Laboratory of Translational Immunology
The major interest of our research group for many years has been natural killer (NK) cell biology in the context of xenotransplantation, ABO blood group incompatibility in allotransplantation, and most recently, target cell elimination by NK cells and other innate immune cells triggered by polyspecific immunoglobulin G (IgG) or monoclonal therapeutic antibodies such as rituximab via Fc-gamma receptors (FcγRs).
The current organ shortage in transplantation medicine stimulates the exploration of new strategies to expand the donor pool, including xenotransplantation. The use of pig organs could offer a way out of the problem. The goal in clinical transplantation is the induction of long-term graft acceptance. Graft infiltration by immune cells and the participation of soluble factors are characteristics of acute and chronic cellular xenograft rejection.
Today, the experimental model of pig-to-non-human primate (NHP) xenotransplantation remains far from the excellent survival times achieved in the clinical setting of allotransplantation in humans. However, new engineering tools for genetic modifications of the donor pigs recently prolonged the pig xenograft survival in NHP. To exploit the power of genetic engineering, it is imperative to improve the testing of the genetically multi-modified pigs before running into complex and costly pig-to-NHP xenotransplantation experiments. Thus, novel in vitro and ex vivo approaches represent sound alternatives to measure the innate immune responses, both cellular and soluble.
In a collaboration of a multidisciplinary team involving experts in pig genetic engineering in Munich, coagulation and endothelial activation in Berne, our overall aim is to develop and test novel tools for the functional assessment of a basic set genetic modifications on cellular innate immunity, in particular monocytes, neutrophils, NK cells, but also examining T cell activation.
Antibodies & IgG
Immunoglobulins (Igs), also referred to as antibodies (Abs), are proteins synthesized by B-lymphocytes and plasma cells. From the five Ig classes, IgG is the most abundant in the human serum. In general, Igs help in the defense against infectious organisms by several mechanisms. On the other hand, Igs also play a major role in transplantation medicine, autoimmunity/chronic inflammation, immunodeficiency, and more lately in cancer immune therapy.
The revolution of therapeutic monoclonal antibodies (mAb) entering various clinical disciplines boosted the interest in the function of innate immune effector cells and the Fc-gamma receptors (FcγRs) to which IgG bind. Innate immune cells including polymorphonuclear cells (PMN), NK cells, and monocytes, represent the first line of cellular defense, differentially express FcγRs, and deplete Ab-coated target cells by antibody-dependent cell cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) mechanisms.
The current line of research aims to increase the general understanding of the molecular mechanisms involved in regulating Ab-mediated therapies; in particular, the effector function of innate immune cells, i.e. NK cell-mediated ADCC and monocyte-mediated ADCP. The results of this project might elucidate inter-individual differences in the responses and side effects of immunoglobulin and monoclonal antibody treatments.