Advances in mesenchymal stem cell therapy for lupus nephritis

Table 3 Clinical studies of mesenchymal stem cell therapy for lupus nephritis

MSCs (sources, timing, dose)	Study design	Sample size (n), LN/SLE	Follow up (months)	Safety and adverse effects	Outcomes	Ref.
UC-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	15/16, refractory LN	3-28	Severe nausea (1/16). No treatment-related mortality or other adverse events	SLEDAI scores decreased gradually during 6 months follow-up (10/16). Anti-dsDNA antibody decreased significantly at 3 months (13/16) and gradually decreased after 6 months (3/16). Reduced proteinuria and improved eGFR during 6 months follow-up (8/16) and further improved during long-term follow-up (2/16)	Sun et al[58], 2010
BM-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	15/15, refractory LN	12-36	No serious adverse events. No GVHD. Upper respiratory tract infections	Decreased SLEDAI score at 12 months follow-up (12/13). Lower titers of anti-dsDNA at 3 months follow-up (11/15). Reduced 24 hours proteinuria at 12 months follow-up (12/12)	Liang et al[57], 2010
BM-MSCs/UC-MSCs (single or double i.v. injection 1 × 106 cells/kg)	Dose comparison trial	50/58, refractory LN	12-48	One death in double transplantation group. Upper respiratory tract infection, intestinal infection, herpes zoster infection, pulmonary tuberculosis considered non transplantation related	Complete remission (16/30) in single transplantation group and (8/27) in multiple transplantation group during 4 years follow-up. Decreased SLEDAI score during 3 years follow-up. Decreased anti-dsDNA titer during 2 years follow-up. Reduced proteinuria and improved eGFR during 3 years follow-up	Wang et al[18], 2012
BM-MSCs/UC-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	73/87, refractory LN	48	Death (5/87), diarrhea (2/87), herpesvirus infection (2/87), agranulocytosis and oral fungus infection (1/87), pulmonary tuberculosis (1/87), bone fracture (1/87), myocardial infarction (1/87) considered non transplantation related	Overall rate of survival was 94% (82/87). Complete clinical remission rate was 28% at 1 year (23/83), 31% at 2 years (12/39), 42% at 3 years (5/12), and 50% at 4 years (3/6). Rates of relapse were 12% (10/83) at 1 year, 18% (7/39) at 2 years, 17% (2/12) at 3 years, and 17% (1/6) at 4 years. The overall rate of relapse was 23% (20/87)	Wang et al[59], 2013
UC-MSCs [double i.v. injection (1 week apart) 1 × 106 cells/kg]	Single arm	38/40, active LN	12	Well tolerated. Herpesvirus infection, death, and tuberculosis infection with no relation to transplantation	Decreased SLEDAI score at 12 months follow-up. Decreased anti-dsDNA titer at 12 months follow-up. Reduced proteinuria and improved eGFR at 6 months follow-up. Four patients relapse at 12 months follow-up	Wang et al[22], 2014
BM-MSCs/UC-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	81/81, active and refractory LN	12	Death (4/87), enteritis and diarrhea (2/87) with no relation to transplantation	Survival rate was 95 % (77/81) during the 12 months follow-up. Complete remission rate was 17.5% (14/80) at 3 months, 18.2% (14/77) at 6 months, and 23.4% (18/77) at 12 months. 60.5% renal remission, 22.4% renal flare. Decreased SLEDAI score and BILAG score, improved GFR at 12 months follow-up	Gu et al[54], 2014
UC-MSCs [double i.v. injection (1 week apart) 2 × 108 cells/each]	Randomized double-blind, placebo-controlled trial	18/18, WHO class III or IV LN	12	Leukopenia, pneumonia, subcutaneous abscess	Remission rate in the UC-MSCs group was 75% (9/12), compared to 83% (5/6) in the placebo group. No effect of UC-MSCs above standard immunosuppression	Deng et al[56], 2017
UC-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	21/21, refractory LN	6	No treatment-related mortality or other adverse events	Decreased SLEDAI score at 6 months follow-up. Reduced proteinuria, maintained eGFR 6 months follow-up. Up-regulation of peripheral blood CD1c+ DCs and serum FLT3L	Yuan et al[39], 2019
AD-MSCs (single i.v. injection, 2 × 106 cells/kg)	Single arm. Phase I clinical trial	9/9, biopsy-proven refractory LN	12	No allergic reaction or other adverse effects	Decreased SLEDAI score. Decreased anti-dsDNA titer at the first month. Reduced proteinuria and improved eGFR at the first 3 months	Ranjbar et al[25], 2022

MSC: Mesenchymal stem cell; LN: Lupus nephritis; SLE: Systemic lupus erythematosus; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; i.v.: Intravenous; SLEDAI: Systemic lupus erythematosus disease activity index; anti-dsDNA: Anti-double stranded DNA; eGFR: Estimated glomerular filtration rate; BM-MSCs: Bone marrow-derived mesenchymal stem cells; GVHD: Graft-vs-host disease; BILAG: British Isles Lupus Assessment Group; WHO: World Health Organization; DCs: Dendritic cells; FLT3L: FMS-related tyrosine kinase 3 ligand; AD-MSCs: Adipose tissue-derived mesenchymal stem cells.