Molecular and therapeutic effects of mesenchymal stem cell-derived exosomes on autoimmune diseases

Table 1 Clinical trials (completed and ongoing) investigating mesenchymal stem cell-based therapies in autoimmune diseases

Study type	MSC source	Disease	Patients (treatment/control)	Administration	Follow-up (months)	Mechanism of action	Outcome measures	Conclusion	Trial registration number	Ref.
-	BM-MSCs (autologous)	SLE	2 (2/0)	1 × 106 cells/kg, IV infusion	4	Immunomodulation	Safety and efficacy, Selena SLEDAI and BILAG scores	CD4+CD25+FoxP3+ cells increased, but the disease did not show remission		[121]
Phase I/II	UC-MSCs (allogeneic)	SLE	244 (211/78)	1 × 106 cells/kg, IV infusion	6	FLT3 L production, CD1c+ DC proliferation, IFN-γ effect	Clinical improvement, CD1c+ DC and FLT3 L levels	Increased FLT3 L levels and increased number of tolerant CD1c+ DCs, suppression of inflammation	NCT01741857	[122]
Phase II	BM-MSCs	SLE	3 (3/0)	9 × 107 cells/kg, IV infusion	9	Immunomodulation	SLEDAI, proteinuria values, renal function	Significant reduction in disease activity and improvement in kidney function		[123]
-	UC-MSCs, BM-MSCs	Persistently active SLE	87 (87/0)	1 × 106 cells/kg, IV infusion	48	Suppression of the proliferation of T and B lymphocytes, modulation of the inflammatory reaction and proliferation of Treg cells	Selena SLEDAI, ANA, dsDNA, clinical remission, relapse, and survival rate	Prolonged clinical remission and improvement in organ function		[124]
Phase I	AD-MSCs (allogeneic)	Refractory lupus nephritis	9 (9/0)	2 × 106 cells/kg, IV infusion	12	Immunomodulation	SLEDAI, 24-h urinary protein excretion, serum creatinine, anti-dsDNA antibodies	Effective in reducing urinary protein excretion and disease activity in the short term, single dose limited for long-term remission		[125]
-	UC-MSCs	Lupus nephritis	37 (17/20)	3 × 107 cells/kg, IV infusion	12	Immunomodulation	SLEDAI, ANA, dsDNA urinary protein excretion, safety, and tolerability	Reduction of disease activity, regulation of the balance of inflammatory cytokines, improvement of serological markers and renal function		[126]
Phase I/II	BM-MSCs (autologous)	RA with knee involvement	30 (15/15)	Intra-articular implantation of 40 million autologous BM-MSCs per knee joint	12	Immunomodulation, suppression of inflammatory cytokines	WOMAC, VAS, time to gelling, pain-free walking distance, standing time	Safe and well tolerated, with a trend towards clinical efficacy with improvements in WOMAC, VAS, gelling time, and pain-free walking distance	NCT01873625	[127]
Phase I/II	UC-MSCs	RA	63 (32 MSC monotherapy group, 31 MSC + IFN-γ group)	UC-MSC transplantation, with some patients receiving recombinant human IFN-γ 1 × 106 cells/kg 1 dose	3	IFN-γ enhanced MSC therapeutic efficacy	EULAR response rates, ACR20 response rates	The combination therapy of MSC and IFN-γ improved RA outcomes with an ACR20 response of 93.3% at 3 months vs 53.3% with MSC alone, with no major safety concerns at 1 year	ChiCTR-INR-17012462	[128]
Phase I/IIa	AD-MSCs (autologous)	DMARD-resistant RA	54 (392/15)	2.0 or 2.86 × 106 cells/kg, IV infusion	12	Immunomodulation	RAPID3, DAS28, and ACR20	Study ongoing	NCT04170426
Phase I/II	UC-MSCs	RA	172 (136/36)	IV infusion of 4 × 107 UC-MSCs in combination with DMARDs	Follow-up examinations after 3, 6, and 8 months	Immunomodulation, suppression of inflammatory cytokines	ACR improvement criteria, DAS28, HAQ, TNF-α, IL-6 levels, CD4+CD25+FoxP3+ Treg percentage	Safe, TNF-α and IL-6 levels decreased, the proportion of Tregs increased, and a clinical improvement was observed. The therapeutic effect lasted 3-6 months and repeated infusions increased the efficacy	NCT01547091	[89]
Phase I/II	MSCs (allogeneic)	RA	30 (15/15)	Dose not specified IV infusion	1	Immunomodulation, suppression of inflammatory response	Safety, tolerability, preliminary efficacy, DAS28	Study ongoing; results not yet published	NCT05925647
Phase I	UC-MSCs (allogeneic) (BX-U001)	RA	16 (8/8)	(0.75-1.5) × 106 cells/kg, BX-U001 IV infusion	24	Immunomodulation and anti-inflammatory effect	Safety and tolerability, ACR20, HAQ, DAS28, CRP, ESR, SDAI, anti-CCP	Study ongoing	NCT03828344
Phase I/II	UC-MSCs (allogeneic)	RA	105 (52/53)	1 × 106 cells/kg, IV infusion	12	Immunomodulation, regulation of Treg/Th17 balance, suppression of inflammatory cytokines	DAS28, HAQ, serum cytokine levels (IFN-γ, IL-10, IL-6), Treg/Th17 ratio	Safe and effective, clinical improvement persisted for 48 weeks, and high IFN-γ levels correlated with better treatment response	ChiCTR-ONC-16008770	[129]
Phase Ib/IIa	AD-MSCs (allogeneic) (Cx611)	Refractory RA	53 (46/7)	1, 2 or 4 × 106/kg, IV infusion	6	Immunomodulation, suppression of inflammatory response	Safety, tolerability, pre-activity	Well tolerated, with no dose-dependent toxicity observed. A trend towards clinical efficacy was observed	NCT01663116	[130]
Phase Ia	UC-MSCs	RA	9 (9/0)	2.5, 5.0 or 10.0 × 107 cells/patient, IV infusion	1	Immunomodulation	Safety, DAS28, ESR, and CRP levels	Significant decrease in DAS28 score at week 4, decrease in ESR and CRP values	NCT02221258	[131]
Phase I	BM-MSCs (autologous)	RA	9 (9/0)	1 × 106 cells/kg, IV injection	12	Immunomodulation	DAS28-ESR, VAS, and ESR	Significant reduction in DAS28-ESR, VAS, and ESR	NCT03333681	[132]
Phase I	Placenta derived MSCs (allogeneic)	SPMS	5 (5/0)	3 × 106 cells/kg, IV injection	6	Immunomodulation	EDSS, cytokines, DTI, fMRI, cognitive and psychological evaluations	Results not yet published	NCT06360861
Phase I/II	MSCs (autologous)	MS	24 (24/0)	1 × 106 cells/kg, IV or intrathecal injection	48	Immunomodulation	EDSS, adverse events	Results not yet published	NCT04823000
Phase I	BM-MSCs (autologous)	MS	7 (7/0)	(1-2) × 106 cells/kg, IV infusion	12	Immunomodulation	EDSS, MRI, adverse events	Results not yet published	NCT03778333
Phase II	BM-MSCs (autologous)	MS	48 (32/16)	1 × 106 cells/kg, IV or intrathecal injection	12	Immunomodulation	EDSS, MRI, ambulation score, relapse rate	Results not yet published	NCT02166021
Phase I/II	UC-MSCs (allogeneic)	MS	20 (20/0)	Dose not specified IV injection	12	Immunomodulation	EDSS, NRS, PASAT, the nine-hole peg test, and 25-foot walking time. Short-form 36	Results not yet published	NCT02034188

