Kent Miner - Academia.edu (original) (raw)

Papers by Kent Miner

Research paper thumbnail of IL4 and IFN{gamma} of Th0 Effector Cells: Role of Autocrine Generation, Persistence, and Modulation

Research paper thumbnail of Augmentation of naive, Th1 and Th2 effector CD4 Responses by IL-6, IL-1 and TNF

European Journal of Immunology, 1998

The role of antigen-presenting cell (APC)-derived cytokines in T cell activation is still controv... more The role of antigen-presenting cell (APC)-derived cytokines in T cell activation is still controversial. Highly purified CD4 T cell populations of the naive and short-term Th1 and Th2 effector subsets were examined. Stimulation from anti-CD3 in the absence of APC was used to analyze directly T occurring cell-mediated effects, and the requirement for co-signaling was addressed using anti-CD28. Exogenous IL-6, IL-1 and TNF each enhanced proliferation and IL-2 secretion from naive cells, although IL-6 was most active in this regard. Peak responses, however, were obtained with IL-1 or TNF in combination with IL-6 resulting in up to 11-fold increases in IL-2 secretion. Enhanced naive T cell responses were only observed with anti-CD3 and anti-CD28, suggesting that co-signaling through surface-bound receptors was required to initiate IL-2 production. Although the cytokines enhanced naive activation, little effect was seen on differentiation into effector populations. IL-6 alone, or in combination, partially suppressed effectors secreting IFN-gamma, but did not promote generation of effectors secreting IL-4. In contrast to reports on cloned cell lines, IL-6, TNF and IL-1 had enhancing activities on all cytokines elicited from already generated Th1 and Th2 effector populations. Again combinations of IL-6, TNF and IL-1 were most effective and generally required CD28 signaling. Induced responses with preexisting effector cells were far less than with naive cells and predominantly directed at augmenting IFN-gamma and IL-5 secretion rather than IL-2 and IL-4. These studies show that APC-derived cytokines can promote T cell responses directly but largely after co-stimulation from accessory molecule co-receptors, that the effect is not specific for one T cell subset or cytokine, and that the naive T cell is the main target of action.

Research paper thumbnail of Co-stimulation of antigen-specific CD4 T cells by 4-1BB ligand

European Journal of Immunology, 2000

4-1BB is a member of the TNF receptor family predominantly expressed on activated T cells, and bi... more 4-1BB is a member of the TNF receptor family predominantly expressed on activated T cells, and binds an inducible ligand found on B cells, macrophages and dendritic cells. Whereas ligation of 4-1BB has been shown to enhance response of purified CD8 T cells to mitogens, and to augment NK activity and generation of cytotoxic T lymphocytes in vivo, there are little direct data on 4-1BB action during CD4 responses. Using pigeon cytochrome c-presenting fibroblast antigen-presenting cells transfected with 4-1BB ligand (4-1BBL), we show that engaging 4-1BB on naive CD4 cells promotes proliferation, cell cycle progression and IL-2 secretion, and suppresses cell death, all to a similar extent as B7-1 engagement of CD28. In addition, 4-1BBL synergizes with B7 and ICAM to enhance naive CD4 proliferation when antigen is limiting. 4-1BBL alone, and to a greater extent with B7, also augmented IL-2 secretion resting antigen-experienced CD4 cells, as typified by T helper clones, whereas short-term effector cells showed similar levels of proliferation and cytokine secretion regardless of whether 4-1BB was engaged. A major role in augmenting IFN-+ , IL-4 or IL-5 was not demonstrated. Blocking studies with activated B cells presenting antigen showed that 4-1BB participates in promoting IL-2 production by resting CD4 cells, confirming that 4-1BBL can play a role in antigen-specific CD4 T cell responses.

