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Papers by Jacqueline Benson

Research paper thumbnail of Markers and Methods for Assessing and Treating Psoriasis and Related Disorders

Research paper thumbnail of Administration of monoclonal antibodies neutralizing the inflammatory mediators tumor necrosis factor alpha and interleukin -6 does not attenuate acute behavioral deficits following experimental traumatic brain injury in the rat

Restorative Neurology and Neuroscience, Feb 1, 2005

Although many previous studies have indicated that the acute inflammatory response following trau... more Although many previous studies have indicated that the acute inflammatory response following traumatic brain injury (TBI) is detrimental, inflammation may also positively influence outcome in the more chronic post-injury recovery period. We evaluated the effects of monoclonal antibodies (mAB), neutralizing either IL-6 (IL-6 mAB) or TNF-alpha (TNF mAB), administered intracerebroventricularly (i.c.v) on acute neurobehavioral outcome following TBI. Male Sprague-Dawley rats (n = 173) were anesthetized (sodium pentobarbital, 60 mg/kg) and subjected to lateral fluid percussion (FP) brain injury of moderate severity (n = 123) or sham injury (n = 50). Beginning 1 h post-injury, TNF mAB (n = 41, of which 25 were brain-injured) or IL-6 mAB (n = 42, of which 25 were brain-injured) at a concentration of 2 mg/mL was infused i.c.v ipsilateral to the injury for 48 hours. Vehicle-treated animals (control IgG; n = 43, of which 26 were brain-injured) served as controls. In Study 1, cognitive function was evaluated in the Morris Water Maze (MWM) followed by evaluation of regional cerebral edema at 48 h post-injury. In Study 2, animals were evaluated for neurological motor function and post-injury learning in the MWM at one week post-injury. FP brain injury caused significant cognitive (p < 0.05) and neurological motor (p < 0.05) deficits and increased regional brain water content in the injured hemisphere. Treatment with either TNF- or IL-6-mAB had no effect on neurological motor, cognitive function or brain edema during the first post-injury week. Evaluation of anti-inflammatory mABs on more chronic behavioral deficits appears warranted.

Research paper thumbnail of Targeting Il-12p40 for immune-mediated disease

Target Validation in Drug Discovery, 2007

Research paper thumbnail of Administration of monoclonal antibodies neutralizing the inflammatory mediators tumor necrosis factor alpha and interleukin -6 does not attenuate acute behavioral deficits following experimental traumatic brain injury in the rat

Restorative neurology and neuroscience, 2005

Although many previous studies have indicated that the acute inflammatory response following trau... more Although many previous studies have indicated that the acute inflammatory response following traumatic brain injury (TBI) is detrimental, inflammation may also positively influence outcome in the more chronic post-injury recovery period. We evaluated the effects of monoclonal antibodies (mAB), neutralizing either IL-6 (IL-6 mAB) or TNF-alpha (TNF mAB), administered intracerebroventricularly (i.c.v) on acute neurobehavioral outcome following TBI. Male Sprague-Dawley rats (n = 173) were anesthetized (sodium pentobarbital, 60 mg/kg) and subjected to lateral fluid percussion (FP) brain injury of moderate severity (n = 123) or sham injury (n = 50). Beginning 1 h post-injury, TNF mAB (n = 41, of which 25 were brain-injured) or IL-6 mAB (n = 42, of which 25 were brain-injured) at a concentration of 2 mg/mL was infused i.c.v ipsilateral to the injury for 48 hours. Vehicle-treated animals (control IgG; n = 43, of which 26 were brain-injured) served as controls. In Study 1, cognitive function...

