hIL34-Tol

Transplantation is the only treatment for patients suffering of a number of diseases. The use of immunosuppressors in organ transplantation has allowed remarkable success in the short and medium term graft survival, but unwanted side effects still lead to high morbidity and mortality, even when avoiding excessive immunosuppression. In the long term, immunosuppressors have not really prolong allograft survival and can even be deleterious in the establishment of tolerance. Therefore, new treatments are needed that will be more specific for anti-donor immune responses or with less side effects and that would allow at least to decrease the use of immunosuppressors. Cytokines and enzymes controlling metabolic pathways have been described as powerful tools for controlling immune responses and it is important to identify new mediators of immune tolerance. Interleukin-34 (IL-34) is a cytokine, described for the first time in 2008. Although IL-34 shared very little homology with M-CSF (CSF1), they share a common receptor (CSF1R) and IL-34 has also 2 distinct receptors, protein-tyrosine-phosphatase zeta (PTPz) and CD138 (syndecan-1). Until now, studies have demonstrated that this cytokine is released by some tissues and involved in the differentiation and survival of macrophages, monocytes and DC in response to inflammation. More recent articles (for review in Guillonneau et al., 2017) including our own work have described the immunoregulatory properties of IL-34. We have demonstrated that IL-34 is secreted by Foxp3+ CD4+ and CD8+ Treg in human and CD8+CD45RClow Tregs in rat. We also demonstrated that blockade of IL-34 in vitro in human and rat MLR assays inhibited both CD4+ and CD8+ Treg suppressive function. Most importantly, we also showed that IL-34 treatment in vivo in a model of cardiac allograft induced transplant tolerance through induction and differentiation of macrophages toward a M2-type regulatory profile and subsequent induction of CD4+ and CD8+ Tregs by these M2-type macrophages. Thus, our results published in 2015 are the first ones to describe tolerance in organ transplantation with IL-34. Therefore, delivering IL-34 could decrease immune responses in human organ transplantation and GVHD. Furthermore, these results are the basis of an international patent deposition (WO2016009041) claiming the use of IL-34 in these therapeutic domains. The overall objective of the project “hIL34-Tol” aims at developing a breakthrough scientific approach in Immunotherapy that could address large unmet medical needs in transplantation. The scientific approach is based on the tolerogenic effect of a new cytokine, IL-34. The gathering of these data will provide important clues on the mechanism of action of IL-34 in in human and whether IL-34 plays a crucial role in immune tolerance. This study will pave the way to a new clinical trial in transplantation.