Our research interest focuses on cell trafficking in human physiology and pathology, with an emphasis on the mechanisms governing fine-tuning modulation of chemokine expression and activity, in order to identify novel therapeutic target for pharmacological intervention. Chemokines are secreted proteins, emerged as key controllers of cell migration. The effects of chemokines are mediated by seven transmembrane domain receptors that are differentially expressed in a wide range of cell types. The diversity of expression of the receptors and their reactivity to chemokines guarantee the correct tissue distribution of the different leukocytes under normal or pathological conditions. Several experimental evidences show the direct involvement of chemokine receptors in many pathological conditions, making this family of receptors a possible target for new and targeted pharmacological therapies. Directional guidance of cells via gradients of chemokines is considered crucial, but we often lack in many pathological conditions, a direct evidence of chemokine receptor functionality, which may be relevant in the development of the disease and can be modulated by the therapy. From the onset of the inflammatory response, the sequential release of exogenous agents (e.g. bacterial and viral products) and the induction of endogenous mediators (e.g. cytokines, chemokines and alarmins) contribute to the recruitment of circulating leukocytes to the inflammatory site. Various mechanisms regulate the inflammatory response, the recruitment of white blood cells and the resolution of inflammation.
Our group has described a mechanism regulating leukocyte migration, which shows how different molecules can induce cell responses to concentrations of chemokines that per se would be inactive, thus lowering their “migratory threshold”. To date there are still various aspects of this effect that we call “synergy” that we need to clarify, in view of having more effective therapies to promote the resolution inflammation, both in acute and chronic pathological conditions, such as in autoimmune diseases.
During viral infections, such as in AIDS, we have demonstrated that the cells of the immune system have an altered response to stimuli, which are important for their recruitment into the organs that need their patrolling, such as the gut. We have highlighted a way to restore the chemokine responses of leukocytes and therefore restore the efficacy of the immune responses in these patients. This discovery laid the foundations for new studies on infectious diseases, focused on the response of the immune system to chemokines and on the mechanisms modulating their responses.
In collaboration with the groups of Davide Robbiani and Andrea Cavalli, we discovered the generation of anti-chemokine autoantibodies in COVID-19, which are maintained for months after infection. These autoantibodies can modulate the response of leukocytes to chemokines and their presence is associated with protection from symptoms related to Long Covid. Anti-chemokine antibodies, neutralising chemokine activities are present not only in COVID-19, but also in autoimmune and other infectious diseases.
Our studies on white blood cell trafficking in humans, can foster the development of new therapies in patients with acute or persistent infections and chronic inflammatory diseases, promoting the restoration of the functions of cell populations active in the immune response, or inhibiting the iper-activation of the response to chemokines.