CD8⁺ Treg cells associated with decreasing disease activity after intravenous methylprednisolone pulse therapy in lupus nephritis with heavy proteinuria

PLoS One. 2014 Jan 27;9(1):e81344. doi: 10.1371/journal.pone.0081344. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Adolescent
  • Apoptosis / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Count
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Granzymes / immunology
  • Humans
  • Interleukin-10 / immunology
  • Lupus Nephritis / complications
  • Lupus Nephritis / drug therapy*
  • Lupus Nephritis / immunology*
  • Methylprednisolone / administration & dosage
  • Methylprednisolone / therapeutic use*
  • Proteinuria / complications
  • Proteinuria / drug therapy*
  • Proteinuria / immunology*
  • Pulse Therapy, Drug / methods*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • RNA, Small Interfering
  • Interleukin-10
  • Granzymes
  • Methylprednisolone

Grants and funding

This work was partially supported by grants from the National Science Council, Taiwan (NSC 98-2314-B-039-006-MY3, 98-2314-B-371-001-MY2, NSC 100-2314-B-371 -005); and China Medium University Hospital (DMR-100-180), Changhua Christian Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.