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Abstract: SA-PO445

Altered Expression of CD46 Mediated Tr1 Cytoplasmic Isoforms Associated with IL-10 Secretion Can Induce Remission of Active Lupus Nephritis

Session Information

  • Pediatric Nephrology - II
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1600 Pediatric Nephrology

Author

  • Lin, Ching-Yuang, Children’s Hospital, China Medical University, Taichung, Taiwan
Background

CD46-costimulated T cells in the presence of IL-2 acquire a Tr1 type Treg phenotype, secreting high amount IL-10 and granzyme B. There was two forms of CD46 cytoplasmic isoforms. Cyt1 inhibits and Cyt2 augments inflammation. To elucidate whether CD46 mediated Cr1 cells can induce remission in active lupus nephritis (LN) by intravenous methylprednisolone (IVMP) therapy, we evaluate IL-10 secreting Tr1 cells in peripheral blood mononuclear cells (PBMCs) and renal biopsy specimens, the capacity of CD46+ Tr1 cells to induce IL-10 production, altered expression of CD46 cytoplasmic ioforms before and after IVMP therapy.

Methods

PBMCs were isolated from fourty pediatric class III or IV LN active LN patients and from ten healthy controls before and after three days of IVMP. Purified CD4+ T cells from patients before and after IVMP as well as healthy controls were stimulated with anti-CD3 and CD46 mAbs in the presence of IL-2 to generated Tr1 cells.

Results

Decreased CD46 expression on CD4+ T cell in PBMCs and renal biopsy specimens from active LN patients versus controls, correlating with higher anti-dsDNA Ab level and lower serum C3, C4 levels. IL-10, granzyme B, CCR4, CCR7 expression and CD4+ T cell proliferation were diminished by CD3/CD46-activated Tr1 cells in active LN. CD4+ T cell from active LN patients showed a statistically increase in IFN-r+ T cells when compared to healthy control T cells following CD3 activation but failed to switch efficiently from IFN-r to IL-10 production following CD3+/CD46 stimulation. After IVMP altered expression of CD46+ Tr1 cell cytoplasmic isoform with increasing CD46-Cyt1/ -Cyt2 ratio. IVMP also increased AKT phosphorylation and enhanced adhesion, migration of CD3/CD46 activated Tr1 cells and IFN-r switch to IL-10 production in active LN patients.

Conclusion

Switching efficiency from IFN-r to IL-10 production of CD3+/CD46 stimulated Tr1 cells was failed in active LN patients. IVMP rescue INF-r switching IL-10 production associated with induction of remission in active LN also increasing adhesion and migratory capacity to suppress inflammation by CD46-mediated Tr1 cells. Thus, pharmacologic intervention to alter pattern of CD46-Cyt1, -Cyt2 expression with inducing IL-10 secretion by CD46 medicated Tr1 cells are viable approach in active LN patients.