ABSTRACT
Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor a subunit (IL-2R a or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ~50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN- g, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2R bg signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Immunoglobulin G/therapeutic use , Immunosuppressive Agents/therapeutic use , Interleukin-2 Receptor alpha Subunit/antagonists & inhibitors , Interleukin-2/immunology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , T-Lymphocytes, Regulatory/drug effects , CD4 Lymphocyte Count , Cell Cycle/drug effects , Cell Cycle/genetics , Daclizumab , Forkhead Transcription Factors/biosynthesis , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Humans , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Interleukin Receptor Common gamma Subunit/immunology , Interleukin-17/biosynthesis , Interleukin-17/immunology , Interleukin-2/biosynthesis , Interleukin-2/blood , Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-2 Receptor beta Subunit/immunology , Multiple Sclerosis, Relapsing-Remitting/immunology , Phosphorylation , Promoter Regions, Genetic , STAT5 Transcription Factor/metabolism , Self Tolerance/drug effects , Self Tolerance/immunology , T-Lymphocytes, Regulatory/immunologyABSTRACT
Fractalkine (FKN), also known as neurotactin, is a CX(3)C chemokine that exists in both secreted and neuronal membrane-bound forms and is upregulated during brain inflammation. There is accumulating evidence that FKN induces chemotaxis by binding to its receptor CX(3)CR1 on leukocytes and microglia. We generated FKN-deficient mice to study the role of FKN in postischemic brain injury. After transient focal cerebral ischemia, FKN-deficient mice had a 28% reduction in infarction size and lower mortality rate, when compared to wild-type littermates. The findings of this study indicate a possible role for FKN in augmenting postischemic injury and mortality after transient focal cerebral ischemia.