Disease relevance of Icosl

• In this study, we have investigated the effect of neutralizing anti-B7h mAb on the development and disease progression of CIA [1].
• In human kidneys with allograft rejection or interstitial nephritis, distinct B7RP-1 staining was also detected in proximal tubules, in areas of mononuclear infiltration [2].
• These studies demonstrate that T(R) cells and the ICOS-ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma [3].
• Taken together, these results indicate that the ICOS-B7h costimulation pathway is required for this autoimmune syndrome and suggest that targeting this pathway might have therapeutic benefits for human autoimmune diseases [4].
• Neither B7-DC or B7RP-1 was augmented after low-dose probiotic or Lactobacillus casei treatment, but B7RP-1 showed increased expression on dendritic cells stimulated with the gram-negative bacterium Escherichia coli [5].

High impact information on Icosl

• Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of T(R) cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS-ICOS-ligand pathway [3].
• Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS-ICOS-ligand interactions [3].
• Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity [3].
• ICOS binds specifically to its counter-receptor B7RP-1 (refs 5,6,7), but not to B7-1 or B7-2 [6].
• Its ligand B7H/B7RP-1 is expressed on B cells and in non-immune tissues after injection of lipopolysaccharide into animals [7].

Chemical compound and disease context of Icosl

• All three diethyl esters inhibit the growth of L1210 murine leukemia and B16 melanotic melanoma in culture, with GI50 values in the micromolar concentration range [8].
• When the aromatic portion of the molecule is a fused heterobicyclic structure (e.g., benzothiazole derivative 7a), potent in vitro antitumor activity was observed in HCT 116 (GI50 = 40 nM) and HT 29 (GI50 = 380 nM) human colon as well in as MCF-7 and MDA 468 human breast cancer cell lines [9].
• Pomolic acid was the most cytotoxic component, and was specific for M-14 melanoma and ME180 cervical carcinoma, with GI50 values of 6.9 and 8.3 micrograms/mL respectively [10].
• Very strong growth inhibition of 1,6-DPD/OH/NH2 was observed against one leukemia line (HL-60(TB)), one NSCLC line (HOP-92), one ovarian cancer line (OVCAR-8) and one breast cancer line (T-47D) with GI50 <1.0 microM, i.e. 0.50, 0.85, 0.62 and 0.75 microM, respectively [11].

Biological context of Icosl

• Further studies reveal that Type I IFN are general suppressors of TLR-mediated up-regulation of B7RP-1 [12].
• Administration of anti-B7h mAb significantly ameliorated the disease as assessed by clinical arthritis score and histology in the joints, and a beneficial effect was also obtained by a delayed treatment after the onset of disease [1].
• Interaction of B7RP-1 with ICOS negatively regulates antigen presentation by B cells [13].
• During antigen-specific B cell activation, costimulation through CD40 signaling can reverse both BCR- and IL-4R-mediated B7h down-regulation [14].
• These data suggest that ICOS/B7RP-1 interactions may not affect the organogenesis, but involve in the functional development of PPs [15].

Anatomical context of Icosl

• These data define a novel costimulatory ligand for T cells and suggest that induction of B7h by TNFalpha may function as a mechanism to directly augment recognition of self during inflammation [16].
• Surprisingly, although B7h is expressed in unstimulated B cells, its expression is induced in both 3T3 cells and embryonic fibroblasts treated with TNFalpha, and it is upregulated in nonlymphoid tissues of mice treated with LPS, a potent activator of TNFalpha [16].
• Costimulation through the inducible costimulator (ICOS) and its ligand (ICOSL) is essential for T cell-dependent B cell responses, but the cellular and temporal dynamics underlying its in vivo effects are poorly defined [17].
• The ICOS-ligand B7-H2, expressed on human type II alveolar epithelial cells, plays a role in the pulmonary host defense system [18].
• Although it is known that blockade of ICOS-B7-related protein 1 (B7RP-1) in vivo dramatically reduces germinal center formation and Ab production, the mechanism(s) remains unclear [19].

