to organ trans-plantation, ie, transplant arteriosclerosis, continues to impede the long-term allograft survival and patency of vascular allografts. 1 Transplant arteriosclerosis is thought to be initiated by alloimmune-mediated injury to graft endothe-lial lining of the vascular bed, resulting in endothelial cell activation, and dysfunction, facilitating perivascular infiltration of lymphocytes. Subsequently, intimal vascular smooth muscle cells (VSMCs) respond through activation, migration into the intima of the vessel, followed by cell proliferation and extracellular matrix deposition, which results in progressive neointimal hyperplasia with impediment of allograft perfusion, and eventual graft failure. Alloantigen presentation by host dendritic cells (DCs) initiates the development of an antialloantigen-specific adaptive immune response. 1 Although involvement of DCs in allograft rejection is presumed, the direct function of DCs in the pathogenesis of transplantation arteriosclerosis still remains to be elucidated. Allograft vascu-lopathy in humans as well as in …