Research paper thumbnail of Efficacy and mechanisms of oral tolerance to myelin basic protein in relapsing experimental autoimmune encephalomyelitis /

Research paper thumbnail of Autoimmune Diseases: Gene Therapy

Encyclopedia of Life Sciences, 2001

Research paper thumbnail of Ustekinumab neutralizes human IL-12 and IL-23 mediated Th1 and Th17 cell function and provides clinical benefit to patients with plaque psoriasis

The Faseb Journal, Mar 1, 2008

Research paper thumbnail of Autoimmune Disease Application in Gene Therapy for Retroviral Transduction for Potential Antigen-Specific T Lymphocytes by Targeting Rare Populations of Murine

Research paper thumbnail of Protein Administration of Myelin Basic TCR-Transgenic Mice After Oral Antigen-Specific T Cells in Rapid Depletion of Peripheral

Research paper thumbnail of of the IL12 p40 Subunit Encephalomyelitis Via T Cell Delivery Experimental Autoimmune Adoptive Immunotherapy of

Research paper thumbnail of Structural Basis for the Dual Recognition of IL-12 and IL-23 by Ustekinumab

Journal of Molecular Biology, 2010

Interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that share a common p40... more Interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that share a common p40 subunit, paired with p35 and p19 subunits, respectively. They represent an attractive class of therapeutic targets for the treatment of psoriasis and other immune-mediated diseases. Ustekinumab is a fully human monoclonal antibody (mAb) that binds specifically to IL-12/IL-23p40 and neutralizes human IL-12 and IL-23 bioactivity. The crystal structure of ustekinumab Fab (antigen binding fragment of mAb), in complex with human IL-12, has been determined by X-ray crystallography at 3.0 Å resolution. Ustekinumab Fab binds the D1 domain of the p40 subunit in a 1:1 ratio in the crystal, consistent with a 2 cytokines:1 mAb stoichiometry, as measured by isothermal titration calorimetry. The structure indicates that ustekinumab binds to the same epitope on p40 in both IL-12 and IL-23 with identical interactions. Mutational analyses confirm that several residues identified in the IL-12/IL-23p40 epitope provide important molecular binding interactions with ustekinumab. The electrostatic complementarity between the mAb antigen binding site and the p40 D1 domain epitope appears to play a key role in antibody/antigen recognition specificity. Interestingly, this structure also reveals significant structural differences in the p35 subunit and p35/p40 interface, compared with the published crystal structure of human IL-12, suggesting unusual and potentially functionally relevant structural flexibility of p35, as well as p40/p35 recognition. Collectively, these data describe unique observations about IL-12p35 and ustekinumab interactions with p40 that account for its dual binding and neutralization of IL-12 and IL-23.

Research paper thumbnail of Targeting Rare Populations of Murine Antigen-Specific T Lymphocytes by Retroviral Transduction for Potential Application in Gene Therapy for Autoimmune Disease

The Journal of Immunology, 2000

CD4 ؉ T cells are important mediators in the pathogenesis of autoimmunity and would therefore pro... more CD4 ؉ T cells are important mediators in the pathogenesis of autoimmunity and would therefore provide ideal candidates for lymphocyte-based gene therapy. However, the number of Ag-specific T cells in any single lesion of autoimmunity may be quite low. Successful gene transfer into autoantigen-specific CD4 ؉ T cells would serve as an ideal vehicle for site-targeted gene therapy if it were possible to transduce preferentially the small number of autoantigen-specific T cells. In this study we have demonstrated that retroviral infection of CD4 ؉ lymphocytes from either autoantigen-stimulated TCR transgenic mice, or Ag-activated immunized nontransgenic mice, with a retroviral vector (pGCIRES), resulted in the transduction of only the limited number of Ag-reactive CD4 ؉ T cells. In contrast, polyclonal activation of the same cultures resulted in transduction of non-antigen-specific lymphocytes.

Research paper thumbnail of IL-23p40 specific immunoglobulin derived proteins

Research paper thumbnail of Anti-IL-23 Antibodies, Compositions, Methods and Uses

Research paper thumbnail of Methods of treatment using human anti-IL-23 antibodies

Research paper thumbnail of Nucleic acids encoding human anti-IL-23 antibodies

Research paper thumbnail of IL-23p40 Specific Immunoglobulin Derived Proteins, Compositions, Epitopes, Methods and Uses

Research paper thumbnail of Human Anti-IL-23 Antibodies, Compositions, Methods and Uses

