Table 2.

Examples of therapeutic interventions tested in the NOD and other primary SjS murine models.

Interest	Intervention	Strain	Possible Mechanisms	Disease phenotype change	Remarks	References
TACI	AAV2-TACI-Fc	NOD	Dual blockade of APRIL and BAFF by TACI-Fc	Reduced inflammatory foci in the SG, owing to a decrease in IgD(+) cells and CD138(+) cells. Reduced IgG and IgM in the SG. Lowered proinflammatory cytokines	Salivary flow unaffected	[174]
Stem cells	Allogeneic BM-MSC	NOD	Directing T cells toward Tregand Th2, while suppressing Th17 and Tfh responses	Suppressed autoimmunity Restored SG secretory function	SDF-1 dependent-MSC migration	[175]
Stem cells	BM-MSC & spleen cells	NOD	Immunomodulatory effects Hox11-expressing spleen cells potentially attributing better efficacy on saliva secretion than MSC	Restored saliva secretion Decreased TNF alpha, TGF beta 1, and B cells Increased EGF and Foxp3⁺ T_reg	Spleen cells superior to MSC at early stage but compatible with MSC at disease stage.	[176]
Rapamycin delivery	FSI nanoparticles with rapamycin	NOD	mTOR	Suppressed lymphocytic infiltration in the LG	Altered mTOR pathway genes in LG	[177]
CD40	AAV2-CD40:Fc	NOD	Co-stimulatory pathway	Focus score, infiltrating cell types, immunoglobulin levels, and salivary gland output similar for treated and control mice.	Possible redundancy of the CD40 pathway	[178]
IL-17	Ad5-IL17R:Fc	C57BL/6.NOD-Aec1Aec2	Reduction of IL17A levels by a blocking viral vector	Reduced SG infiltration Normalization of ANA repertoire Improved saliva flow	Effective both in early and late stage of disease	[79]
CTLA-4	AAV2-CTLA4IgG	C57BL/6.NOD-Aec1Aec2	B7:CD28 co-stimulatory pathway inhibition Deactivation of DCs, macrophages and B cells	Blocked B7 expression on macrophages Improved secretion Decreased infiltration and cytokines Increase in TGF-β1 expression	No alteration of anti-Ro or anti-La antibodies	[173]
Immunization	Hsp60 or Hsp60-derived peptide (aa 437–460)	NOD	Potential involvement in chemotaxis, neovascularization, and regulatory pathways	Normal exocrine function in 50% of Hsp60-injected mice and 33% of aa 437–460-injected mice	Quantitative alterations in 36 biomarkers following immunization	[179]
Oxidative stress	EGCG	NOD.B10.Sn-H2 mice	Normalization of antioxidant enzymes PRDX6, catalase, and SOD as well as PCNA	Disease phenotype not examined in this study	Pre-disease stage examined (6, 8, 10, 12, 14 weeks)	[67]
Mucosal protective agent	rebamipide	NFS/sld	Decrease in autoantigen-specific T cell proliferation	Improved saliva secretion Decreased TUNEL + cells in SG/LG Suppressed CD4+T and Th1 cytokines Inhibition of autoantibodies, IgM, and IgG1	Oral administration starting at 4 weeks to 8 weeks of age	[99]
CXCL-13	anti-CXCL13 (mAb 5378)	Primary:Id3^−/− Secondary: MRL/MpJ NOD	CXCL13-mediated Monocyte chemotaxis & migration in Id3 B cell chemotaxis in NOD	Improved SG inflammation No effect on diabetes in NOD but with disrupted B-cell organization	Effectiveness at the late stage of disease not tested.	[180]

SG: salivary gland

BAFF: B cell-activating factor

APRIL: a proliferation-inducing ligand

SDF-1: stromal cell-derived factor-1

CXCR4: C-X-C chemokine receptor type 4

BM-MSC, bone marrow-derived mesenchymal stem cells

LG, lacrimal gland

FSI: FKBP-S48I48

mTOR, mammalian target of Rapamycin

CTLA-4: cytotoxic T-lymphocyte antigen

EGCG: green tea polyphenol epigallocatechin-3-gallate

PCNA: proliferating cell nuclear antigen

PRDX6: peroxiredoxin 6

SOD: superoxide dismutase

Hsp60, heat-shock protein

TACI: transmembrane activator and CAML interactor

TGF-β1: transforming growth factor