Journal of Immunology Research

Review Article

Exogenous Control of the Expression of Group I CD1 Molecules Competent for Presentation of Microbial Nonpeptide Antigens to Human T Lymphocytes

Table 2

Pharmacological modulation of CD1 molecule expression.


Drug class	Agent	Therapeutic use	CD1^a	ED^b	Ref^c	Observations

Angiotensin receptor antagonists	Losartan (AT1-R) PD123319 (AT2-R)	Hypertension	D U	ED-1 ED-1	[107]	Assay performed on day 7.

Anti-asthma	Suplatast tosilate	Inhibitor of Th-2 responses	D	ED-1 ED-2	[108]	In ED-1 the assay was performed on day 7. DCs were obtained from pts with asthma.

Anti-depressant	Lithium	Bipolar disorders	D	ED-1	[109]	MOs, obtained from bipolar pts, were incubated with G4.
			U	IvDC	[109]	In vitro generated DCs from lithium-treated pts showed higher CD1a expression than DCs from untreated pts.
			D	ED-1	[110]	Mechanism: CD1 down-regulation is likely mediated through the GSK-3β pathway.

Anti-estrogens	Tamoxifen Toremifene	Breast cancer	D	ED-1 ED-2	[111]	Assay performed on day 7.

Anti-inflammatory corticosteroids	Beclomethasone dipropionate (BDP, inhaled)	Asthma	D	IvDC	[112]	In bronchial mucosa of asthmatic pts there is an increase of CD1a⁺ DCs. Following long-term treatment with BDP the number of CD1a⁺DCs went to normal levels of non-asthmatic pts.
	Dexamethasone (DEX)	Inflammatory diseases	D	ED-1 ED-4	[113]	Strong CD1a down-regulation. Mechanism: high IL-10 via Extracellular signal-regulated kinases (ERK) phosphorylation.
			D	OED	[114]	CD34⁺ cord blood stem cells were cultured with SCS, Flt3-ligand and GM-CSF (Pre-DC). After 5 days, TNFα and IL-4 were added (differentiation stage). On day, 10 CD-40 ligand and anti-human CD40-ligand were also added (maturation stage). DEX, added during differentiation stage, suppresses CD1a at the end of the immature (day 10) and at the mature stage (day 12). On the contrary, CD1a was expressed at normal levels when DEX exposure was limited to the 2 day maturation stage.
				ED-1 ED-3 ED-4	[115]	The MO-derived DCs were obtained from neonatal cord and adult blood.
	Various including DEX		NC	OED	[116]	CD1a⁺ cells derived from bronchoalveolar lavage showed lower APC function if treated with DEX in vitro.
Anti-tubercular agents	Rifampicin		U	ED-1	[117] [118]	Test on CD1b: the drug does not affect the functional activity of the T-cell clone capable of recognizing the mycolic acid of M. tuberculosis origin, presented by CD1b proteins. Test on CD1b: effect obtained at clinical concentration of the drug.

Antiviral	AZT Entecavir	HIV treatment Hepatitis B treatment	NC U	ED-1 ED-1	[119] [120]	AZT inhibits DC proliferation, thereby reducing the total number of DCs.

Bisphosphonates	Zoledronic acid	Osteoporosis	D	ED-4 ED-2	[121]	Mechanism: possibly via IL-10 induction, antagonized by geranylgeraniol.

Disinfectants	Sodium Chlorate		D	ED-1	[122]	Sodium chlorate reduces GAG sulfation on MO surface. Reduction of sulfated CSB impairs IL-4 mediated DC differentiation and CD1a expression.

HDAC inhibitors	MS-275 Sodium valproate	Antitumor	D	ED-4 ED-1	[123]	Mechanism: NF-kB, IRF-3 and IRF-8 inhibition. Possible use in inflammatory and autoimmune disorders.
HDAC inhibitors	Na butyrate		D	ED-1	[124]	The agent prevents CD1 upregulation induced by activation of TLR-2.
Immuno stimulant agents	Imiquimod (imidazo quinoline)	Topical use in squamous cell carcinoma	D	IvDC	[125]	In skin biopsies after topical treatment.
Immuno stimulant agents	OK-432	In cancer treatment	U	ED-2	[126]	The maturation step was performed with OK-432 which promotes a higher expression of CD1a in respect to that obtained with LPS.