Research paper thumbnail of Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders

mAbs

Monoclonal antibody (mAb) therapy was first established upon the approval of a mouse antibody for... more Monoclonal antibody (mAb) therapy was first established upon the approval of a mouse antibody for treatment of human acute organ rejection. However, the high incidence of immune response against the mouse mAb restricted therapeutic utility. Development of chimeric, "humanized" and human mAbs broadened therapeutic application to immune-mediated diseases requiring long-term treatment. Indeed, mAb therapeutics targeting soluble cytokines are highly effective in numerous immune-mediated disorders. A recent example is ustekinumab, a first-in-class therapeutic human immunoglobulin G1 kappa mAb that binds to the interleukins (IL)-12 and IL-23, cytokines that modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets. Ustekinumab was generated via recombinant human IL-12 immunization of human immunoglobulin (hu-Ig) transgenic mice. Ustekinumab binds to the p40 subunit common to IL-12 and IL-23 and prevents their interaction with the IL-12 receptor β1 subunit of ...

Research paper thumbnail of Oral administration of myelin basic protein is superior to myelin in suppressing established relapsing experimental autoimmune encephalomyelitis

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1999

Oral administration of a myelin component, myelin basic protein (MBP), induces immunological unre... more Oral administration of a myelin component, myelin basic protein (MBP), induces immunological unresponsiveness to CNS Ags and ameliorates murine relapsing experimental autoimmune encephalomyelitis (REAE). However, a recent clinical trial in which multiple sclerosis patients were treated with repeated doses of oral myelin was unsuccessful in reducing disease exacerbations. Therefore, we directly compared the tolerizing capacity of myelin vs MBP during REAE in B10.PL mice. Oral administration of high doses of myelin, either before disease induction or during REAE, did not provide protection from disease or decrease in vitro T cell responses. In contrast, repeated oral administration of high doses of MBP suppressed established disease and MBP-specific T cell proliferation and cytokine responses. The frequency of IL-2-, IFN-gamma-, and IL-5-secreting MBP-specific T cells declined with MBP feeding, implicating anergy and/or deletion as the mechanism(s) of oral tolerance after high Ag dose...

Research paper thumbnail of Markers and Methods for Assessing and Treating Psoriasis and Related Disorders

Research paper thumbnail of Administration of monoclonal antibodies neutralizing the inflammatory mediators tumor necrosis factor alpha and interleukin -6 does not attenuate acute behavioral deficits following experimental traumatic brain injury in the rat

Restorative Neurology and Neuroscience, Feb 1, 2005

Although many previous studies have indicated that the acute inflammatory response following trau... more Although many previous studies have indicated that the acute inflammatory response following traumatic brain injury (TBI) is detrimental, inflammation may also positively influence outcome in the more chronic post-injury recovery period. We evaluated the effects of monoclonal antibodies (mAB), neutralizing either IL-6 (IL-6 mAB) or TNF-alpha (TNF mAB), administered intracerebroventricularly (i.c.v) on acute neurobehavioral outcome following TBI. Male Sprague-Dawley rats (n = 173) were anesthetized (sodium pentobarbital, 60 mg/kg) and subjected to lateral fluid percussion (FP) brain injury of moderate severity (n = 123) or sham injury (n = 50). Beginning 1 h post-injury, TNF mAB (n = 41, of which 25 were brain-injured) or IL-6 mAB (n = 42, of which 25 were brain-injured) at a concentration of 2 mg/mL was infused i.c.v ipsilateral to the injury for 48 hours. Vehicle-treated animals (control IgG; n = 43, of which 26 were brain-injured) served as controls. In Study 1, cognitive function was evaluated in the Morris Water Maze (MWM) followed by evaluation of regional cerebral edema at 48 h post-injury. In Study 2, animals were evaluated for neurological motor function and post-injury learning in the MWM at one week post-injury. FP brain injury caused significant cognitive (p < 0.05) and neurological motor (p < 0.05) deficits and increased regional brain water content in the injured hemisphere. Treatment with either TNF- or IL-6-mAB had no effect on neurological motor, cognitive function or brain edema during the first post-injury week. Evaluation of anti-inflammatory mABs on more chronic behavioral deficits appears warranted.

