Inflammation is a critical component of the immune response that plays a pivotal role in maintaining tissue homeostasis. However, the failure to mount an optimal inflammatory response can lead to chronic diseases and impaired healing processes. Excessive inflammation is usually initiated by dysregulated innate immune response with excessive pro-inflammatory cytokines production and amplified by impaired immunoregulatory mechanisms. Examples of such dysregulated immune responses include the severe inflammatory manifestations observed in viral infections like COVID-19, where an uncontrolled cytokine storm contributes to severity and poor outcomes. Clinical situations with antigen persistence favors a sustained activation of the immune system with a chronic low-grade inflammation, thus leading to tissue damage and T cell exhaustion. In allotransplantation, inflammatory processes jeopardize graft survival and vascular lesions, while tumors exploit immune suppression to evade specific anti-tumor T cell responses.

For example, consider the scenario of kidney transplantation: thromboinflammation and vascular dysfunction are prevalent complications that can culminate in graft failure. Thromboinflammation, alongside complement activation, creates a pro-thrombotic state, prompting endothelial activation and heightened expression of adhesion molecules. This sequence leads to the formation of microthrombi and inflammation within the graft. The interplay of inflammation, thrombosis, and vascular dysfunction severely compromises graft perfusion and functionality, often resulting in graft failure. Emerging research reveals that these hypotheses and pathogenesis-based transcripts, which reflect thromboinflammation and endothelial activation, precisely classify antibody-mediated rejection in kidney transplantation. They not only correlate with the extent of injury and disease activity but are also proposed as diagnostic markers. Additionally, they represent a groundbreaking avenue for drug development and repurposing, offering new hope for enhancing graft survival and patient outcomes.

Moreover, considering immunosuppressive barrier in tumors is crucial for effective cancer therapy. Tumors create a suppressive microenvironment using immune checkpoint molecules, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cytokines like TGF-β, IL-10, and VEGF. Strategies to overcome this include using immune checkpoint inhibitors like pembrolizumab, targeting Tregs and MDSCs with drugs like low-dose cyclophosphamide, and reprogramming TAMs with CSF-1R or PI3Kγ inhibitors. Blocking cytokines with antibodies disrupts suppressive signals, and cancer vaccines or adoptive cell therapy like CAR-T cells can enhance anti-tumor responses. Combining these approaches can restore immune function and improve cancer treatment outcomes, making continued research essential. Thus immunomodulation, the intentional modification of the intensity of immune response through pharmacological interventions, cell therapy and genome editing, emerges as a promising avenue to address these challenges. This Research Topic aims to explore the intricate mechanisms of immunomodulation, seeking to decipher how it can effectively rebalance maladaptive inflammation and restore tissue homeostasis.

Moreover, the intense inflammatory response during sepsis triggers a paradoxical state of immunosuppression, creating an environment ripe for superinfections and viral reactivations. This phenomenon has been also demonstrated especially in long COVID and COVID-19 complications, where emerging literature is shedding light on novel therapeutic and diagnostic avenues with promising potential in terms of immune modulation. The dynamic interplay between inflammation and immunosuppression in these conditions is unlocking groundbreaking insights that could soon revolutionize patient care and treatment strategies.

This Research Topic aims to stimulate studies that highlights immunomodulation as a promising strategy to:
• Mitigate excessive inflammation in severe infections episodes to prevent tissue damage and impaired immune response.
• Enhance graft survival in the context of allotransplantation, minimizing alloimmune responses.
• Break the immunosuppressive barrier in tumors, re-establishing specific anti-tumor T cell responses.
• Address thromboinflammation and vascular dysfunction by elucidating the interplay between immune responses and coagulation pathways.
• This approach aims to unravel the mechanisms driving these processes in various diseases, including severe infections, chronic inflammatory conditions, and cancer. Understanding this interplay is crucial for developing targeted therapies that can prevent the exacerbation of vascular dysfunction and improve clinical outcomes.

This Research Topic accepts Original Research, Review and Mini-Review, Clinical Trial, General Commentary, and Opinion articles. We welcome manuscripts focusing on, but not limited to, the following sub-topics:
• Comprehensive overview of the recent advances in immunomodulatory protocols including pharmacological interventions, cell therapy and genome editing.
• Mechanisms of excessive inflammation in severe infections and the potential of immunomodulation to modulate the immune response.
• Targeting the inappropriate activation of innate immune system in autoinflammatory and autoimmune diseases.
• Novel strategies for immunomodulation in allotransplantation to improve graft survival and reduce alloimmune reactions.
• Overcoming immunosuppression in the tumor microenvironment through targeted immunomodulation.
• Immunomodulatory approaches to prevent secondary infections and viral reactivations following sepsis.
• Investigating the role of thromboinflammation and vascular dysfunction in disease progression and the potential of immunomodulatory strategies to mitigate these effects.

Impact

Frontiers in Immunology

Immunological Tolerance and Regulation

Systems Immunology