¹A total of 166 patients with systemic lupus erythematous were included in the study. There were 21 patients with systemic lupus erythematous who did not respond to conventional treatment and were treated. ²Nine subjects in phase 1 and 30 subjects in phase IIa. MSC: Mesenchymal stem cell; BM-MSCs: Bone marrow derived mesenchymal stem cells; SLE: Systemic lupus erythematous; IV: Intravenous; SLEDAI: Systemic lupus erythematous disease activity index; BILAG: British Isles lupus assessment group; UC-MSCs: Umbilical cord derived mesenchymal stem cells; FLT3 L: FMS-like tyrosine kinase 3 ligand; DC: Dendritic cells; IFN-γ: Interferon-gamma; ANA: Antinuclear antibody; dsDNA: Double-stranded DNA; AD-MSCs: Adipose tissue derived mesenchymal stem cells; RA: Rheumatoid arthritis; WOMAC: Western Ontario and McMaster Universities Arthritis Index; VAS: Visual analogue scale; EULAR: European Alliance of Associations for Rheumatology; ACR20: American College of Rheumatology 20; DMARD: Disease-modifying antirheumatic drug; RAPID3: Routine assessment of patient index data 3; DAS28: 28-joint Disease activity score; HAQ: Health Assessment Questionnaire; TNF-α: Tumor necrosis factor-alpha; IL-6: Interleukin-6; Treg: Regulatory T cell; CRP: C-reactive protein; ESR: Erythrocyte sediment rate; SDAI: Simplified Disease Activity Index; anti-CCP: Anti-cyclic citrullinated peptide; SPMS: Secondary progressive multiple sclerosis; MS: Multiple sclerosis; EDSS: Expanded Disability Status Scale; DTI: Diffusion tensor imaging; fMRI: Functional magnetic resonance imaging; MRI: Magnetic resonance imaging; NRS: Neurological rating scale; PASAT: Paced auditory serial addition test; Th: T helper cell.