Research paper thumbnail of Part 1: Structure–Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

Bioorganic & Medicinal Chemistry Letters, 2009

A novel class of fused pyrazole-derived inhibitors of p38a mitogen-activated protein kinase (MAPK... more A novel class of fused pyrazole-derived inhibitors of p38a mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38a enzyme, the secretion of TNFa in a LPS-challenged THP1 cell line and TNFa-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC 50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED 50 of 0.1 mg/kg while 10q was found to have an ED 50 of 0.05-0.07 mg/kg.

Research paper thumbnail of Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

Bioorganic & Medicinal Chemistry Letters, 2010

A novel class of pyrazolopyridazine p38a mitogen-activated protein kinase (MAPK) inhibitors is di... more A novel class of pyrazolopyridazine p38a mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38a enzyme, the secretion of TNFa in a LPS-challenged THP1 cell line and TNFa-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC 50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38a inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38a/b over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED 50 of ca. 0.08 mg/kg.

Research paper thumbnail of A novel modality of BAFF-specific inhibitor AMG623 peptibody reduces B-cell number and improves outcomes in murine models of autoimmune disease

Clinical and experimental rheumatology

AMG623, also known as A-623, is an antagonist of B-cell activating factor (BAFF). The present stu... more AMG623, also known as A-623, is an antagonist of B-cell activating factor (BAFF). The present study was to evaluate the effects of AMG623 on murine models of autoimmune diseases. AMG623 was generated through phage library. Inhibitory activities of AMG623 against human and murine BAFF were measured by biacore binding and BAFF-mediated B-cell proliferation assay. Pharmacological effects of AMG623 were studied in BALB/c mice, collagen-induced arthritis model (CIA) and in the NZBxNZW F1 lupus model. AMG623 binds to both soluble and cell surface BAFF. AMG623 blocks both human murine BAFF binding to the receptors. Treatment of AMG623 resulted in B-cell number reduction, and improvement of arthritis and lupus development in mice. AMG623 is a novel modality of BAFF antagonist. AMG623 is a potential therapeutic agent for the treatment of SLE, rheumatoid arthritis, and other B-cell-mediated autoimmune diseases.

Research paper thumbnail of Discovery and in Vivo Evaluation of Dual PI3Kβ/δ Inhibitors

Journal of Medicinal Chemistry, 2012

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors.... more Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases. a Reagents and conditions: (i) bis(2-bromoethyl) ether, 150°C, 67%; (ii) HCl, 84−86%; (iii) NaNO 2 , KI, 65%; (iv) NaH, bis(2-bromoethyl) ether, 36%; (v) Fe/AcOH, 72%; (vi) Red-Al, 64%; (vii) Ac 2 O, DMAP, 86%; (viii) Pd 2 dba 3 , morpholine, XPhos, 72%. a Reagents and conditions: (i) NaH, dimethylformamide, 2−51%; (ii) Pd 2 dba 3 , BINAP, Cs 2 CO 3 , 29−62%; (iii) H 2 , Pd/C, 31−38%; (iv) CuI, K 2 CO 3 , L-proline, 13−23%. a Reagents and conditions: (i) Pd 2 dba 3 , RuPhos, 26−57%, 23d; (ii) HCl, 51%.

Research paper thumbnail of TACI Is a TRAF-interacting Receptor for TALL-1, a Tumor Necrosis Factor Family Member Involved in B Cell Regulation

