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.

TargetsTreatmentMouse modelMechanismsMain outcomesRefClinical trial

Targeting cytokines

IL-6IL-6R mAbMRL/lprNephritis, anti-dsDNA Ab[105]Tocilizumab*
IL-6R mAbNZB/W F1Inhibits IgG class switchSurvival↑, IgG ANA, proteinuria[107]A Phase I trial showed both decreased disease activity and side effects [106]
IL-6 mAbNZB/W F1Suppresses autoreactive B cell and T cellNephritis, anti-dsDNA Ab [108]

IL-10IL-10 inhibitor (AS101)NZB/W F1Decreases IL-10, increases TNF-αDelayed onset, anti-DNA Ab, proteinuria, glomerular deposition[109]Antagonizing anti- IL-10 mAb
A small-scale trial showed efficacy. [110]
IL-10 mAbNZB/W F1Neutralizes IL-10, increases TNF-αDelayed onset, survival↑, ANA[111]
rIL-10MRL/lprSuppresses Th1 responseIgG2a anti-dsDNA[112]
AAV-IL-10 (low exp.)B6 Sle1 Sle2 S
le3
Suppresses Th1 responseANA, GN, T cell activation [113]

TNF-αrTNF-αNZB/W F1Decreases cellular responseDelayed 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-αIFN-α kinoid vaccinationNZB/W F1Induces anti IFN-α neutralizing AbDelayed 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-βIFN-βMRL/lprReduces both cellular and humoral responses and cytokine productionSurvival↑, proteinuria, skin lesions, ANA, splenomegaly [119]

IFN-γIFN-γ cDNA vaccinationMRL/lprInduces anti IFN-γ neutralizing AbSurvival↑, lymphoid hyperplasia, ANA, GN [120]AMG 811
Phase I trial in progress
IFN-γ mAbNZB/W F1Survival↑, proteinuria, anti-DNA Ab[121]

IL-17Rock2 inhibitor (Fasudil)MRL/lprInhibits IRF4 phosphorylation and reduces IL-17 and IL-21 productionAnti-dsDNA Ab, glomerular deposition, proteinuria[122]

IL-21IL-21R FcMRL/lprDecreases T cell numbers and alters B cell functionsTotal Ig , anti-dsDNA Ab, proteinuria skin lesions, lymphadenopathy [123]

IL-18IL-18 cDNA vaccinationMRL/lprInduces anti-IL-18 neutralizing AbSurvival↑, GN, IFN- [124]

BAFFAdenovirus-BAFF-R-IgNZM2410Depletes B cell, decreases T cell activation and myeloproliferationSurvival↑, proteinuria, splenomegaly, reverses disease[125]Belimumab
Anti-BAFF-IgB6·lyn-/-Nephritis,[129]Phase III met primary complex end point. [126, 127].
BAFF and AprilHuman TACI-IgNZB/WF1Blocks BAFF and April signalingSurvival↑, 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 F1Blocks BAFF and April signaling splenic B cell depletionSurvival↑, delayed onset,, ANA, proteinuria, nephritis, reverses disease only when CTLA4-Ig coadministered [131]
Adenovirus-TACI-FcMRL/lpr,
NZB/W F1,
Blocks BAFF and April signalingIn MRL/lpr: survival↑, GN, proteinuria,In NZB/W F1: anti-TACI antibodies neutralized TACI-Fc [132]
Adenovirus-TACI-IgNZM2410Blocks on BAFF and April signaling;Survival↑, proteinuria, splenomegaly, reverses disease[125]

B cell depletion

CD20Anti-CD20 mAbMRL/lprADCC, CDCSerum Ab and ANA, nephritis, proteinuria, dermatitis[133]Rituximab
Failed to reach primary end point [134, 135]
Anti-CD20 mAbNZB/W F1ADCC, CDCTreatment on 12–28-wk-old mice ameliorates disease, while treatment on 4-wk old mice hastens disease [137]Ocrelizumab
Phase III terminated [136]

