Table 2.

Preclinical and clinical studies on T cell co-stimulatory and co-inhibitory molecules of the TNF and TNFR superfamilies.

Molecule on APC	Receptor on T cell	Experimental model	Effects on AD	Related cytokines	Perspectives/limitations	Ref.
Type V subfamily
OX40L	OX40	In vitro cell study	OX40L DCs trigger Th2 differentiation	TSLP, IFN-γ, CXCL10, IL-31, CCL11, CCL17, TSLPR, IL-23p19, IL-8	Phase 2 clinical trials achieve promising results	84
		Lesional skin of AD patients	↑OX40L+ DCs			85, 86
		Skin of AD patients	↑ OX40 expression on skin-homing T cells Co-localization of OX40 and OX40L on skin MCs			87
		▪ Skin lesions of AD patients ▪ Treatment with GBR 830	↓OX40 T-cell ↓OX40L DCs ↓Th2, Th1, Th17, Th22 cell numbers ↓Expression of IFN-γ, CXCL10, IL-31, CCL11, CCL17, TSLPR, IL-23p19, IL-8, S100A			88
		▪ AD patients ▪ Treatment with KHK4083	↓OX40+ cells Continued improvements in eczema area, severity index, and global assessment scores			89
		▪ AD patients ▪ Treatment with KY1005	No therapeutic effect data			90
CD70	CD27	MC903-treated C57BL/6 mice	↑CD27 expression on LCs	IL-12	Require more studies	91
		AD patients	↑CD27 expression on CD4+ T cells			92
CD30L	CD30	Serum samples of AD patients	↑sCD30 sCD30 levels were positively correlated with AD disease severity	–	Lack animal model validation and relevant research on blocking antibodies	93–107
		Serum samples of AD patients	↓sCD30 levels after treatment			93, 95, 98, 103, 107
		Serum samples of AD patients	The sCD30 concentration was correlated with the disease activity and total serum IgE			101–103, 108
Type L subfamily
HVEM	LIGHT	Human KCs	LIGHT directly promoted TSLP expression in KCs	TSLP	A promising biomarker for AD treatment	109
		LIGHT-deficient mice and K14-cre HVEM mice	↓Clinical symptoms			110
		Human KCs	LIGHT promoted KC proliferation and was prevented by siRNA knockdown of HVEM			110
		▪ HDM-sensitized C57BL/6 mice ▪ Anti-HVEM antibody treatment	↓SCORAD ↓Epidermal and dermal thickness ↓Periostin and TSLP expression			110
		Serum samples of AD patients	↑sHVEM and LIGHT levels			111
		Plasma samples of AD patients	Plasma LIGHT concentrations correlated with IgE levels and SCORAD, decreased as the symptoms were improved by treatment			112
CD40	CD40L	Peripheral blood of AD patients	↑CD40L on T cells	–	Target the pathway may benefit AD patients	113
		Skin lesions and peripheral blood of AD patients	↑CD40+ cells CD40+ cells as a positive correlation with disease severity and lgE levels			114
		PBMCs of AD patients	↑CD40 expression on B cells			114

APC, antigen-presenting cell; OX40L, OX40 ligand; CD30L, CD30 ligand; LIGHT, homologous to lymphotoxin, a receptor expressed on T lymphocytes, also known as HVEM-L; CD40L, CD40 ligand.