Fcγ Receptors in Solid Organ Transplantation.

In the current era, one of the major factors limiting graft survival is chronic antibody-mediated rejection (ABMR), whilst patient survival is impacted by the effects of immunosuppression on susceptibility to infection, malignancy and atherosclerosis. IgG antibodies play a role in all of these processes, and many of their cellular effects are mediated by Fc gamma receptors (FcγRs). These surface receptors are expressed by most immune cells, including B cells, natural killer cells, dendritic cells and macrophages. Genetic variation in FCGR genes is likely to affect susceptibility to ABMR and to modulate the physiological functions of IgG. In this review, we discuss the potential role played by FcγRs in determining outcomes in solid organ transplantation, and how genetic polymorphisms in these receptors may contribute to variations in transplant outcome.MRC is supported by the NIHR Cambridge BRC, the NIHR Blood and Transplant Research Unit (Cambridge) and by a Medical Research Council New Investigator Grant (MR/N024907/1).This is the final version of the article. It first appeared from Springer via https://doi.org/10.1007/s40472-016-0116-

Inhibition of NK cell-mediated Cytotoxicity by Tubular Epithelial Cell Expression of Clr Proteins

Cytotoxic effector cells can target and kill parenchymal cells of the kidney which results in injury and loss of function. Endogenous regulatory systems may exist to attenuate Natural Killer (NK) and other effector cell activation and cytotoxicity in diverse conditions, including ischemia-reperfusion injury associated with kidney transplantation. Understanding these mechanisms will direct new therapeutic strategies. Kidney tubular epithelial cells (TEC), the predominant cell type in kidneys, may negatively regulate NK cell activation by surface expression of C-type lectin-related proteins (Clr). Clr-b and -f were found to be expressed by wild type (WT) TEC. Clr-b was upregulated by TNFα+IFNγ in vitro. Elimination of both Clr-b and Clr-f expression with siRNA resulted in increased NK killing of TEC compared to individual silencing of Clr-b or Clr-f TEC (p\u3c0.01), or WT control TEC (p\u3c0.001). NK cells treated in vitro with soluble Clr-b and Clr-f reduced their capacity to kill Clr-b/-f -/- TEC as compared to untreated NK cells (p\u3c0.05). NK cells therefore are regulated by proteins expressed by TEC and thus may represent an important endogenous regulatory system in the kidney to limit organ injury. As no current drugs exist to specifically target NK cells, Clr-b and Clr-f soluble proteins that bind to NK cells may represent a novel and clinically feasible strategy to protect organs from NK cell-mediated inflammation during ischemia-reperfusion and other kidney injury models

Unraveling the Role of Allo-Antibodies and Transplant Injury.

Alloimmunity driving rejection in the context of solid organ transplantation can be grossly divided into mechanisms predominantly driven by either T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), though the co-existence of both types of rejections can be seen in a variable number of sampled grafts. Acute TCMR can generally be well controlled by the establishment of effective immunosuppression (1, 2). Acute ABMR is a low frequency finding in the current era of blood group and HLA donor/recipient matching and the avoidance of engraftment in the context of high-titer, preformed donor-specific antibodies. However, chronic ABMR remains a major complication resulting in the untimely loss of transplanted organs (3-10). The close relationship between donor-specific antibodies and ABMR has been revealed by the highly sensitive detection of human leukocyte antigen (HLA) antibodies (7, 11-15). Injury to transplanted organs by activation of humoral immune reaction in the context of HLA identical transplants and the absence of donor specific antibodies (17-24), strongly suggest the participation of non-HLA (nHLA) antibodies in ABMR (25). In this review, we discuss the genesis of ABMR in the context of HLA and nHLA antibodies and summarize strategies for ABMR management

Regulation of NK cell-mediated tubular epithelial cell death and kidney ischemia-reperfusion injury by the NKR-P1B receptor and Clr-b

Renal ischemia-reperfusion injury (IRI) occurs following reduced renal blood flow and is a major cause of acute injury in both native and transplanted kidneys. We have previously demonstrated that NK cells can mediate tubular cell death and kidney IRI. Natural killer receptor-protein 1B (NKR-P1B) has been shown to interact with C-type lectin-related protein B (Clr-b), resulting in the suppression of NK cell-mediated cytotoxicity. Clr-b mRNA and protein expression in the kidney were up-regulated after renal IRI. Similar upregulation of Clr-b expression was seen in cytokine-challenged primary-cultured tubular epithelial cells (TEC). Furthermore, NK cytotoxicity assays demonstrated enhanced necrotic death in TEC after Clr-b siRNA knockdown. Our results indicate that Clr-b expression in TEC and the kidney is upregulated after injury. The blockade of Clr-b enhances NK cell-mediated TEC death and kidney injury. These studies suggest that enhancing the inhibitory Clr-b in transplant patients may protect the kidney from NK cell-mediated cytotoxicity

Immunopathology of Kidney Transplantation

Renal transplantation is currently the best alternative for patients with end-stage renal disease. Immune responses activated against the allograft are a decisive factor in transplantation outcomes and patient survival. Although short-term graft and patient survival have improved significantly as a result of better donor matching systems, novel immunosuppressive agents and enhanced care, long-term outcomes remain unfavorable and reflect sub-clinical injury caused by chronic rejection. The immune system lies at the intersection of immunogenic tolerance and graft failure; thus, it is a major determinant of pathology in the context of renal transplantation. During the early stages of transplantation increased expression of cytokines has been observed in addition to increased expression of adhesion proteins and immune cells. This early inflammatory response does not necessarily end in graft rejection, although this will depend on the severity of the inflammation. Activation of Toll-like Receptors (TLRs), damaging molecular patterns (DAMPs), and other components of innate immunity is key to the formation of atherosclerotic plaques and the development of autoimmune diseases. Initially the donor antigens are presented to the T lymphocytes of the recipient. This activation induces their proliferation, differentiation and cytokine production. Successful kidney transplant recipients need to develop immunologic tolerance against donor antigens. In this chapter, we address some of the innate and adaptive immune mechanisms associated with kidney transplantation; emphasizing their role in allograft rejection

The effect of two novel C-type lectins, Ba100 and Ba25, isolated from the venom of the puff adder, Bitis arietans on T lymphocyte proliferative responses

Includes abstract. Includes bibliographical references (p. 233-318)

Increased CD16 expression on NK cells is indicative of antibody-dependent cell-mediated cytotoxicity in chronic-active antibody-mediated rejection

Chronic-active antibody mediated rejection (c-aABMR) contributes significantly to late renal allograft failure. The antibodies directed against donor-derived antigens, e.g. anti-HLA antibodies, cause inflammation at the level of the microvascular endothelium. This is characterized by signs of local activation of the complement system and accumulation of immune cells within the capillaries. Non-invasive biomarkers of c-aABMR are currently not available but could be valuable for early detection. We therefore analyzed the activation profiles of circulating T and B cells, NK cells and monocytes in the peripheral blood of 25 kidney transplant recipients with c-aABMR and compared them to 25 matched recipients to evaluate whether they could serve as a potential biomarker. No significant differences were found in the total percentage and distribution of NK cells, B cells and T cells between the c-aABMRpos and c-aABMRneg cases. There was however a higher percentage of monocytes present in c-aABMRpos cases (p < .05). Additionally, differences were found in activation status of circulating monocytes, NK cells and γδ T cells, mainly concerning the activation marker CD16. Although statistically significant, these differences were not sufficient for use as a biomarker of c-aABMR