CD22Anti-CD22 mAbNZB/W F1ADCC, targets inhibitory receptorAble to deplete several B cell subsets. No significant effect on improving survival [137]Epratuzumab
Phase IIb trial showed positive result [138, 139]

CD79Anti-CD79 α and Anti-CD79 β mAbMRL/lprSurvival↑, IgG antichromatin, skin lesions Inflammatory infiltrates[140]

ProteasomeProteasome inhibitor bortezomibNZB/W F1 and MRL/lprEliminates both short-lived and long-lived plasma cellsSurvival↑, ANA, GN[141]

Targeting T cell-APC interactions

CTLA4-IgNZB/W F1Inhibits B7-CD28 interactionSurvival↑, ANA [142, 143]Abatacept
The ACCESS trial is in progress [144]

CD28-B7Adenovirus-CTLA4-IgNZB/W F1Inhibits B7-CD28 interactionSurvival↑, ANA, GN [145]
CTLA4-Ig transgeneB6 lyn-/-Inhibits B7-CD28 interactionMyeloid hyperplasia, splenomegaly IgG ANA, renal disease unaffected[146]
CTLA4-Ig and anti-gp39NZB/W F1Simultaneously inhibits B7-CD28 and CD40/gp39 interactionSurvival↑, ANA, GN, effects are more significant than CTLA4-Ig alone [143]

Targeting T follicular helper cells

CD3Nasal anti-CD3 AbNZB/W F1Downregulates the expression of IL17 and IL21 by Tfh cellsANA, GN[147]

ICOS-B7RP-1anti-B7RP-1 AbNZB/W F1Downregulates ICOS and reduces Tfh cell numberSurvival, anti-dsDNA Ab, proteinuria [148]

Targeting other receptors

FcgRIIBFcgRIIB expressing retrovirusNZM2410, BXSB, B6Fcgr2b-/-Restores FcgRIIB levelANA, immune complex deposition, proteinuria, GN, lung pathology[149]

TLR7/TLR9Immunoregulatory sequence (IRS) 954NZB/W F1Reduces the production of IFN-αSurvival↑, ANA, proteinuria, GN, [150]

Programmed death-1 (PD-1)Neutralizing PD-1AbNZB/W F1Promotes suppressive CD8+ T cellsSurvival↑, delayed nephritis, IgG, anti-dsDNA IgG[151]

Targeting cell signaling

SykSyk inhibitor R788NZB/W F1Blocks B cell receptor (BCR) and FcR signalingSurvival↑, proteinuria, renal disease[152]
Syk inhibitor R788MRL/lpr or BAK/BAX-/-Blocks BCR and FcR signalingSkin lesions lymphadenopathy and splenomegaly, renal disease[153]

PI3K γAS605240 compoundMRL/lprReduces T and B cell activationSurvival↑, renal infiltrates, GN [154]

mTORRapamycinNZB/W F1ImmunosuppressionSurvival↑, anti-dsDNA Ab, splenomegaly, albuminuria[155]Rapamycin
A small scale trial showed efficacy [156]

Cellular therapies

Regulatory B cells (Breg)Anti-CD40 injectionMRL/lprAgonistic anti-CD40 expands BregSurvival↑, anti-dsDNA Ab, proteinuria, skin lesions [157]

Regulatory T cells (Treg)Adoptive transfer of ex vivo expanded TregNZB/W F1T cell suppressionSurvival↑, renal IC deposition, proteinuria, GN [158, 159]

Umbilical cord
mesenchymal stem cells (MSC)
MRL/lprimmunosuppressive and anti-inflammatory propertiesanti-dsDNA Ab, Proteinuria, renal disease[160]A small-scale trial showed positive result [161]
Umbilical cord
mesenchymal stem cells (MSC)
NZB/W F1immunosuppressive and anti-inflammatory propertiesSurvival↑, anti-dsDNA Ab, proteinuria, renal disease[162]