Research paper thumbnail of Targeting Il-12p40 for immune-mediated disease

Target Validation in Drug Discovery, 2007

Research paper thumbnail of Administration of monoclonal antibodies neutralizing the inflammatory mediators tumor necrosis factor alpha and interleukin -6 does not attenuate acute behavioral deficits following experimental traumatic brain injury in the rat

Restorative neurology and neuroscience, 2005

Although many previous studies have indicated that the acute inflammatory response following trau... more Although many previous studies have indicated that the acute inflammatory response following traumatic brain injury (TBI) is detrimental, inflammation may also positively influence outcome in the more chronic post-injury recovery period. We evaluated the effects of monoclonal antibodies (mAB), neutralizing either IL-6 (IL-6 mAB) or TNF-alpha (TNF mAB), administered intracerebroventricularly (i.c.v) on acute neurobehavioral outcome following TBI. Male Sprague-Dawley rats (n = 173) were anesthetized (sodium pentobarbital, 60 mg/kg) and subjected to lateral fluid percussion (FP) brain injury of moderate severity (n = 123) or sham injury (n = 50). Beginning 1 h post-injury, TNF mAB (n = 41, of which 25 were brain-injured) or IL-6 mAB (n = 42, of which 25 were brain-injured) at a concentration of 2 mg/mL was infused i.c.v ipsilateral to the injury for 48 hours. Vehicle-treated animals (control IgG; n = 43, of which 26 were brain-injured) served as controls. In Study 1, cognitive function...

Research paper thumbnail of Efficacy and mechanisms of oral tolerance to myelin basic protein in relapsing experimental autoimmune encephalomyelitis /

Research paper thumbnail of Autoimmune Diseases: Gene Therapy

Encyclopedia of Life Sciences, 2001

Research paper thumbnail of Ustekinumab neutralizes human IL-12 and IL-23 mediated Th1 and Th17 cell function and provides clinical benefit to patients with plaque psoriasis

The Faseb Journal, Mar 1, 2008

Research paper thumbnail of Autoimmune Disease Application in Gene Therapy for Retroviral Transduction for Potential Antigen-Specific T Lymphocytes by Targeting Rare Populations of Murine

Research paper thumbnail of Protein Administration of Myelin Basic TCR-Transgenic Mice After Oral Antigen-Specific T Cells in Rapid Depletion of Peripheral

Research paper thumbnail of of the IL12 p40 Subunit Encephalomyelitis Via T Cell Delivery Experimental Autoimmune Adoptive Immunotherapy of

Research paper thumbnail of Structural Basis for the Dual Recognition of IL-12 and IL-23 by Ustekinumab

Journal of Molecular Biology, 2010

Interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that share a common p40... more Interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that share a common p40 subunit, paired with p35 and p19 subunits, respectively. They represent an attractive class of therapeutic targets for the treatment of psoriasis and other immune-mediated diseases. Ustekinumab is a fully human monoclonal antibody (mAb) that binds specifically to IL-12/IL-23p40 and neutralizes human IL-12 and IL-23 bioactivity. The crystal structure of ustekinumab Fab (antigen binding fragment of mAb), in complex with human IL-12, has been determined by X-ray crystallography at 3.0 Å resolution. Ustekinumab Fab binds the D1 domain of the p40 subunit in a 1:1 ratio in the crystal, consistent with a 2 cytokines:1 mAb stoichiometry, as measured by isothermal titration calorimetry. The structure indicates that ustekinumab binds to the same epitope on p40 in both IL-12 and IL-23 with identical interactions. Mutational analyses confirm that several residues identified in the IL-12/IL-23p40 epitope provide important molecular binding interactions with ustekinumab. The electrostatic complementarity between the mAb antigen binding site and the p40 D1 domain epitope appears to play a key role in antibody/antigen recognition specificity. Interestingly, this structure also reveals significant structural differences in the p35 subunit and p35/p40 interface, compared with the published crystal structure of human IL-12, suggesting unusual and potentially functionally relevant structural flexibility of p35, as well as p40/p35 recognition. Collectively, these data describe unique observations about IL-12p35 and ustekinumab interactions with p40 that account for its dual binding and neutralization of IL-12 and IL-23.