Associations of Icosl with chemical compounds

• Evodiamine inhibited the proliferation of NCI/ADR-RES cells in a concentration-dependent manner with a GI50 of 0.59 +/- 0.11 microM [20].
• The 2-phenyl-1,8-naphthyridin-4-ones (44-49) with a methoxy group at the 3'-position showed potent cytotoxicity against most tumor cell lines with GI50 values in the low micromolar to nanomolar concentration range in the National Cancer Institute's 60 human tumor cell line in vitro screen [21].
• Incubation of L1210 cells with the sulfoxide in vitro results in a rapid increase in the intracellular concentration of the glyoxalase I inhibitor (kapp = 1. 41 +/- 0.03 min-1 (37 degrees C)) and inhibition of cell growth (GI50 = 0.5 +/- 0.1 microM) [22].
• In comparison to a standard cytotoxic agent such as doxorubicin (GI50 = 45.3 nM), 3 (GI50 = 17.9 nM) inhibited LNCaP cell growth more potently [23].
• 1 (AJM3/23), 2 (GHP-TM-III-07w), and 3 (GHP-KB-06) inhibited cell growth with 3 being the most potent in C1A (GI50 = 18.0 nM), C2H (GI50 = 17.0 nM), and LNCaP (GI50 = 17.9 nM) cells [23].

Regulatory relationships of Icosl

• In conclusion, the B7RP-1/ICOS pathway is negatively regulating T cell activation by B cells and may play a role similar to that of the PD-L1/PD-1 pathway [13].
• Unexpectedly, blocking antibodies for B7RP-1 and ICOS enhanced the IL-2 response in both T cells [13].
• CONCLUSIONS: These data show that the B7RP-1/ICOS interaction inhibits Th1 and Th2 T-cell responses in the setting of foreign antigen presentation by renal TECs [24].
• These findings suggest that the ICOS-B7RP-1 costimulatory pathway serves primarily to control IFN-gamma production, thereby promoting a cytokine environment conducive to limited hepatic damage [25].
• Overall, the data demonstrate a critical role played by ICOS-L-expressing and IL-10-producing DCs from Chlamydia-infected mice in the infection-mediated inhibition of allergic responses [26].

Other interactions of Icosl

• We studied the efficacy of systemic treatment of tumors with murine B7.2-IgG or GL50-IgG fusion proteins, and the therapeutic potential of B7.1 or GL50 vaccines given during various phases of the antitumor responses [27].
• B7h can costimulate proliferation of purified T cells through a receptor on T cells distinct from CD28 or CTLA-4 [16].
• Exploiting the adoptive transfer of T or B cells from primed Icosl(-/-) mice, we provided genetic evidence that costimulation through ICOSL was essential for primary but not secondary helper T cell responses and for the control of both T and B cell activities, resulting in T cell-dependent IgG1 production [17].
• Antagonism between MyD88- and TRIF-dependent signals in B7RP-1 up-regulation [12].
• Blockade of B7RP-1/ICOS lead to an increased IFN-gamma response in Th1 cells (A.E7) and an increased IL-4 response in Th2 cells (D10.G4.1) [13].

Analytical, diagnostic and therapeutic context of Icosl

• The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity [28].
• In the spleen, anti-B7RP-1 mAb-treated or ICOS-deficient mice showed substantially impaired development of CXCR5+ T(FH) cells and peanut agglutinin+ germinal center B cells in response to primary or secondary immunization with SRBC [29].
• Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand [30].
• METHODS: Flow cytometry was used to demonstrate expression of B7RP-1 on TECs, and expression of ICOS on A.E7 (Th1 clone) and D10.G4 (Th2 clone) cells [24].
• Protein arrays demonstrated an increase in Th2 cytokine levels upon blockade of the B7RP-1/ICOS pathway [24].

References