Stefania Gallucci, MD

Research Summary

The main interest of the laboratory is the initiation and regulation of the immune response. In particular, we study dendritic cells (DCs), the most important antigen-presenting cells and pivotal stimulators of the immune response as well as the induction of immunological tolerance. Our goals are to understand how dendritic cells activate and test in animal models novel factors able to modulate DC function and, therefore, regulate the immune response.

Dendritic cell activation. Our long-term goal is to discover novel biologic factors able to activate the function of dendritic cells in order to improve DC-based and other innovative vaccines needed to fight tumors and infectious diseases.
 
Endogenous Danger Signals. DCs reside in the different tissues and organs of our body in a resting state and monitor the environment for Danger Signals, stimuli able to activate DCs. Danger Signals can be endogenous, derived from tissues undergoing stress, damage or non-physiologic cell death, or can be exogenous, derived from pathogens. Weak vaccines require the addition of effective adjuvants to improve their immunogenicity and investigating Endogenous Danger signals can suggest novel adjuvants to be used in vaccine development.  We are studying the Type I Interferons (IFNs), a family of endogenous Danger Signals involved in the activation of DCs and in the regulation of the immune response. Through the investigation of the signaling pathways triggered downstream of the Type I Interferon Receptor (IFNAR), we aim to discover ways to augment but also to inhibit the response of the immune cells to Type I IFNs.
 
Induction of Tolerance. Our long-term goal is to discover biologic factors able to induce a stable tolerogenic function in dendritic cells that can be used in immunotherapy of conditions, such as transplantation and autoimmunity, in which excessive and inappropriate immune responses are causing morbidity and mortality.
 
Role of Dendritic cells in lupus pathogenesis.  We investigate the role of DCs in the pathogenesis of the autoimmune disease Systemic Lupus Erythematosus (SLE). We study spontaneous and induced models of murine lupus to determine how the DCs affect the autoimmune process; we have found that DC costimulatory and cytokine profile, APC activity and life span are altered (Colonna 2006) and we are focusing our efforts on the role of Type I IFNs in such abnormalities. Indeed, we have shown that, similarly to many SLE patients, DCs from lupus prone mice express a type I Interferon Signature, even before disease onset (Sriram, 2012). These findings have great significance because they show that: 1) the Interferon Signature precedes lupus disease and it may be a cause; 2) DCs are a primary and intrinsic source of Interferon and suggest that they should be a therapeutic target in lupus; 3) the lupus prone mice that we investigated are an optimal model to study the human lupus Interferon Signature. Using techniques of traditional cellular immunology and cutting edge molecular biology, we are studying a diverse range of molecules, such as cytokines and energy modulators, that can suppress the response of DCs to Type I IFNs, and we are testing in vivo novel therapeutic approaches to ameliorate the severity and ultimately to cure the autoimmune disease.
 
Regulation of Type I Interferons. In 1999, we were the first group to show that Type I Interferons, now so important in lupus pathogenesis, activate DCs and act as an adjuvant in vivo (Gallucci, 1999). Because of its pathogenic role in lupus, we have been studying ever since the regulation of type I Interferon to develop novel therapeutic approaches to inhibit Type I Interferons in autoimmunity. My lab has shown that TH2 cytokine IL-4 suppresses DC response to Type I Interferons by inhibiting their signaling pathway (Sriram, 2007), and that IL-4 also inhibits the activation of DCs induced by TLR7 and TLR9 ligands, which are major inducers of Interferons, and also autoantigens and natural adjuvants in lupus pathogenesis (Sriram, 2014). These results suggest that inducers of IL-4 should be tested as therapeutics in lupus.
To investigate Interferon regulatory pathways, we are actively collaborating with Dr. Ana Gamero in the Department of Medical Genetics and Molecular Biochemistry to elucidate the role of the transcription factor STAT2 in DC activation. STAT2 is a downstream molecule pivotal in Type I Interferon Receptor signal transduction. We recently helped the Gamero’s group make the discovery that STAT2 is required in restricting tumor growth in a murine model of melanoma by driving the antitumor effects of therapeutic Interferon (Yue, 2014). Presently, we are investigating with Dr. Gamero the requirement of STAT2 in the activation and antigen-presenting functions of DCs.

Role of sex hormones cells in lupus pathogenesis.  Systemic Lupus Erythematosus is a disease more prevalent in women, with the peak of incidence in child-bearing age. Estrogens are considered pathogenic in Systemic Lupus Erythematosus but the molecular mechanisms are unclear. We are investigating how estrogens and other sex hormones affect lupus pathogenesis and whether sex hormones enhance the production of Type I Interferons. We are testing whether estrogen inhibition affects the Interferon Signature in lupus dendritic cells, the molecular network involved and their disease outcomes. This project aims to discover a novel regulatory pathway of autoimmunity, explain the different susceptibilities of women and men to SLE and suggest a novel therapeutic target.

Role of infections in lupus pathogenesis. Infections are considered to play a pathogenic role in Systemic lupus erythematosus, and more recent work is suggesting a role for the commensal flora as well, but the molecular culprits are still to be discovered. In collaboration with Dr. C. Tukel from the Department of Microbiology-Immunology and Dr. Caricchio from the Section of Rheumatology, Department of Medicine, we are studying the effects of biofilm-producing bacteria in the pathogenesis of lupus. Dr. C. Tukel has recently discovered that bacterial and also eukaryotic DNA is incorporated into curli fibers, functional bacterial amyloids present in many bacterial biofilms, including Salmonella and E. coli biofilms (Gallo 2015). In collaboration with Dr Tukel, we have found that curli/DNA complexes in biofilms activate DCs and induce the production of Type I interferons. In vivo injection of curli/DNA complexes activated DCs, T and B cells, indicating that curli are a new class of composite danger signals. Administration of purified curli/DNA complexes, as well as infections with curli-expressing bacteria, like the pathogen Salmonella and the commensal E. coli Nissle, triggered lupus onset in mice, suggesting curli/DNA complexes from biofilms as novel players in SLE pathogenesis (Gallo 2015). Using murine models and samples from SLE patients, we are presently studying the cellular and molecular mechanisms of the contribution of enteric infections, and possibly the microbiome, to the pathogenesis of SLE. Our studies aim to determine whether the systemic exposure to curli-expressing bacteria, including commensals, is a major pathogenic stimulus and therapeutic target to decrease inflammation and prevent flares in SLE.

Role of cell death in regulating the immune response and autoimmunity. In collaboration with Dr. Caricchio from the Section of Rheumatology, Department of Medicine, we are investigating the role of necrotic and apoptotic cells death in modulating inflammation, autoimmunity and immune-mediated tissue damage. Indeed, we demonstrated that during autoimmunity, DCs are exposed to apoptotic cells, which had translocated autoantigens and were opsonized by autoantibodies. This exposure increases in DCs phagocytosis and presentation of lupus autoantigens, suggesting an important pathogenic pathway to autoimmunity (Frisoni, 2005). Moreover, we collaborated in the studies of the role of an important molecular regulator of energy metabolism and cell death, PARP, in the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation (Jog 2009). Our present studies aim to determine the role of gender and sex hormones in regulating necrotic death and the pathways of tissue damage in autoimmunity.