Journal of Experimental Medicine, 2000

We and others recently reported tumor necrosis factor (TNF) and apoptosis ligand-related leukocyt... more We and others recently reported tumor necrosis factor (TNF) and apoptosis ligand-related leukocyte-expressed ligand 1 (TALL-1) as a novel member of the TNF ligand family that is functionally involved in B cell proliferation. Transgenic mice overexpressing TALL-1 have severe B cell hyperplasia and lupus-like autoimmune disease. Here, we describe expression cloning of a cell surface receptor for TALL-1 from a human Burkitt's lymphoma RAJI cell library. The cloned receptor is identical to the previously reported TNF receptor (TNFR) homologue transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI). Murine TACI was subsequently isolated from the mouse B lymphoma A20 cells. Human and murine TACI share 54% identity overall. Human TACI exhibits high binding affinities to both human and murine TALL-1. Soluble TACI extracellular domain protein specifically blocks TALL-1-mediated B cell proliferation without affecting CD40-or lipopolysaccharide-mediated B cell proliferation in vitro. In addition, when injected into mice, soluble TACI inhibits antibody production to both T cell-dependent and -independent antigens. By yeast two-hybrid screening of a B cell library with TACI intracellular domain, we identified that, like many other TNFR family members, TACI intracellular domain interacts with TNFR-associated factor (TRAF)2, 5, and 6. Correspondingly, TACI activation in a B cell line results in nuclear factor B and c-Jun NH 2 -terminal kinase activation. The identification and characterization of the receptor for TALL-1 provides useful information for the development of a treatment for B cellmediated autoimmune diseases such as systemic lupus erythematosus.

Research paper thumbnail of Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS

International Immunology, 2000

Optimal T cell activation requires the interactions of co-stimulatory molecules, such as those in... more Optimal T cell activation requires the interactions of co-stimulatory molecules, such as those in the CD28 and B7 protein families. Recently, we described the co-stimulatory properties of the murine ligand to ICOS, which we designated as B7RP-1. Here, we report the co-stimulation of human T cells through the human B7RP-1 and ICOS interaction. This ligand-receptor pair interacts with a K D~3 3 nM and an off-rate with a t 1/2 Ͼ 10 min.

Research paper thumbnail of Part 1: Structure–Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

Bioorganic & Medicinal Chemistry Letters, 2009

A novel class of fused pyrazole-derived inhibitors of p38a mitogen-activated protein kinase (MAPK... more A novel class of fused pyrazole-derived inhibitors of p38a mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38a enzyme, the secretion of TNFa in a LPS-challenged THP1 cell line and TNFa-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC 50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED 50 of 0.1 mg/kg while 10q was found to have an ED 50 of 0.05-0.07 mg/kg.

Research paper thumbnail of Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

Bioorganic & Medicinal Chemistry Letters, 2010

A novel class of pyrazolopyridazine p38a mitogen-activated protein kinase (MAPK) inhibitors is di... more A novel class of pyrazolopyridazine p38a mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38a enzyme, the secretion of TNFa in a LPS-challenged THP1 cell line and TNFa-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC 50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38a inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38a/b over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED 50 of ca. 0.08 mg/kg.

Research paper thumbnail of Murine collagen antibody induced arthritis (CAIA) and primary mouse hepatocyte culture as models to study cytochrome P450 suppression

Biochemical Pharmacology, 2012

Research paper thumbnail of Collagen Antibody Induced Arthritis (CAIA) In Mice and Primary Mouse Hepatocyte Culture as Models to Study P450 Suppression: In Vivo/In Vitro Similarities and Differences

The murine collagen antibody-induced arthritis (CAIA) model and primary mouse hepatocytes treated... more The murine collagen antibody-induced arthritis (CAIA) model and primary mouse hepatocytes treated with IL-1β, IL-6, or TNFa alone and in combination were used to investigate changes in cytochrome P450 expression incurred by inflammatory disease. CAIA in female mice increased serum IL-1β, IL-6 and hepatic mRNA of the acute phase response (APR) marker, serum amyloid A (SAA). The CAIA model significantly altered cytochrome P450s mRNA and activity levels and UGTs mRNA levels. Most P450s and UGTs were down-regulated, although some isoforms, such as Cyp3a13, were up-regulated. Hepatic P450-related effects of CAIA and the effects of IL-6, IL-1β, and TNFa on mouse hepatocytes were compared at in vitro cytokine concentrations similar to those measured in CAIA mouse serum in vivo. In vivo/in vitro suppression by cytokines was congruent for some P450 isoforms (Cyp1a2, Cyp2c29, and Cyp3a11) but not for others (cytochrome P450 oxidoreductase (POR) and Cyp2e1). In mouse hepatocyte culture, IL-6 a...

