Author Archives: Monsonego

In collaboration with Prof. Cohen Smadar, The Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel 

Engineering of cell-based constructs for treating a variety of immune-related diseases by local transplantation of the cells in a pre-designed matrix is an emerging therapeutic approach, which can potentially reduce the side effects associated with systemic cell injection. Stromal cells have been shown to exert immunosuppressive properties and thus can be exploited for autoimmune regulation and cell transplantation. We demonstrated a stromal cell-based construct, which serves as a lymphoid-like organ with immune regulatory characteristics whereby stromal cells are co-seeded with dendritic cells (DC) in a macro-porous alginate scaffold containing the encephalitogenic myelin-derived peptide, proteolipid protein (PLP). Alginate scaffolds herein are replacing the extracellular matrix (ECM), providing both a physical support and biological cues for the seeded cells and closing the gap to in vivo conditions (Kaminer et al., 2010). In a recent study by Orr et al., 2016, we investigated the feasibility of generating an immunoregulatory environment in a highly vascularized macroporous alginate scaffold by affinity-binding of the transforming growth factor-β (TGF-β) in a manner mimicking its binding to heparan sulfate. Using this device to transplant allofibroblasts under the kidney capsule resulted in the induction of local and peripheral TGF-β-dependent immunotolerance, characterized by higher frequency of immature dendritic cells and regulatory T cells within the device and by markedly reduced allofibroblast-specific T-cell response in the spleen, thereby increasing the viability of the transplanted cells. We thus demonstrate a novel platform for transplantation devices, designed to promote an immunoregulatory microenvironment suitable for cell transplantation and autoimmune regulation. Current studies are performed to determine the capacity of immunoregulatory 3D scaffolds to protect from the rejection of allogeneic insulin-producing cells in animal models of diabetes.

It has been well established that stress may substantially affect the homeostatic regulation of the immune system. In most animal models studied thus far, stressful triggers such as fear, maternal deprivation, social threat or physiological challenge have been shown to induce immunosuppression associated with increased susceptibility to allergies and infectious diseases. These effects are mediated by the hypothalamic-pituitary-adrenal (HPA) axis, a complex network linking the nervous, endocrine and immune systems.   

In line with the critical role of the HPA axis in suppressing pathogenic autoimmunity and clinical observations linking stress with disease exacerbation, our recent study (Harpaz et al., 2013) shows that prolonged stress exposure worsens, rather than ameliorates, clinical symptoms in a mouse model of multiple sclerosis; a phenomenon, however, which could be prevented by blocking glucocorticoid signaling throughout the stress exposure period. We also show that glucocorticoid levels under basal conditions are significantly lower in male than in female mice, associated with exacerbated disease symptoms. Finally, we show that stress decreases the Treg/Teff ratio, and increases the Th1-Th17/Th2 ratio, within the Teff-cell subsets. Taken together, our findings raise the possibility that while the HPA axis provides immunosuppression under basal conditions (i.e., in non-stressed females), prolonged exposure to chronic stress results in an attenuated CORT response to stimuli primarily in pro-inflammatory effector CD4 T cells, predisposing to higher susceptibility to pathogenic autoimmunity.

The notion that overactivation of the HPA axis disrupts a key homeostatic regulation of inflammation, prompt us to broaden our research goals. Current studies in the lab thus address the impact of chronic stress on gut inflammation, autoimmunity, brain inflammation and psychiatric disorders.