Table 2.

Immune mediated goblet cell loss/prevention in mouse dry eye models

Author/year	Animal model	Strain	Principal Findings
Strong/2005115	DS	C57BL/6	• Topical cyclosporine A significantly inhibited DS induced conjunctival epithelial apoptosis and goblet cell loss
Niederkorn/2006116	DS	C57BL/6	• CD25 depletion during DS worsens GC loss
de Paiva/2007117	DS	C57BL/6/IFN-γKO	• DS increases GC loss in wild type, but IFN-γKO are resistant to dry eye-induced GC loss • GC loss and expression of cornification marker SPRR2 were increased by subconjunctival IFN- γ injection during DS in wild type and IFN-γKO.
Yoon/2007118	DS	NOD.B10.H2b	• Decreased GC density at 16 weeks of age compared to 4-week-old mice. • Further decrease in GC density under DS
Yeh/2009119	Spontaneous autoimmune dry eye	C57BL/6/AIREKO	• AIREKO strain have decreased GC density compared to wild-type mice
de Paiva/20104	DS	C57BL/6/IL-13KO	• Naïve IL-13KO mice have decreased GC density compared to wild-type • Exogenous administration of IL-13 during DS prevents GC loss • Cyclosporine A administration during DS increases GC density, while decreasing IFN-γ
de Paiva/2010120 de Paiva/2015121	Spontaneous autoimmune dry eye	CD25KO	• CD25KO has increased concentration of IFN-γ in tears compared to wild type • Decreased GC density in CD25KO compared to wild-type • CD25-IFN-γ double KO have greater GC density compared to parental CD25KO strain
Schaumburg/2011122	DS/Adoptive transfer	C57BL/6	• Clodronate treatment to deplete APCs during DS improved GC density and decreased pathogenicity of transferred CD4+T cells.
de Paiva/2011123	Spontaneous autoimmune dry eye	DN-TGF-BRII	• Decreased GC density compared to wild-type • Increased IFN-γ mRNA in conjunctiva
Zhang/2011124	DS/Adoptive transfer	C57BL/6	• IFN-γ neutralization in RAG1KO recipients decreased conjunctival apoptosis after adoptive transfer
de Paiva/2012125	DS	C57BL/6	• Topical treatment with Resolvin E1 prevents DS-induced goblet cell loss.
Li/2012 126	DS	C57BL/6	• Topical anti-TNF-α during DS decreases frequency of CD4+CXCR3+ cells in the conjunctiva and improves GC density.
Zhang/2013127	DS	C57BL/6	• IFN-γ neutralization during DS improves GC density • Adoptive transfer recipients from anti IFN-γ treated have attenuated dry eye phenotype
Coursey/2013128	DS/Adoptive transfer	C57BL/6/CXCR3KO	• CXCR3KO mice are resistant to DS induced GC loss • Decreased production of IFN-γ in the ocular surface • Adoptive transfer of CXCR3KO CD4+T cells primed during DS do not induce GC loss in recipients
McClellan/201467 Bian/2018129	Aging/Adoptive transfer	C57BL/6	• Loss of GC starts around 9 months of age • Adoptive transfer of aged CD4+T cells transfer dry eye phenotype, inclusive of GC loss • Aged APCs prime greater frequency of CD4+IFN-γ+ than young APCs • Adoptive transfer of aged CD4+CXCR3+T cells induce greater GC loss than young CD4+CXCR3+ cells.
Krauss/2015130	DS	C57BL/6	• Topical treatment with a4b1 integrin prevents DS-induced goblet cell loss
You/2015131	Spontaneous autoimmune dry eye	AEC	• Decreased GC density compared to wild-type • Increased IFN-γ mRNA in conjunctiva and lacrimal gland • Increased frequency of CD4+CXCR3+ cells in lacrimal gland
Coursey/2016132	DS	C57BL/6	• Subconjunctival anti-IFN-γ receptor antibody injection decreases expression of unfolded protein response genes
Volpe/201680	Aging	C57BL/6/IFN-γKO	• IFN-γKO mice are partially protected from age-induced GC loss
Choi/2016 133	DS	C57BL/6	• Anti-oxidant topical therapy during DS decreased IFN-γ protein levels in CJ, improved GC density and decreased the frequency of CD4+CXCR3+ cells
Coursey/2017134	Aging/adoptive transfer	NOD.B10.H2b	• Aged mice develop GC loss • Increased IFN-γ in conjunctiva, lacrimal gland,serum and splenocytes • Adoptive transfer of aged CD4+T cells transfer dry eye phenotype, inclusive of GC loss
Portal/2017135	BAK	C57BL/6	• Recombinant IL-13 prevents goblet cell density in BAK treated mice
Zhang/2017136	DS	C57BL/6	• Topical application of Mizoribine improved GC density
Li/2017 137	DS	C57BL/6	• Topical adiponectin application during DS decreases IFN-γ protein concentration in conjunctiva, improves GC density and decreases the frequency of CD4+CXCR3+ cells.
de Souza/201845	DS	C57BL/6	• Topical treatment with Lifitegrast improves GC density while decreasing IFN-γ, CXCL9 and CXCL10 expression in conjunctiva.
Wang/2018138	Germ-free	C57BL/6	• Spontaneous SS-like KCS, with significant GC loss compared to conventional mice • Increased levels of IL-12+ cells in conjunctiva and greater frequency of CD4+IFN-γ+ cells in the lacrimal gland
Zaheer/2018139	Germ-free/Adoptive transfer	CD25KO	• Early onset and worse dacryoadenitis in germ-free CD25KO mice and greater spontaneous frequency of CD4+IFN-γ+ cells • IL-12 antibody depletion decreases CD4+IFN-γ+ infiltration in lacrimal gland and improves dacryoadenitis
Ko/201888	Naïve	C57BL/6/SPDEFKO	• SPDEF KO mice have no goblet cells • SPDEF KO APCs prime greater frequency of CD4+IFN-γ+ than wild-type • Loss of mucosal tolerance
You/2018 140	DS	C57BL/6	• Topical treatment with 0.3% and 0.18% hyalorunic acid improved GC density
Li/2019 141	DS	B6/NOD2KO	• NOD2KO mice are resistant to DS-induced changes • Greater GC density and decreased tear IFN-γ protein levels in NOD2KO mice

Abbreviations: DS=desiccation stress; KO= gene knockout mouse strain; GC= goblet cell; APC= antigen-presenting cells; BAK= benzalkonium chloride; DS= desiccating stress; GC= goblet cell; KO= knock-out; CXCR3: C-X-C motif chemokine receptor 3; SS= Sjogren syndrome; KCS= keratoconjunctivitis sicca