Cytokine immunomodulation for the treatment of infectious diseases: lessons from primary immunodeficiencies

Abstract

Traditionally, management of infectious diseases focuses on identification of the causative microbe and the use of pathogen-targeted therapy. With increasing antimicrobial resistance, novel approaches are required. One strategy is to modulate those natural host immune responses that critically mediate resistance to specific microbes. Clinically, this host-directed tactic could be used either alone or in combination with antimicrobial therapy. While conceptually attractive, there is potential concern that the pathways governing host resistance to pathogens in animal models may not extrapolate linearly to humans. Targeting these immune processes clinically may precipitate damaging, epiphenomenal responses. The field of Primary Immunodeficiencies focuses on the characterization of humans with inborn errors of immunity. These rare conditions permit the identification of those molecular and cellular processes that are central to human susceptibility to microbes. In efforts to compensate for defective host responses, this field has also provided a wealth of clinical experience in the effective use of cytokines to treat various active infections, while demonstrating their safety. In this review, we provide a historical perspective of the treatment of infectious diseases, evolving from a focus on the microbe, to an understanding of human immunity; we then outline the growing contribution of Primary Immunodeficiencies to the rational use of adjunctive cytokine immunotherapy in the management of infections.

Keywords::

• colony-stimulating factor
• cytokine
• immunotherapy
• infection
• infectious diseases
• interferon
• interleukin
• primary immunodeficiency
• treatment

Financial & competing interests disclosure

DC Vinh is supported by a start-up award from the Department of Medicine, McGill University Health Centre and a Research Grant from La Fondation du Grand défi Pierre Lavoie. He is supported as a Chercheur Boursier - Clinicien Junior 1 of the Fonds de recherche du Québec - Santé (FRQS). He has also received a Young Investigator Clinical Research & Educational Grant from CSL Behring Canada and a Research Grant from Astellas Canada. He has served on advisory committees to CSL Behring Canada. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• With increasing antimicrobial resistance, treatment of infectious diseases is becoming more difficult.

• Adjunctive cytokine therapeutic immunomodulation (TIM) represents a novel approach to treat infections.

• Cytokine TIM has been successfully used to treat active, often recalcitrant, infections in patients with primary immunodeficiencies (primary immunodeficiencies (PIDs); inborn errors of immunity).

• The cytokines that have been used to treat infections in PIDs include: G-CSF, GM-CSF, IL-2, IL-7, IFN-α, IFN-β and IFN-γ. These have targeted various viral, bacterial, mycobacterial, and fungal infections.

• The experience with most cytokine TIM used in PIDs spans decades, demonstrating good safety and tolerability profiles.

• The lessons learned from the use of cytokine TIM to treat infectious diseases in PID may provide guidance on its use to treat corresponding infections in other patient groups.