Murine Models of Systemic Lupus Erythematosus

Table 1

Summary of treatments tested in mouse models of lupus, their targets, proposed mechanisms, outcomes in the mouse, and follow up in clinical trials.

Targets	Treatment	Mouse model	Mechanisms	Main outcomes	Ref	Clinical trial
Targeting cytokines
IL-6	IL-6R mAb	MRL/lpr		Nephritis↓, anti-dsDNA Ab↓	[105]	Tocilizumab*
	IL-6R mAb	NZB/W F1	Inhibits IgG class switch	Survival↑, IgG ANA↓, proteinuria↓	[107]	A Phase I trial showed both decreased disease activity and side effects [106]
	IL-6 mAb	NZB/W F1	Suppresses autoreactive B cell and T cell	Nephritis↓, anti-dsDNA Ab↓	[108]
IL-10	IL-10 inhibitor (AS101)	NZB/W F1	Decreases IL-10, increases TNF-α	Delayed onset, anti-DNA Ab↓, proteinuria↓, glomerular deposition↓	[109]	Antagonizing anti- IL-10 mAb; A small-scale trial showed efficacy. [110]
	IL-10 mAb	NZB/W F1	Neutralizes IL-10, increases TNF-α	Delayed onset, survival↑, ANA↓	[111]
	rIL-10	MRL/lpr	Suppresses Th1 response	IgG2a anti-dsDNA↓	[112]
	AAV-IL-10 (low exp.)	B6⋅Sle1⋅Sle2⋅S; le3	Suppresses Th1 response	ANA↓, GN↓, T cell activation↓	[113]
TNF-α	rTNF-α	NZB/W F1	Decreases cellular response	Delayed onset, survival↑	[114]	Infliximab; A small-scale trial showed both efficacy and side effects [115]; Etanercept; Phase II trial for discoid lupus in progress
IFN-α	IFN-α kinoid vaccination	NZB/W F1	Induces anti IFN-α neutralizing Ab	Delayed onset, survival↑, proteinuria↓	[116]	MEDI-545 (sifalimumab); Phase I trial showed positive result [117]; rhuMab IFN-α (Rontalizumab); Phase I trial showed positive result [118]
IFN-β	IFN-β	MRL/lpr	Reduces both cellular and humoral responses and cytokine production	Survival↑, proteinuria↓, skin lesions↓, ANA↓, splenomegaly↓	[119]
IFN-γ	IFN-γ cDNA vaccination	MRL/lpr	Induces anti IFN-γ neutralizing Ab	Survival↑, lymphoid hyperplasia↓, ANA↓, GN↓	[120]	AMG 811; Phase I trial in progress
	IFN-γ mAb	NZB/W F1		Survival↑, proteinuria↓, anti-DNA Ab↓	[121]
IL-17	Rock2 inhibitor (Fasudil)	MRL/lpr	Inhibits IRF4 phosphorylation and reduces IL-17 and IL-21 production	Anti-dsDNA Ab↓, glomerular deposition↓, proteinuria↓	[122]
IL-21	IL-21R⋅Fc	MRL/lpr	Decreases T cell numbers and alters B cell functions	Total Ig ↓, anti-dsDNA Ab↓, proteinuria↓ skin lesions↓, lymphadenopathy↓	[123]
IL-18	IL-18 cDNA vaccination	MRL/lpr	Induces anti-IL-18 neutralizing Ab	Survival↑, GN↓, IFN- 𝛾↓	[124]
BAFF	Adenovirus-BAFF-R-Ig	NZM2410	Depletes B cell, decreases T cell activation and myeloproliferation	Survival↑, proteinuria↓, splenomegaly↓, reverses disease	[125]	Belimumab
	Anti-BAFF-Ig	B6·lyn^-/-		Nephritis↓,	[129]	Phase III met primary complex end point. [126, 127].
