ABSTRACT
Earlier studies have shown that high doses of TNF-alpha increase apoptosis in human autoimmune T-cell clones. Based on these studies, a treatment approach was proposed to reduce or eliminate autoimmune T cells in patients with type 1 diabetes using drugs that temporarily elevate TNF levels. Here, we report the treatment of ankylosing spondylitis patient with a single high oral dose of Likopid (glucosaminyl-muramyl dipeptide), which aimed at increasing the levels of TNF-alpha in order to induce apoptosis of autoreactive T cells. The flow cytometric analysis of blood samples collected before and after treatment demonstrated massive elimination of CD8(+) T cells. However, the treatment did not result in any notable therapeutic effect, and real-time PCR analysis demonstrated that stably expanded T-cell clones that were earlier tracked in this patient were unaffected. This report suggests that the controversial approach to eliminate autoimmune T-cell clones through overstimulation is not effective in treating ankylosing spondylitis.
Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Adjuvants, Immunologic/therapeutic use , Spondylitis, Ankylosing/drug therapy , Acetylmuramyl-Alanyl-Isoglutamine/therapeutic use , Adalimumab , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/therapeutic use , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/pathology , Cell Death/drug effects , Dose-Response Relationship, Drug , Flow Cytometry , Humans , Leukocyte Count , Male , Middle Aged , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/pathology , Treatment FailureABSTRACT
Increasing evidence points to a role for killer immunoglobulin-like receptors (KIRs) in the development of autoimmune diseases. In particular, a positive association of KIR3DS1 (activating receptor) and a negative association of KIR3DL1 (inhibitory receptor) alleles with ankylosing spondylitis (AS) have been reported by several groups. However, none of the studies analyzed these associations in the context of functionality of polymorphic KIR3DL1. To better understand how the KIR3DL1/3DS1 genes determine susceptibility to AS, we analyzed the frequencies of alleles and genotypes encoding functional (KIR3DL1*F) and non-functional (KIR3DL1*004) receptors. We genotyped 83 AS patients and 107 human leukocyte antigen (HLA)-B27-positive healthy controls from the Russian Caucasian population using a two-stage sequence-specific primer PCR, which distinguishes KIR3DS1, KIR3DL1*F and KIR3DL1*004 alleles. For the patients carrying two functional KIR3DL1 alleles, those alleles were additionally genotyped to identify KIR3DL1*005 and KIR3DL1*007 alleles, which are functional but are expressed at low levels. KIR3DL1 was negatively associated with AS at the expense of KIR3DL1*F but not of KIR3DL1*004. This finding indicates that the inhibitory KIR3DL1 receptor protects against the development of AS and is not simply a passive counterpart of the segregating KIR3DS1 allele encoding the activating receptor. However, analysis of genotype frequencies indicates that the presence of KIR3DS1 is a more important factor for AS susceptibility than the absence of KIR3DL1*F. The activation of either natural killer (NK) or T cells via the KIR3DS1 receptor can be one of the critical events in AS development, while the presence of the functional KIR3DL1 receptor has a protective effect. Nevertheless, even individuals with a genotype that carried two inhibitory KIR3DL1 alleles expressed at high levels could develop AS.
