Role of Invariant Natural Killer T (iNKT) Cells in Systemic Lupus Erythematosus

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Abstract:

Natural killer T (NKT) cells represent a unique T cell lineage. The NKT cells bearing an invariant TCR (iNKT cells) recognize a small variety of glycolipid antigens in the context of CD1d (non-classical MHC-I) presentation. CD1d-restricted iNKT cells play a regulatory role during an immune response by producing cytokines (IFN-γ, and IL-4). The identification of α-galactosyl-ceramide (α- GalCer), a marine sponge derivative as a potent stimulator of iNKT cells has raised the potential of therapeutic iNKT cell activation.

Invariant NKT cells have been implicated in several different autoimmune diseases in mice and humans, including systemic lupus erythematosus (SLE). Abnormalities in the number and functions of NKT cells have been observed in SLE patients and mouse strains genetically predisposed to lupus (MRL/lpr, NZB/W F1). Moreover, inverse correlation between the frequency of NKT cells and IgG levels has been observed. Elevated IgG levels in relatives of patients with lupus as well as in patients with lupus were associated with low frequencies of NKT cells.

This review focuses on the potential roles of NKT cells in the pathogenesis of SLE. It summarizes recent advances in glycolipid therapy for murine lupus. First, it has been demonstrated, that repeated administration of α-GalCer to MRL/lpr mice alleviated inflammatory dermatitis but did not influence kidney disease. Treatment of NZB/W mice with α-GalCer resulted in amelioration of SLE symptoms in young mice, but treatment of older animals resulted in disease exacerbation.

The effects of NKT cell activation using α -GalCer, on disease progression, were influenced by a variety of parameters, including the genetic background of mice, the α -GalCer dose, number of injections and the stage of the disease process when treatment was performed. Manipulation of NKT cells in the human system may be a promising treatment alternative for the future, however possible deleterious effects have to be carefully investigated first.

Keywords: CD1d; Natural killer T (NKT) cells; Systemic lupus erythematosus; glycolipids

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986708785132988

Affiliations: Semmelweis University, Institute of Pathophysiology, H-1089 Budapest, Nagyvarad ter 4.

Publication date: August 1, 2008

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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