BAFF and April	Human TACI-Ig	NZB/WF1	Blocks BAFF and April signaling	Survival↑, proteinuria↓, no significant change in anti-dsDNA Ab level	[130]	Atacicept; Phase II terminated [128]
	Adenovirus-TACI-Ig (w/ or w/o CTLA4-Ig co-administration)	NZB/W F1	Blocks BAFF and April signaling splenic B cell depletion	Survival↑, delayed onset,, ANA↓, proteinuria↓, nephritis↓, reverses disease only when CTLA4-Ig coadministered	[131]
	Adenovirus-TACI-Fc	MRL/lpr,; NZB/W F1,	Blocks BAFF and April signaling	In MRL/lpr: survival↑, GN↓, proteinuria↓,In NZB/W F1: anti-TACI antibodies neutralized TACI-Fc	[132]
	Adenovirus-TACI-Ig	NZM2410	Blocks on BAFF and April signaling;	Survival↑, proteinuria↓, splenomegaly↓, reverses disease	[125]
B cell depletion
CD20	Anti-CD20 mAb	MRL/lpr	ADCC, CDC	Serum Ab and ANA↓, nephritis↓, proteinuria↓, dermatitis↓	[133]	Rituximab; Failed to reach primary end point [134, 135]
	Anti-CD20 mAb	NZB/W F1	ADCC, CDC	Treatment on 12–28-wk-old mice ameliorates disease, while treatment on 4-wk old mice hastens disease	[137]	Ocrelizumab; Phase III terminated [136]
CD22	Anti-CD22 mAb	NZB/W F1	ADCC, targets inhibitory receptor	Able to deplete several B cell subsets. No significant effect on improving survival	[137]	Epratuzumab; Phase IIb trial showed positive result [138, 139]
CD79	Anti-CD79 α and Anti-CD79 β mAb	MRL/lpr		Survival↑, IgG antichromatin↓, skin lesions↓ Inflammatory infiltrates↓	[140]
Proteasome	Proteasome inhibitor bortezomib	NZB/W F1 and MRL/lpr	Eliminates both short-lived and long-lived plasma cells	Survival↑, ANA↓, GN↓	[141]
Targeting T cell-APC interactions
	CTLA4-Ig	NZB/W F1	Inhibits B7-CD28 interaction	Survival↑, ANA↓	[142, 143]	Abatacept; The ACCESS trial is in progress [144]
CD28-B7	Adenovirus-CTLA4-Ig	NZB/W F1	Inhibits B7-CD28 interaction	Survival↑, ANA↓, GN↓	[145]
	CTLA4-Ig transgene	B6 lyn^-/-	Inhibits B7-CD28 interaction	Myeloid hyperplasia↓, splenomegaly↓ IgG ANA↓, renal disease unaffected	[146]
	CTLA4-Ig and anti-gp39	NZB/W F1	Simultaneously inhibits B7-CD28 and CD40/gp39 interaction	Survival↑, ANA↓, GN↓, effects are more significant than CTLA4-Ig alone	[143]
Targeting T follicular helper cells
CD3	Nasal anti-CD3 Ab	NZB/W F1	Downregulates the expression of IL17 and IL21 by Tfh cells	ANA↓, GN↓	[147]
ICOS-B7RP-1	anti-B7RP-1 Ab	NZB/W F1	Downregulates ICOS and reduces Tfh cell number	Survival↓, anti-dsDNA Ab↓, proteinuria↓	[148]
Targeting other receptors
FcgRIIB	FcgRIIB expressing retrovirus	NZM2410, BXSB, B6Fcgr2b^-/-	Restores FcgRIIB level	ANA↓, immune complex deposition↓, proteinuria↓, GN↓, lung pathology↓	[149]
TLR7/TLR9	Immunoregulatory sequence (IRS) 954	NZB/W F1	Reduces the production of IFN-α	Survival↑, ANA↓, proteinuria↓, GN↓,	[150]
Programmed death-1 (PD-1)	Neutralizing PD-1Ab	NZB/W F1	Promotes suppressive CD8^+ T cells	Survival↑, delayed nephritis, IgG↓, anti-dsDNA IgG↓	[151]
Targeting cell signaling
Syk	Syk inhibitor R788	NZB/W F1	Blocks B cell receptor (BCR) and FcR signaling	Survival↑, proteinuria↓, renal disease↓	[152]
	Syk inhibitor R788	MRL/lpr or BAK/BAX^-/-	Blocks BCR and FcR signaling	Skin lesions↓ lymphadenopathy and splenomegaly↓, renal disease↓	[153]
PI3K γ	AS605240 compound	MRL/lpr	Reduces T and B cell activation	Survival↑, renal infiltrates↓, GN↓	[154]
mTOR	Rapamycin	NZB/W F1	Immunosuppression	Survival↑, anti-dsDNA Ab↓, splenomegaly↓, albuminuria↓	[155]	Rapamycin; A small scale trial showed efficacy [156]
Cellular therapies
Regulatory B cells (Breg)	Anti-CD40 injection	MRL/lpr	Agonistic anti-CD40 expands Breg	Survival↑, anti-dsDNA Ab↓, proteinuria↓, skin lesions↓	[157]
