Reversal of autoimmune disease in lupus-prone New Zealand black/New Zealand white mice by nonmyeloablative transplantation of purified allogeneic hematopoietic stem cells

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1370-1378 ◽  
Author(s):  
Stephanie Smith-Berdan ◽  
Daphne Gille ◽  
Irving L. Weissman ◽  
Julie L. Christensen
Keyword(s):  
New Zealand ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Circulating Immune Complexes ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Complete Replacement ◽  
Nuclear Antigens ◽  
Autoimmune Pathology ◽  
Mhc Haplotype

Abstract Patients with severe systemic lupus erythematosus (SLE) refractory to conventional treatment are candidates for autologous hematopoietic stem cell (HSC) transplantation if the intent is to reset the immunologic clock. These patients might be candidates for allotransplantation with (SLE)-resistant major histocompatibility complex (MHC) haplotype-matched HSC if partial or complete replacement of an autoimmune-prone system is the intent. Using lupus-prone New Zealand black × New Zealand white (NZBW) mice, we investigated the use of highly enriched, haplomismatched, allogeneic HSC to prevent development of or to treat established autoimmune pathology. Young NZBW mice receiving purified allogeneic HSC transplants had improved survival, decreased proteinuria, circulating immune complexes, and autoantibodies to nuclear antigens than did untreated mice or mice given NZBW HSCs. NZBW mice with established lupus-like disease that received nonmyeloablative conditioning and transplants of (MHC) haplomismatched allogeneic HSCs also had greatly increased overall survival. Mice that received transplants exhibited stabilization or reversal of their lupus symptoms; stabilized or decreased proteinuria, and a lower frequency of elevated circulating immune complexes or autoantibodies than did control mice. Induction of durable mixed chimerism by transplantation of purified allogeneic HSCs after nonmyeloablative conditioning has the potential to reverse symptoms of established NZBW lupus.

Prevention and Reversal of Lupus in NZB/NZW Mice by Transplantation of Purified Allogeneic Hematopoietic Stem Cells (HSC) with Non-Myeloablative Conditioning (NMT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3198-3198
Author(s):  
Stephanie Smith-Berdan ◽  
Daphne Gille ◽  
Julie L. Christensen
Keyword(s):  
Lupus Erythematosus ◽  
Matched Control ◽  
Mixed Chimerism ◽  
Final Time ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Living Well ◽  
Nuclear Antigens ◽  
Final Time Point ◽  
Antibodies To Dsdna

Abstract Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease. Patients’ refractory to therapy may be considered for hematopoietic stem cell transplantation. Using lupus prone female NZB x NZW (NZBW) mice, we tested the ability of highly enriched, allogeneic HSC to prevent and reverse autoimmune symptoms with FACS purified haplo-identical allogeneic HSC. Ablative conditioning: 92 animals were given lethal TBI (14.5 Gy) and divided among 4 groups (Table 1). Urine and serology tested monthly, final time point before death tabulated. Transplantation with either syngeneic HSC or WBM accelerated disease in these mice, resulting in a rate of death exceeding age matched controls. Allogeneic transplanted mice had significantly greater survival above all groups (p= 0.0243). Proteinuria, elevated levels of circulating immune complexes (CIC), and auto-antibodies to dsDNA, nuclear antigens (ANA) and histones were lower in allo-HSC animals compared to the other ablative conditioning groups (p≤ 0.0001). Overall survival (OS) in allo-HSC animals was still unexceptional, possibly due to regimen related toxicity (TRM). Table 1: Ablative age@TX=75 days Age Matched Control Syngeneic WBM Syngeneic HSC Allogeneic HSC N 15 21 28 28 OS@420 days of age 20% 0% 0% 53% Proteinuria 100% 74% 75% 15% CIC 93% 81% 100% 25% Anti-dsDNA 100% 91% 100% 39% Anti-ANA 100% 86% 93% 39% Anti-Histone 93% 91% 100% 46% NMT conditioning: To determine if we could attenuate disease in NZBW mice already progressing into lupus-like disease with transplantation of allogeneic, purified HSC and reduce TRM, we developed a non-myeloablative conditioning protocol (2x5 Gy TBI + ATG + a-ASIALO-GM1) achieving an average mixed chimerism of 50%. Animals were treated at ~241 days with established symptoms of lupus (Table 2). While the group receiving conditioning alone, had a slight survival advantage over age matched control mice, the transplanted mice had greatly increased OS with 70% living well beyond 500 days of age (>250 days from transplant). Allo-HSC mice showed reversal or stabilization of their lupus symptoms including proteinuria, CIC, dsDNA and histone. Table 2: NMT age@Tx=241 days Age Matched Control Allogeneic HSC Conditioned Only N 10 33 30 OS@500 days of age 0% 70% 0% Proteinuria@Tx 20% 49% 47% Final Proteinuria 100% 39% 67% CIC 67% 50% 74% Anti-dsDNA 85% 15% 44% Anti-Histone 100% 37% 66% Conclusions: Ablative and NMT transplant can treat lupus; OS after NMT exceeds ablative conditioning; Induction of mixed chimerism with purified allogeneic HSC using NMT conditioning treats established lupus. The ability of pure HSC transplant and establishment of durable mixed chimerism to reverse established lupus makes it a reasonable strategy to test in man.

