CD8+ Treg Cells Associated with Decreasing Disease Activity after Intravenous Methylprednisolone Pulse Therapy in Lupus Nephritis with Heavy Proteinuria

Yi-Giien Tsai,Tze-Yi Lin,Chia-Ying Lee,Ching-Yuang Lin,Deyu Fang

doi:10.1371/journal.pone.0081344

Abstract

We focus on the role of CD8+ Treg cell in Intravenous methyl-prednisolone (IVMP) pulse therapy in forty patients with active Class III/IV childhood lupus nephritis (LN) with heavy proteinuria. IVMP therapy for five days. From peripheral blood mononuclear cells (PBMCs) and renal tissues, we saw IVMP therapy definitely restoring both CD4+CD25+FoxP3+ and CD8+CD25+Foxp3+ Treg cell number plus greater expression with intracellular IL-10 and granzyme B in CD8+FoxP3+ Treg from PBMCs. IVMP-treated CD8+CD25+ Treg cells directly suppressed CD4+ T proliferation and induced CD4+CD45RO+ apoptosis. Histologically, CD4+FoxP3+ as well as CD8+FoxP3+ Treg cells appeared in renal tissue of LN patients before IVMP by double immunohistochemical stain. CD8+FoxP3+ Treg cells increased in 10 follow-up renal biopsy specimens after IVMP. Reverse correlation of serum anti-C1q antibody and FoxP3+ Treg cells in PBMNCs (r = −0.714, P<0.01). After IVMP, serum anti-C1q antibody decrease accompanied increase of CD4+FoxP3+ Treg cells. CD8+Treg cells reduced interferon-r response in PBMCs to major peptide autoepitopes from nucleosomes after IVMP therapy; siRNA of FoxP3 suppressed granzyme B expression while decreasing CD8+CD25+Treg-induced CD4+CD45RO+ apoptosis. Renal activity of LN by SLEDAI-2k in childhood LN was significantly higher than two weeks after IVMP (P<0.01). CD8+FoxP3+ Treg cells return in post-IVMP therapy and exert crucial immune modulatory effect to control autoimmune response in LN.Trial Registration DMR97-IRB-259

Highlights

Childhood lupus nephritis (LN) remains a significant therapeutic challenge due to its complex etiopathogenesis and unpredictable course
This study focuses on the role of CD8+ Treg cells in Intravenous methyl-prednisolone (IVMP) therapy, 40 LN patients receiving IVMP and 10 historical control patients only treated with oral prednisolone
There was a sharp rise of SLE Disease Activity Index (SLEDAI) score two weeks after IVMP treatment (Table 2)

Summary

Introduction

Childhood lupus nephritis (LN) remains a significant therapeutic challenge due to its complex etiopathogenesis and unpredictable course. Systemic lupus erythematosus (SLE) is characterized by autoantigen-deriven interactions between autoreactive Th and B cells, spawning production of somatically mutated IgG autoautibodies against apoptotic nuclear antigens (Ags) [1,2], pathogenic IgG autoantibodies belonging to Th1- or interferon gamma (IFNr)-dependent subclass contributing differentiation of autoimmune Th cell with concomitant decrease in regulatory T (Treg) cells [3]. CD4+CD25+ Treg cells have potent immunosuppressive function and contribute to immunological self-tolerance in SLE [4,5]. Recent studies demonstrate Treg cell number as inversely correlated with disease activity, a mechanism that may benefit treatment of LN [4,5]

Methods

Results

Conclusion