Immuno suppressive agents	Gold sodium thiomalate (GST)	Rheumatoid arthritis (RA)	D	ED-1 ED-2 ED-4	[127]	DCs were obtained from healthy donors or RA pts. The suppression of DC differentiation and function might explain the in vivo effect of GST on RA patients.
	Glatiramer acetate (GA) + minocycline (MIN)	Multiple sclerosis (MS)	D	ED-1 ED-4	[128]	DCs were obtained from untreated and GA-treated MS pts. The possible additive effects of GA and MIN on MO-derived DCs, seem to support the use of such combination therapy in MS.
	GA + IFNβ	MS	D	IvDC	[129]	MOs were obtained from untreated or treated MS pts and from healthy donors. Combination therapy with IFNβ + GA resulted in a more pronounced decrease of circulating CD1a compared to monotherapy with IFNβ.
	GA + IFNβ	MS	D	ED-1	[130]	Assay was performed on day 7. DC were obtained from MS pts. Synergistic effects of GA and IFNβ.
	Monomethyl-fumarate (MMF)	Psoriasis	D	ED-1 ED-4	[131]	MMF interfered with the MO-derived DC differentiation, resulting in impaired maturation of these cells.
	Pimecrolimus	Atopic dermatitis	NC	ED-1	[132]	No interference with the function of DCs, whereas the activation of effector T-cells was inhibited.
	Pimecrolimus	Atopic dermatitis	U	IvDC	[133]	In epidermal cells (biopsy) after topical treatment.
	Rapamycin	Immuno-suppressant	U	ED-1 ED-4	[134]	Reduction of MHC-I, MHC-II and Ag uptake.
	Sinomenine		U	ED-1	[135]	The drug prevents LPS-induced DC maturation.
	Tacrolimus (FK506)		D	ED-1 ED-2 ED-4	[136]	Effect on LPS-induced DCs in vitro.
			D	IvDC	[137]	Topical treatment of epidermal CD1a⁺, in pts with atopic dermatitis.
			U	OED	[138]	Generation of DCs from CD34⁺ peripheral blood progenitors obtained by culturing the cells with GM-CSF, TNFα, stem cell factor for 14 days. FK506 was added throughout the culture starting on day 0.
	Triptolide	Polycystic Kidney disease	D	ED-1 ED-2	[139]	Suppression of DC differentiation and maturation by triptolide may explain some of its immunosuppressive properties.

Insecticides	Rotenone		D	ED-1	[140]	Mechanism: increased levels of reactive oxygen species that seem to trigger the differentiation process of DC.

Multidrug resistance (MDR) protein antagonists	MK571[multi drug resistance protein 1 (MRP1) blocker] PSC833 (P-gp blocker)	Possible use in MDR	D	ED-4	[141]	MRP1 transporter activity is important for DC differentiation.
Multidrug resistance (MDR) protein antagonists		Possible use in MDR	NC	OED		Langerhans-like DCs were obtained from human acute myeloid leukemia cell line MUTZ-3, cultured with TGF-β1, GM-CSF and TNFα for 10 days, and MDR antagonists were added on day 4, 7, and 10.

Monoclonal antibodies	Infliximab	Anti-TNFα	D	ED-1 ED-4	[142]	MOs from psoriasis pts. Reduction of antigen-presenting capacity of DCs, proliferation and IFNγ release by psoriatic T-cells.

NSAID	Acetylsalicylic acid (ASA)	Inflammation	D	ED-1 ED-4	[143]	The new nitric oxide releasing-ASA (NCX-4040, NCX-4016) did not affect the expression of CD1a during maturation stage (ED-4).
NSAID	Niflumic acid (NFA)	Inflammation	D	ED-4	[144]	NFA inhibits LPS-induced DC maturation by inhibiting co-stimulatory molecule expression and IL-12p70 production.

Microsomal triglyceride transfer protein (MTP) inhibitors	BMS212122	Anti-lipid	D	ED-1	[145]	MTP inhibitors down-regulate self as well as exogenous lipid antigen presentation.

NO donors	DEA-NO, SIN-1, DETA-NO		U NC	ED-1 ED-2 ED-1	[146]	The drugs are TNFα receptor inhibitors.

