Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1

Abstract

Summary A patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound. We had previously found a dominant interleukin-23–interleukin-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder. Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition. We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23–dependent production of interleukin-17. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

Primary immunodeficiencies reveal the essential role of tissue neutrophils in periodontitis

“…In this case, our patient was a 19‐year‐old male with moderate LAD‐I disease, but severe periodontitis and a deep non‐healing cutaneous sacral wound, which had progressed over 2 years despite numerous courses of antibiotics and surgical debridements. Treatment with IL‐12/IL‐23 blockade (ustekinumab), resulted in significant reduction in oral inflammation and complete resolution of the deep cutaneous ulcer without significant adverse reactions . This work revealed IL‐23‐mediated inflammation as the driving force of mucosal and cutaneous disease in LAD‐I and suggested further exploration of IL‐23 blockade for the treatment of LAD‐I‐associated disease.…”

“…These human observations and preclinical studies became the basis of IL‐23 blockade in LAD‐I‐associated periodontitis. Recently, our group and collaborators treated a single LAD‐I patient with ustekinumab, an antibody that binds the p40 subunit of interleukin‐23 and interleukin‐12 and thereby blocks the activity of these cytokines, inhibiting interleukin‐23‐dependent production of interleukin‐17 . In this case, our patient was a 19‐year‐old male with moderate LAD‐I disease, but severe periodontitis and a deep non‐healing cutaneous sacral wound, which had progressed over 2 years despite numerous courses of antibiotics and surgical debridements.…”

“…Periodontitis in LAD‐I is recalcitrant to standard of care treatment and antibiotics and patients often lose their entire dentition at a very early age (teenage or young adulthood) . Significant intraoral findings also include recurrent painful oral ulcers that often impede eating . Until recently, there has not been an effective treatment for LAD‐I periodontitis.…”

Innate lymphoid cells are present in gingivitis and periodontitis

“…Interestingly, this is in agreement with a case‐report describing a patient with severe periodontitis who received treatment with Ustekinumab. The patient presented resolution of the inflammatory lesions following treatment . It has been demonstrated that periodontitis is associated with increased IFN‐γ levels in serum, gingival crevicular fluid, and saliva .…”

Dental implants in a patient with suspected leucocyte adhesion deficiency

“…Interestingly, preliminary clinical studies have shown that treatment with biologics targeting IL-17 or IL-23 receptor is safe and promising for the treatment of inflammatory diseases such as rheumatoid arthritis and psoriasis 17 18. Importantly, a recent report by Moutsopoulos et al demonstrated successful treatment of oral inflammatory lesions in a patient with LAD-1 using ustekinumab, an antibody that of blocks the activity interleukin-23 and interleukin-12 and thereby inhibiting IL-23-dependent production of IL-17 19. Modulation of oral inflammatory response using targeted therapies might help to improve the success of dental implants in patients with LAD.…”