Bone marrow derived mese-
nchymal stem cell (BM-MSC)
NZB/W F1Inhibition of B cell proliferation and differentiation dependent on IFN-γGlomerular IC deposition, lymphocytic infiltration, glomerular proliferation, anti-dsDNA Ab and proteinuria unaffected[163]

Sex hormone modulation

EstrogenNafoxidineNZB/W F1Delayed onset, survival↑, ANA, proteinuria[164]Tamoxifen
A small-scale trial showed no effect [165]
EstrogenTamoxifenNZB/W F1Reduces IgG3 ANA productionSurvival↑, IgG3 ANA, proteinuria, thrombocytopenia, glomerular deposits [166, 167]Fulvestrant (estrogen receptor downregulator)
A small-scale trial showed some efficacy [168]
EstrogenRaloxifeneNZB/W F1Inhibits B cell functionAnti-DNA Ab, kidney damage[169]
EstrogenIndole-3-carbinolNZB/W F1Blocks B cell and T cell differentiationSurvival↑, ANA, nephritis [170]

AndrogenAndrogen treatment on castrated femaleNZB/W F1UnspecifiedSurvival↑, IgG ANA[171]Dehydroepiandrosterone
Little clinical effect [172]
AndrogenAndrogen treatmentNZB/W F1, MRL/lprUnspecifiedSurvival↑, anti-DNA Ab,[173]

Peptide-based immunotherapy

LamininLaminin derived peptidesMRL/lprLaminin derived peptides competitively bind with ANA and prevent their deposition in the kidneySurvival↑, proteinuria, GN[174]

HSC chaperone proteinU1-70K snRNP derived peptide administered in saline (P140)MRL/lprImpairs autoimmune T cell responseSurvival↑, proteinuria, anti-dsDNA Ab [175, 176]P140
A phase IIa study showed positive result [177]

Autoreactive B and T cellsHistone peptide H2B10-33, H416-39, H471-94(SWR/ NZB)F1Impairs autoimmune B and T cellSurvival↑, proteinuria, ANA [178]

Suppressive CD8+ T cellspCONSNZB/W F1Promotes suppressive CD8+ T cells by regulating Foxp3 and PD-1Survival↑, nephritis, ANA [179181]

UnclearCDR1 of human anti-DNA Ab (hCDR1)NZB/W F1Modulation of cytokines, regulatory T cells and T cell apoptosisANA, nephritis, CNS symptoms[182]hCDR1
A small-scale trial showed positive result [182]

Other therapies

Histone deacetylaseHistone deacetylase inhibitors TSA and SAHAMRL/lprDecreases transcription of key cytokines involved in SLESplenomegaly, proteinuria, renal disease[183]

Topoisomerase ITopoisomerase I Inhibitor irinotecanNZB/W F1Prevents anti-dsDNA Ab from binding to dsDNASurvival↑, proteinuria subendothelial immune deposit[184]

ACEACE inhibitor CaptoprilNZB/W F1 and MRL/lprReduces TGF- β, IL-4 and IL-10 productionDelayed onset, proteinuria, renal lesion [185]

HMG-CoA reductaseHMG-CoA reductase inhibitor StatinNZB/W F1Immunomodulatory effects on B and T cells and APCsANA, serum urea, proteinuria, nephritis [186]

ACE and HMG-CoA reductaseCoadministration of Statin and ACE inhibitor ImidaprilMRL/lprSynergistic effectSurvival↑, ANA, proteinuria, glomerular deposits, renal monocyte attractant CCL2/MCP-1 [187]

CCL2/MCP-1Spiegelmer mNOX-E36MRL/lprmNOX-E36 blocks CCL2 without induction of IFN-α productionSurvival↑, nephritis, skin lesion, peribronchial inflammation[188]

*Drug names are shown in italic font.