Regulatory T cells (Treg)	Adoptive transfer of ex vivo expanded Treg	NZB/W F1	T cell suppression	Survival↑, renal IC deposition↓, proteinuria↓, GN↓	[158, 159]
Umbilical cord; mesenchymal stem cells (MSC)		MRL/lpr	immunosuppressive and anti-inflammatory properties	anti-dsDNA Ab↓, Proteinuria↓, renal disease↓	[160]	A small-scale trial showed positive result [161]
Umbilical cord; mesenchymal stem cells (MSC)		NZB/W F1	immunosuppressive and anti-inflammatory properties	Survival↑, anti-dsDNA Ab↓, proteinuria↓, renal disease↓	[162]
Bone marrow derived mese-; nchymal stem cell (BM-MSC)		NZB/W F1	Inhibition of B cell proliferation and differentiation dependent on IFN-γ	Glomerular IC deposition↓, lymphocytic infiltration↓, glomerular proliferation↓, anti-dsDNA Ab and proteinuria unaffected	[163]
Sex hormone modulation
Estrogen	Nafoxidine	NZB/W F1		Delayed onset, survival↑, ANA↓, proteinuria↓	[164]	Tamoxifen; A small-scale trial showed no effect [165]
Estrogen	Tamoxifen	NZB/W F1	Reduces IgG3 ANA production	Survival↑, IgG3 ANA↓, proteinuria↓, thrombocytopenia↓, glomerular deposits↓	[166, 167]	Fulvestrant (estrogen receptor downregulator); A small-scale trial showed some efficacy [168]
Estrogen	Raloxifene	NZB/W F1	Inhibits B cell function	Anti-DNA Ab↓, kidney damage↓	[169]
Estrogen	Indole-3-carbinol	NZB/W F1	Blocks B cell and T cell differentiation	Survival↑, ANA↓, nephritis↓	[170]
Androgen	Androgen treatment on castrated female	NZB/W F1	Unspecified	Survival↑, IgG ANA↓	[171]	Dehydroepiandrosterone; Little clinical effect [172]
Androgen	Androgen treatment	NZB/W F1, MRL/lpr	Unspecified	Survival↑, anti-DNA Ab↓,	[173]
	Peptide-based immunotherapy
Laminin	Laminin derived peptides	MRL/lpr	Laminin derived peptides competitively bind with ANA and prevent their deposition in the kidney	Survival↑, proteinuria↓, GN↓	[174]
HSC chaperone protein	U1-70K snRNP derived peptide administered in saline (P140)	MRL/lpr	Impairs autoimmune T cell response	Survival↑, proteinuria↓, anti-dsDNA Ab↓	[175, 176]	P140; A phase IIa study showed positive result [177]
Autoreactive B and T cells	Histone peptide H2B10-33, H416-39, H471-94	(SWR/ NZB)F1	Impairs autoimmune B and T cell	Survival↑, proteinuria↓, ANA↓	[178]
Suppressive CD8^+ T cells	pCONS	NZB/W F1	Promotes suppressive CD8^+ T cells by regulating Foxp3 and PD-1	Survival↑, nephritis↓, ANA↓	[179–181]
Unclear	CDR1 of human anti-DNA Ab (hCDR1)	NZB/W F1	Modulation of cytokines, regulatory T cells and T cell apoptosis	ANA↓, nephritis↓, CNS symptoms↓	[182]	hCDR1; A small-scale trial showed positive result [182]
Other therapies
Histone deacetylase	Histone deacetylase inhibitors TSA and SAHA	MRL/lpr	Decreases transcription of key cytokines involved in SLE	Splenomegaly↓, proteinuria↓, renal disease↓	[183]
Topoisomerase I	Topoisomerase I Inhibitor irinotecan	NZB/W F1	Prevents anti-dsDNA Ab from binding to dsDNA	Survival↑, proteinuria↓ subendothelial immune deposit↓	[184]
ACE	ACE inhibitor Captopril	NZB/W F1 and MRL/lpr	Reduces TGF- β, IL-4 and IL-10 production	Delayed onset, proteinuria↓, renal lesion↓	[185]
HMG-CoA reductase	HMG-CoA reductase inhibitor Statin	NZB/W F1	Immunomodulatory effects on B and T cells and APCs	ANA↓, serum urea↓, proteinuria↓, nephritis↓	[186]
ACE and HMG-CoA reductase	Coadministration of Statin and ACE inhibitor Imidapril	MRL/lpr	Synergistic effect	Survival↑, ANA↓, proteinuria↓, glomerular deposits↓, renal monocyte attractant CCL2/MCP-1↓	[187]
CCL2/MCP-1	Spiegelmer mNOX-E36	MRL/lpr	mNOX-E36 blocks CCL2 without induction of IFN-α production	Survival↑, nephritis↓, skin lesion↓, peribronchial inflammation↓	[188]

*Drug names are shown in italic font.