U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3229-3234 ◽  
Author(s):  
Emina Savarese ◽  
Ohk-wha Chae ◽  
Simon Trowitzsch ◽  
Gert Weber ◽  
Berthold Kastner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Dependent Manner ◽  
Stem Loop ◽  
Murine Bone Marrow ◽  
Small Nuclear Ribonucleoprotein ◽  
Nuclear Antigens

Abstract Plasmacytoid dendritic cells (PDCs), which produce IFN-α in response to autoimmune complexes containing nuclear antigens, are thought to be critically involved in the pathogenesis of systemic lupus erythematosus (SLE). One of the immunostimulatory components of SLE immune complexes (SLE-ICs) is self DNA, which is recognized through Tlr9 in PDCs and B cells. Small nuclear ribonucleoproteins (snRNPs) are another major component of SLE-ICs in 30% to 40% of patients. In this study, we show that murine PDCs are activated by purified U1snRNP/anti-Sm ICs to produce IFN-α and proinflammatory cytokines and to up-regulate costimulatory molecules. The induction of IFN-α and IL-6 by U1snRNPs in murine bone marrow–derived PDCs required the presence of intact U1RNA and was largely dependent on Tlr7 but independent of Tlr3. Intracellularly delivered isolated U1snRNA and oligoribonucleotides derived from the stem loop regions and the Sm-binding site of U1snRNA efficiently induced IFN-α and IL-6 in Flt3L-cultured DCs in a Tlr7-dependent manner. The U1snRNA component of U1snRNP immune complexes, found in patients with SLE, acts as an endogenous “self” ligand for Tlr7 and triggers IFN-α and IL-6 production in PDCs.

scholarly journals Method for the determination of immune complexes by reaction with polyethylene glycol

1982 ◽  
Vol 63 (2) ◽  
pp. 10-13
Author(s):  
B. A. Molotilov ◽  
A. N. Mayansky ◽  
N. D. Pozdnyak ◽  
L. Ch. Samerkhanova
Keyword(s):  
Polyethylene Glycol ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Clinical Laboratory ◽  
Circulating Immune Complexes ◽  
Healthy Donors ◽  
Highly Sensitive ◽  
Photoelectric Colorimeter ◽  
Health And Disease

A study of circulating immune complexes was carried out using a reaction with polyethylene glycol. The method turned out to be simple, highly sensitive and affordable for any clinical laboratory with a photoelectric colorimeter. Analysis of the survey data of 115 healthy donors, 63 patients with rheumatoid arthritis and 16 patients with systemic lupus erythematosus made it possible to establish the level of circulating immune complexes in health and disease. The circulating immune complexes were studied in patients with rheumatism and chronic tonsillitis. To assess the results of the reaction, human aggregated gamma globulin (manufactured by Kazan NIIEM) was used.

scholarly journals The model of circulating immune complexes and interleukin-6 improves the prediction of disease activity in systemic lupus erythematosus

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Chokchai Thanadetsuntorn ◽  
Pintip Ngamjanyaporn ◽  
Chavachol Setthaudom ◽  
Kenneth Hodge ◽  
Nisara Saengpiya ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Interleukin 6 ◽  
Circulating Immune Complexes ◽  
Systemic Lupus
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