Research paper thumbnail of Targeting Rare Populations of Murine Antigen-Specific T Lymphocytes by Retroviral Transduction for Potential Application in Gene Therapy for Autoimmune Disease

The Journal of Immunology, 2000

CD4 ؉ T cells are important mediators in the pathogenesis of autoimmunity and would therefore pro... more CD4 ؉ T cells are important mediators in the pathogenesis of autoimmunity and would therefore provide ideal candidates for lymphocyte-based gene therapy. However, the number of Ag-specific T cells in any single lesion of autoimmunity may be quite low. Successful gene transfer into autoantigen-specific CD4 ؉ T cells would serve as an ideal vehicle for site-targeted gene therapy if it were possible to transduce preferentially the small number of autoantigen-specific T cells. In this study we have demonstrated that retroviral infection of CD4 ؉ lymphocytes from either autoantigen-stimulated TCR transgenic mice, or Ag-activated immunized nontransgenic mice, with a retroviral vector (pGCIRES), resulted in the transduction of only the limited number of Ag-reactive CD4 ؉ T cells. In contrast, polyclonal activation of the same cultures resulted in transduction of non-antigen-specific lymphocytes.

Research paper thumbnail of IL-23p40 specific immunoglobulin derived proteins

Research paper thumbnail of Anti-IL-23 Antibodies, Compositions, Methods and Uses

Research paper thumbnail of Methods of treatment using human anti-IL-23 antibodies

Research paper thumbnail of Nucleic acids encoding human anti-IL-23 antibodies

Research paper thumbnail of IL-23p40 Specific Immunoglobulin Derived Proteins, Compositions, Epitopes, Methods and Uses

Research paper thumbnail of Human Anti-IL-23 Antibodies, Compositions, Methods and Uses

Research paper thumbnail of Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders

mAbs

Monoclonal antibody (mAb) therapy was first established upon the approval of a mouse antibody for... more Monoclonal antibody (mAb) therapy was first established upon the approval of a mouse antibody for treatment of human acute organ rejection. However, the high incidence of immune response against the mouse mAb restricted therapeutic utility. Development of chimeric, "humanized" and human mAbs broadened therapeutic application to immune-mediated diseases requiring long-term treatment. Indeed, mAb therapeutics targeting soluble cytokines are highly effective in numerous immune-mediated disorders. A recent example is ustekinumab, a first-in-class therapeutic human immunoglobulin G1 kappa mAb that binds to the interleukins (IL)-12 and IL-23, cytokines that modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets. Ustekinumab was generated via recombinant human IL-12 immunization of human immunoglobulin (hu-Ig) transgenic mice. Ustekinumab binds to the p40 subunit common to IL-12 and IL-23 and prevents their interaction with the IL-12 receptor β1 subunit of ...

Research paper thumbnail of Oral administration of myelin basic protein is superior to myelin in suppressing established relapsing experimental autoimmune encephalomyelitis

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1999

Oral administration of a myelin component, myelin basic protein (MBP), induces immunological unre... more Oral administration of a myelin component, myelin basic protein (MBP), induces immunological unresponsiveness to CNS Ags and ameliorates murine relapsing experimental autoimmune encephalomyelitis (REAE). However, a recent clinical trial in which multiple sclerosis patients were treated with repeated doses of oral myelin was unsuccessful in reducing disease exacerbations. Therefore, we directly compared the tolerizing capacity of myelin vs MBP during REAE in B10.PL mice. Oral administration of high doses of myelin, either before disease induction or during REAE, did not provide protection from disease or decrease in vitro T cell responses. In contrast, repeated oral administration of high doses of MBP suppressed established disease and MBP-specific T cell proliferation and cytokine responses. The frequency of IL-2-, IFN-gamma-, and IL-5-secreting MBP-specific T cells declined with MBP feeding, implicating anergy and/or deletion as the mechanism(s) of oral tolerance after high Ag dose...