Research paper thumbnail of IL4 and IFN{gamma} of Th0 Effector Cells: Role of Autocrine Generation, Persistence, and Modulation

Research paper thumbnail of Augmentation of naive, Th1 and Th2 effector CD4 Responses by IL-6, IL-1 and TNF

European Journal of Immunology, 1998

The role of antigen-presenting cell (APC)-derived cytokines in T cell activation is still controv... more The role of antigen-presenting cell (APC)-derived cytokines in T cell activation is still controversial. Highly purified CD4 T cell populations of the naive and short-term Th1 and Th2 effector subsets were examined. Stimulation from anti-CD3 in the absence of APC was used to analyze directly T occurring cell-mediated effects, and the requirement for co-signaling was addressed using anti-CD28. Exogenous IL-6, IL-1 and TNF each enhanced proliferation and IL-2 secretion from naive cells, although IL-6 was most active in this regard. Peak responses, however, were obtained with IL-1 or TNF in combination with IL-6 resulting in up to 11-fold increases in IL-2 secretion. Enhanced naive T cell responses were only observed with anti-CD3 and anti-CD28, suggesting that co-signaling through surface-bound receptors was required to initiate IL-2 production. Although the cytokines enhanced naive activation, little effect was seen on differentiation into effector populations. IL-6 alone, or in combination, partially suppressed effectors secreting IFN-gamma, but did not promote generation of effectors secreting IL-4. In contrast to reports on cloned cell lines, IL-6, TNF and IL-1 had enhancing activities on all cytokines elicited from already generated Th1 and Th2 effector populations. Again combinations of IL-6, TNF and IL-1 were most effective and generally required CD28 signaling. Induced responses with preexisting effector cells were far less than with naive cells and predominantly directed at augmenting IFN-gamma and IL-5 secretion rather than IL-2 and IL-4. These studies show that APC-derived cytokines can promote T cell responses directly but largely after co-stimulation from accessory molecule co-receptors, that the effect is not specific for one T cell subset or cytokine, and that the naive T cell is the main target of action.

Research paper thumbnail of Co-stimulation of antigen-specific CD4 T cells by 4-1BB ligand

European Journal of Immunology, 2000

4-1BB is a member of the TNF receptor family predominantly expressed on activated T cells, and bi... more 4-1BB is a member of the TNF receptor family predominantly expressed on activated T cells, and binds an inducible ligand found on B cells, macrophages and dendritic cells. Whereas ligation of 4-1BB has been shown to enhance response of purified CD8 T cells to mitogens, and to augment NK activity and generation of cytotoxic T lymphocytes in vivo, there are little direct data on 4-1BB action during CD4 responses. Using pigeon cytochrome c-presenting fibroblast antigen-presenting cells transfected with 4-1BB ligand (4-1BBL), we show that engaging 4-1BB on naive CD4 cells promotes proliferation, cell cycle progression and IL-2 secretion, and suppresses cell death, all to a similar extent as B7-1 engagement of CD28. In addition, 4-1BBL synergizes with B7 and ICAM to enhance naive CD4 proliferation when antigen is limiting. 4-1BBL alone, and to a greater extent with B7, also augmented IL-2 secretion resting antigen-experienced CD4 cells, as typified by T helper clones, whereas short-term effector cells showed similar levels of proliferation and cytokine secretion regardless of whether 4-1BB was engaged. A major role in augmenting IFN-+ , IL-4 or IL-5 was not demonstrated. Blocking studies with activated B cells presenting antigen showed that 4-1BB participates in promoting IL-2 production by resting CD4 cells, confirming that 4-1BBL can play a role in antigen-specific CD4 T cell responses.

