Although closely related, RhoA and RhoC have distinct molecular targets and functional roles in cell migration and invasion.

Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA-A2-specific CARs were engineered: one comprising a CD28-CD3ζ signaling domain (CAR) and one lacking an intracellular signaling domain (ΔCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or ΔCAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and ΔCAR Tregs preferentially transmigrated across HLA-A2-expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune-mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation.

Oxidized lipids are generated from (poly)unsaturated diacyl- and alk(en)ylacyl glycerophospholipids under conditions of oxidative stress. The great variety of reaction products is defined by the degree of modification, hydrophobicity, chemical reactivity, physical properties and biological activity. The biological activities of these compounds may depend on both, the recognition of the particular molecular structures by specific receptors and on the unspecific physical and chemical effects on their target systems (membranes, proteins). In this review, we aim at highlighting the molecular features that are essential for the understanding of the biological actions of pure oxidized phospholipids. Firstly, their chemical structures are described as a basis for an understanding of their physical and (bio)chemical properties in membrane- and protein-bound form. Secondly, the biological activities of oxidized phospholipids are discussed in terms of their unspecific effects on the membrane level as well as their potential interactions with specific targets (receptors) affecting a large set of (signaling) molecules. Finally, the role of oxidized phospholipids as important mediators in pathophysiology is discussed with emphasis on atherosclerosis.