Statins	Atorvastatin	Dyslipidemia	U	OED	[147]	MO-derived DCs were obtained from healthy donors. MOs exposed to atorvastatin in combination with IFNα, showed an increased levels of CD1a compared to IFNα alone.
Statins	Lovastatin		D	ED-2	[148]	DCs were obtained from MS pts. Lovastatin was added after G4, simultaneously with TNFα.

TLR agonists	Pam CSK resiquimod (R848)	Immune response modifier	U	OED	[149]	Induction of CD1a⁺ cells in freshly isolated BM CD34⁺ progenitor cells cultured with TLR agonists without cytokines.

Tyrosine Kinase Inhibitors	Imatinib	Antitumor	D	ED-1 ED-4	[150]	In ED-1 the assay was performed on day 7. Mechanism: NF-kB and AKT inhibition.
	Imatinib	Antitumor	D	OED	[151]	In vitro effects of imatinib, added to the culture together with different cytokines, on the development of mobilized human CD34⁺ peripheral blood progenitor cells into DCs.
	Sorafenib	Antitumor	D	ED-1	[152]	In ED-1 sorafenib was added on day 5.
	Sorafenib			ED-2		Mechanism: P13MAPK and NF-kB inhibition.

Various	All trans-retinoic acid (ATRA)	Various	U	ED-1	[153]	In ED-1 ATRA was associated with GM-CSF without IL-4.
	Retinoic acid (Am80)	Various	D	ED-1	[154]	Am80 treatment ameliorated macro- and microscopic damage in dextran sodium sulfate-induced colitis in mice, and suppressed the colitis induced elevation of IL-12.
	Thalidomide	Multiple myeloma (MM)	D	OED	[155]	MOs were obtained from peripheral blood of MM pts treated or not with thalidomide. For in vitro DCs generation standard cytokines were used.
	Thalidomide	Sarcoidosis	U	IvDC	[156]	In skin biopsies of sarcoidosis pts treated or not with thalidomide.
	Trimethyl psoralen + PUVA	Psoriasis	D	IvDC	[157]	Biopsies of lesional skin were performed in pts with psoriasis, before treatment, after 2 weeks of treatment or at the end of treatment.
	Dehydro- epiandro-sterone		D	ED-1	[158]	Slight down-regulation. The assay was performed on day 7. Reduction of IL-10 (opposite effect respect to DEX).
	Terpenes: Calamenene T-cadinol	Anti-inflammatory, anti-septic	U	ED-2	[159]
	Terpenes: Epicubenol, Ferruginol	Anti-septic	U	OED	[160]	MOs were cultured with G4, followed by another 2 days with the drugs. Surprisingly both induce IL-10 generating Treg.
	Piceatannol (stilbene derivative)	Anti-inflammatory, immunomodulatory and anti-proliferative	U	OED	[161]	MOs were cultured with G4 for 6 days, followed by another 2 days in the presence of piceatannol alone. On the contrary high concentration of resveratrol, another stilbene derivative, markedly reduces CD1b expression on G4-induced iDCs (Fuggetta et al., in preparation).

Vegetal products	Ginseng saponins (M1 and M4)	Various	U	ED-2	[162]	After G4 DCs were treated on day 6 only with M1 or M4.

Vitamins	Alpha dihydroxy vitamin D3	MS	D	ED-1	[163]	1,25(OH)2D3 hampers the maturation of fully active immunostimulatory MHC-II⁺, CD1a⁺, CD80⁺DCs from MOs.
			D	ED-1 OED	[164]	CD34⁺ cells were collected by apheresis either from cancer pts after chemotherapy or from healthy donors after G-CSF treatment. For DC generation the cells were cultured with standard cytokines.
			D	ED-2	[165]	DCs were obtained from MS pts. Beneficial action of vitamin D in MS may be associated with its inhibition on both differentiation and maturation of DCs.
			D	ED-4	[166]	Accompanied by overexpression of miR-378 and low expression of miR-155 that could have a role in DC function.
			D	ED-1	[167]	D3 up-regulates colony stimulating factor 1 and downregulates its receptors.
			D	ED-1	[168]	Assay was performed on day 7. Inhibition of DC differentiation and maturation.
	Calcipotriol (vit. D3 analog)	Topical in psoriasis	D	OED	[169]	In vivo treated psoriatic skin.

^aEvaluation of CD1a expression if not otherwise specified: U: upregulation; D: down-regulation; NC: no change.
^bExperimental design code (see Figure 2).
^cReference number.