Research paper thumbnail of Part 1: Structure–Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

Bioorganic & Medicinal Chemistry Letters, 2009

A novel class of fused pyrazole-derived inhibitors of p38a mitogen-activated protein kinase (MAPK... more A novel class of fused pyrazole-derived inhibitors of p38a mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38a enzyme, the secretion of TNFa in a LPS-challenged THP1 cell line and TNFa-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC 50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED 50 of 0.1 mg/kg while 10q was found to have an ED 50 of 0.05-0.07 mg/kg.

Research paper thumbnail of Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

Bioorganic & Medicinal Chemistry Letters, 2010

A novel class of pyrazolopyridazine p38a mitogen-activated protein kinase (MAPK) inhibitors is di... more A novel class of pyrazolopyridazine p38a mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38a enzyme, the secretion of TNFa in a LPS-challenged THP1 cell line and TNFa-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC 50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38a inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38a/b over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED 50 of ca. 0.08 mg/kg.

Research paper thumbnail of A novel modality of BAFF-specific inhibitor AMG623 peptibody reduces B-cell number and improves outcomes in murine models of autoimmune disease

Clinical and experimental rheumatology

AMG623, also known as A-623, is an antagonist of B-cell activating factor (BAFF). The present stu... more AMG623, also known as A-623, is an antagonist of B-cell activating factor (BAFF). The present study was to evaluate the effects of AMG623 on murine models of autoimmune diseases. AMG623 was generated through phage library. Inhibitory activities of AMG623 against human and murine BAFF were measured by biacore binding and BAFF-mediated B-cell proliferation assay. Pharmacological effects of AMG623 were studied in BALB/c mice, collagen-induced arthritis model (CIA) and in the NZBxNZW F1 lupus model. AMG623 binds to both soluble and cell surface BAFF. AMG623 blocks both human murine BAFF binding to the receptors. Treatment of AMG623 resulted in B-cell number reduction, and improvement of arthritis and lupus development in mice. AMG623 is a novel modality of BAFF antagonist. AMG623 is a potential therapeutic agent for the treatment of SLE, rheumatoid arthritis, and other B-cell-mediated autoimmune diseases.

Research paper thumbnail of Discovery and in Vivo Evaluation of Dual PI3Kβ/δ Inhibitors

Journal of Medicinal Chemistry, 2012

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors.... more Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases. a Reagents and conditions: (i) bis(2-bromoethyl) ether, 150°C, 67%; (ii) HCl, 84−86%; (iii) NaNO 2 , KI, 65%; (iv) NaH, bis(2-bromoethyl) ether, 36%; (v) Fe/AcOH, 72%; (vi) Red-Al, 64%; (vii) Ac 2 O, DMAP, 86%; (viii) Pd 2 dba 3 , morpholine, XPhos, 72%. a Reagents and conditions: (i) NaH, dimethylformamide, 2−51%; (ii) Pd 2 dba 3 , BINAP, Cs 2 CO 3 , 29−62%; (iii) H 2 , Pd/C, 31−38%; (iv) CuI, K 2 CO 3 , L-proline, 13−23%. a Reagents and conditions: (i) Pd 2 dba 3 , RuPhos, 26−57%, 23d; (ii) HCl, 51%.

Research paper thumbnail of TACI Is a TRAF-interacting Receptor for TALL-1, a Tumor Necrosis Factor Family Member Involved in B Cell Regulation

