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

Abstract

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.).

Figure 1. Interleukin-17–Dominated Inflammation in Leukocyte Adhesion Deficiency Type 1 (LAD1)

Panels A and B show histologic sections from gingival tissue (A) and sacral-wound skin (B), stained with hematoxylin and eosin at low magnification (subpanel a) and higher magnification (subpanel b), as well as with interleukin (IL)–17 (subpanel c) (brown staining is positive). Panels C and D show expression of IL23A (encoding the p19 subunit of IL-23) messenger RNA (mRNA) (C) and IL17A mRNA (D) in tissues from patients with no oral inflammation (healthy), chronic periodontitis (chronic), and LAD1 periodontitis (LAD1; the current patient is indicated in red). Panels E and F show the results of a flow cytometric analysis of cells isolated from the gingival tissues of our patient (E) and a healthy volunteer with gingivitis (F). IL-17 production in total hematopoietic (CD45+) cells and in CD45+CD3+CD8-CD56– cells (presumed to be CD4+ T cells) is shown.

Figure 2. Response to Ustekinumab Treatment

Panel A shows clinical photographs of the gingival tissues of our patient before treatment and at 3 weeks and 14 months after treatment. Panel B shows clinical detection of inflammation in the oral cavity (percentage of sites with bleeding on probing) according to time relative to treatment. Panels C and D show relative levels of expression of IL23A mRNA (C) and IL17A mRNA (D) before and during treatment. Panel E shows clinical photographs of the sacral wound before treatment and at 10 and 14 months after treatment. No sharp débridements were performed during this period.