Dr Cees van Kooten, PhD

Leiden University Medical Center, The Netherlands

Title: A radical way to induce immune regulation

Abstract:

Kyra A. Gelderman, Marina Kraaij, Sandra W. van der Kooij, Karin Koekkoek, and Cees van Kooten  Dept of Nephrology, LUMC, Leiden, the Netherlands

Previously it was shown in a mouse and rat model that reactive oxygen species (ROS) produced by macrophages suppress T cell responses in vitro and in vivo and prevent autoimmunity. ROS can thus be beneficial when produced in small quantities, whereas large amounts mediate the well documented oxidative stress.

Macrophages can occur in pro- or anti inflammatory forms and several experimental conditions haven been described to mimick this in vitro by culturing CD14+ monocytes in different cytokines. Pro-inflammatory macrophage type1 (Mph1) can be generated by culturing monocytes in GM-CSF and whereas culture in M-CSF is a very efficient way to generate anti-inflammatory Mph2. Both cell types have different morphological and phenotypic features and are characterized by a strongly polarized cytokine production profile.

We investigated functional polarization of human Mph subsets generated from CD14+ monocytes and ROS production upon PMA stimulation was measured. Oxidative burst capacity was highest in Mph2 but almost absent in Mph1. Mph2 was a potent inhibitor of T cell activation as induced by anti-CD3/28, which could be reversed by apocynin, a specific inhibitor of the NADPH oxidase complex. T cells cocultured with Mph2, but not with Mph1, expressed higher levels of FoxP3 and were shown to suppress PHA induced proliferation of other T cells. Apocynin reversed this effect, indicating that Treg induction by Mph2 was ROS dependent.

In congenic DA.Ncf1 rats that have normal ROS production, treatment with dexamethasone resulted in increased macrophage/ monocyte ROS production and increased number of Treg. In contrast, in normal DA rats which have a hampered ROS production, neither of these effects were observed. Finally, ROS-hampered DA Mph2 induced an allogeneic DTH response, whereas ROS-sufficient DA.Ncf1 Mph2 prevented DTH in vivo and could suppress T cell responses by inducing Treg in vivo.

Thus the property to produce ROS enables Mph2 to dampen immune responses by inducing Treg in humans and rats. Mph2 may be used as cellular therapy to prevent T cell activation in autoimmunity and transplantation

Biography:

Dr Cees van Kooten is head of the immunology research laboratory of the department of Nephrology of the Leiden University Medical Center (Leiden, The Netherlands). During his PhD at the University of Amsterdam, he studied the role of cytokines in normal and malignant B cells During a post-doctoral period at the laboratory of dr Jacques Banchereau in Dardilly, France, this work was further extended in the direction of mechanisms of T-B cell interaction and the critical role of CD40-CD40L.

Since 1995, he has been appointed at the department of Nephrology of the LUMC. Here he has made major contributions in the field of renal inflammation and renal transplant immunology, including the role of both innate and adaptive immunity. This included research on IgA nephropathy: the regulation of IgA production and effector functions of IgA like interactions with Fc-receptors and the complement system. Moreover, there has been a major attention for the functional role of both professional antigen presenting cells like dendritic cells and macrophages, as well as human renal epithelial cells. Both in human and rats, functional modulation of dendritic cells and macrophages has been studied in vitro and in vivo, with the aim to skew their immuneregulatory mechanisms and to explore the possibility to prolong allograft survival. Quantification and characterization of human DC subsets in renal biopsies has been explored to monitor renal transplantation in the clinic.

He has been author on more than 160 peer reviewed papers. At present he is treasurer of the Dutch Society for Immunology (NVVI) and member of the Scientific Advisory Board of the Dutch Kidney Foundation.