Journal of Experimental Medicine, 2000

We and others recently reported tumor necrosis factor (TNF) and apoptosis ligand-related leukocyt... more We and others recently reported tumor necrosis factor (TNF) and apoptosis ligand-related leukocyte-expressed ligand 1 (TALL-1) as a novel member of the TNF ligand family that is functionally involved in B cell proliferation. Transgenic mice overexpressing TALL-1 have severe B cell hyperplasia and lupus-like autoimmune disease. Here, we describe expression cloning of a cell surface receptor for TALL-1 from a human Burkitt's lymphoma RAJI cell library. The cloned receptor is identical to the previously reported TNF receptor (TNFR) homologue transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI). Murine TACI was subsequently isolated from the mouse B lymphoma A20 cells. Human and murine TACI share 54% identity overall. Human TACI exhibits high binding affinities to both human and murine TALL-1. Soluble TACI extracellular domain protein specifically blocks TALL-1-mediated B cell proliferation without affecting CD40-or lipopolysaccharide-mediated B cell proliferation in vitro. In addition, when injected into mice, soluble TACI inhibits antibody production to both T cell-dependent and -independent antigens. By yeast two-hybrid screening of a B cell library with TACI intracellular domain, we identified that, like many other TNFR family members, TACI intracellular domain interacts with TNFR-associated factor (TRAF)2, 5, and 6. Correspondingly, TACI activation in a B cell line results in nuclear factor B and c-Jun NH 2 -terminal kinase activation. The identification and characterization of the receptor for TALL-1 provides useful information for the development of a treatment for B cellmediated autoimmune diseases such as systemic lupus erythematosus.

Research paper thumbnail of Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS

International Immunology, 2000

Optimal T cell activation requires the interactions of co-stimulatory molecules, such as those in... more Optimal T cell activation requires the interactions of co-stimulatory molecules, such as those in the CD28 and B7 protein families. Recently, we described the co-stimulatory properties of the murine ligand to ICOS, which we designated as B7RP-1. Here, we report the co-stimulation of human T cells through the human B7RP-1 and ICOS interaction. This ligand-receptor pair interacts with a K D~3 3 nM and an off-rate with a t 1/2 Ͼ 10 min.

Research paper thumbnail of Part 1: Structure–Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

Bioorganic & Medicinal Chemistry Letters, 2009

A novel class of fused pyrazole-derived inhibitors of p38a mitogen-activated protein kinase (MAPK... more A novel class of fused pyrazole-derived inhibitors of p38a mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38a enzyme, the secretion of TNFa in a LPS-challenged THP1 cell line and TNFa-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC 50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED 50 of 0.1 mg/kg while 10q was found to have an ED 50 of 0.05-0.07 mg/kg.

Research paper thumbnail of Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

Bioorganic & Medicinal Chemistry Letters, 2010

A novel class of pyrazolopyridazine p38a mitogen-activated protein kinase (MAPK) inhibitors is di... more A novel class of pyrazolopyridazine p38a mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38a enzyme, the secretion of TNFa in a LPS-challenged THP1 cell line and TNFa-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC 50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38a inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38a/b over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED 50 of ca. 0.08 mg/kg.

Research paper thumbnail of Murine collagen antibody induced arthritis (CAIA) and primary mouse hepatocyte culture as models to study cytochrome P450 suppression

Biochemical Pharmacology, 2012

Research paper thumbnail of Collagen Antibody Induced Arthritis (CAIA) In Mice and Primary Mouse Hepatocyte Culture as Models to Study P450 Suppression: In Vivo/In Vitro Similarities and Differences

The murine collagen antibody-induced arthritis (CAIA) model and primary mouse hepatocytes treated... more The murine collagen antibody-induced arthritis (CAIA) model and primary mouse hepatocytes treated with IL-1β, IL-6, or TNFa alone and in combination were used to investigate changes in cytochrome P450 expression incurred by inflammatory disease. CAIA in female mice increased serum IL-1β, IL-6 and hepatic mRNA of the acute phase response (APR) marker, serum amyloid A (SAA). The CAIA model significantly altered cytochrome P450s mRNA and activity levels and UGTs mRNA levels. Most P450s and UGTs were down-regulated, although some isoforms, such as Cyp3a13, were up-regulated. Hepatic P450-related effects of CAIA and the effects of IL-6, IL-1β, and TNFa on mouse hepatocytes were compared at in vitro cytokine concentrations similar to those measured in CAIA mouse serum in vivo. In vivo/in vitro suppression by cytokines was congruent for some P450 isoforms (Cyp1a2, Cyp2c29, and Cyp3a11) but not for others (cytochrome P450 oxidoreductase (POR) and Cyp2e1). In mouse hepatocyte culture, IL-6 a...