Lactoferrin: Cytokine Modulation and Application in Clinical Practice

Multiple properties of lactoferrin have been reported in the literature so far. Decades of in vitro and in vivo studies have demonstrated the important antimicrobial, anti-inflammatory, anti-oxidant, and immunomodulating properties. It suggests the use of lactoferrin as an effective and safe option for the treatment of several common disorders. Herein, we show the applications of lactoferrin in clinical practice, highlighting its evidence-based capacities for the treatment of heterogeneous disorders, such as allergic, gastrointestinal, and respiratory diseases, and hematologic, oncologic, gynecologic, dermatologic, and dental disorders. Moreover, the widespread use of lactoferrin in neonatology is summarized here. As a result of its antiviral properties, lactoferrin has also been proposed as a valid option for the treatment for COVID-19 patients. Here, the uses of lactoferrin in clinical practice as a new, safe, and evidence-based treatment for many types of disorders are summarized.

Primary Immune Thrombocytopenia and Essential Thrombocythemia: So Different and yet Somehow Similar—Cases Series and a Review of the Literature

This article collects several published cases in which immune thrombocytopenic purpura (ITP) is followed by essential thrombocythemia (ET) and vice versa. This surprising clinical condition is possible, but very rare and difficult to diagnose and manage. We have made an attempt to analyse the possible causes of the sequential appearance of ITP and ET taking into consideration the following: alteration of the thrombopoietin (TPO) receptor, the role of autoimmunity and inflammation, and cytokine modulation. A better understanding of these interactions may provide opportunities to determine predisposing factors and aid in finding new treatment modalities both for ITP and ET patients.

Human-relevant near-organ neuromodulation of the immune system via the splenic nerve

Neuromodulation of immune function by stimulating the autonomic connections to the spleen has been demonstrated in rodent models. Consequently, neuroimmune modulation has been proposed as a new therapeutic strategy for the treatment of inflammatory conditions. However, demonstration of the translation of these immunomodulatory mechanisms in anatomically and physiologically relevant models is still lacking. Additionally, translational models are required to identify stimulation parameters that can be transferred to clinical applications of bioelectronic medicines. Here, we performed neuroanatomical and functional comparison of the mouse, rat, pig, and human splenic nerve using in vivo and ex vivo preparations. The pig was identified as a more suitable model of the human splenic innervation. Using functional electrophysiology, we developed a clinically relevant marker of splenic nerve engagement through stimulation-dependent reversible reduction in local blood flow. Translation of immunomodulatory mechanisms were then assessed using pig splenocytes and two models of acute inflammation in anesthetized pigs. The pig splenic nerve was shown to locally release noradrenaline upon stimulation, which was able to modulate cytokine production by pig splenocytes. Splenic nerve stimulation was found to promote cardiovascular protection as well as cytokine modulation in a high- and a low-dose lipopolysaccharide model, respectively. Importantly, splenic nerve–induced cytokine modulation was reproduced by stimulating the efferent trunk of the cervical vagus nerve. This work demonstrates that immune responses can be modulated by stimulation of spleen-targeted autonomic nerves in translational species and identifies splenic nerve stimulation parameters and biomarkers that are directly applicable to humans due to anatomical and electrophysiological similarities.

Oxytocin signalling in dendritic cells regulates immune tolerance in the intestine and alleviates DSS-induced colitis

Background: Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that is associated with immune dysfunction. Recent studies have indicated that the neurosecretory hormone oxytocin (OXT) has been proven to alleviate experimental colitis. Methods: We investigated the role of OXT/OXT receptor (OXTR) signalling in dendritic cells (DCs) using mice with specific OXTR deletion in CD11c+ cells (OXTRflox/flox×CD11c-cre mice) and a dextran sulfate sodium (DSS)-induced colitis model. Results: The level of OXT was abnormal in the serum or colon tissue of DSS-induced colitis mice or the plasma of UC patients. Both bone marrow-derived DCs (BMDCs) and lamina propria DCs (LPDCs) express OXTR. Knocking out OXTR in DCs exacerbated DSS-induced acute and chronic colitis in mice. In contrast, the injection of OXT-pretreated DCs significantly ameliorated colitis. Mechanistically, OXT prevented DC maturation through the phosphatidylinositol 4,5-bisphosphate 3-kinase (Pi3K)/AKT pathway and promoted phagocytosis, adhesion and cytokine modulation in DCs. Furthermore, OXT pre-treated DCs prevent CD4+ T cells differentiation to T helper 1 (Th1) and Th17. Conclusions: Our results suggest that OXT-induced tolerogenic DCs efficiently protect against experimental colitis via Pi3K/AKT pathway. Our work provides evidence that the nervous system participates in the immune regulation of colitis by modulating DCs. Our findings suggest that generating ex vivo DCs pretreated with OXT opens new therapeutic perspectives for the treatment of UC in humans.