Engraftment of Peripheral Blood Mononuclear Cells from Systemic Lupus Erythematosus and Antiphospholipid Syndrome Patient Donors into BALB-RAG-2-/- IL-2Rγ-/- Mice: a Promising Model for Studying Human Disease

Overview

Journal Arthritis Rheum

Specialty Rheumatology

Date 2011 May 12

PMID 21560114

Citations 36

Authors

Danieli Andrade

Patricia B Redecha

Milena Vukelic

Xiaoping Qing

Giorgio Perino

Jane E Salmon

Gloria C Koo

Affiliations

Soon will be listed here.

Abstract

Objective: To construct a humanized mouse model of systemic lupus erythematosus (SLE) that resembles the human disease in order to define the pathophysiology and targets for treatments.

Methods: We infused peripheral blood mononuclear cells (PBMCs) from SLE patients into BALB- RAG-2-/- IL-2Rγ-/- double-knockout (DKO) mice, which lack T cells, B cells, and natural killer cells. PBMCs from 5 SLE patients and 4 normal donors were infused intravenously/intraperitoneally at a density of 3-5×10(6) cells per animal into nonirradiated 4-5-week-old mice. We evaluated the engraftment of human CD45+ cells and monitored the plasma levels of human IgG, anti-double-stranded DNA (anti-dsDNA) antibody, and anticardiolipin antibody (aCL), as well as proteinuria and kidney histology.

Results: There was 100% successful engraftment in 40 DKO mice infused with human PBMCs. In the PBMC fraction from SLE PBMC-infused DKO (SLE-DKO) mice and normal donor PBMC-infused DKO (ND-DKO) mice, an average of 41% and 53% human CD45+ cells, respectively, were observed at 4 weeks postengraftment, with 70-90% CD3+ cells. There were fewer CD3+CD4+ cells (mean±SEM 5.5±2.1%) and more CD3+CD8+ cells (79.4±3.6%) in the SLE-DKO mice as in the SLE patients from which the PBMCs were derived. CD19+ B cells and CD11c+ monocytic cells were found in the spleen, lung, liver, and bone marrow. There was no significant difference in plasma levels of human IgG and anti-dsDNA antibodies between SLE-DKO and ND-DKO mice. Levels of aCL were significantly higher in all SLE-DKO mice infused with PBMCs from an SLE patient who had high titers of aCL. SLE-DKO mice had proteinuria, human IgG deposits in the kidneys, and a shorter life span. In SLE-DKO mice engrafted with PBMCs from the aCL-positive patient, we found microthrombi and infiltration of CD3+, CD8+, and CD19+ cells in the glomeruli, recapitulating the human antiphospholipid syndrome in these mice.

Conclusion: We established a novel humanized SLE-DKO mouse exhibiting many of the immunologic and clinical features of human SLE.

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