Device and method for attenuating an immune response
First Claim
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1. A method for attenuating an immune response, comprising:
- identifying a subject suffering from or at risk of a disease or disorder mediated by the immune response;
placing at least a portion of a lead comprising an electrode within a tissue of the subject at a location in which stimulation of the tissue by the electrode is capable of stimulating a sympathetic neuron;
applying a plurality of electrical stimulation pulses to the tissue via the electrode to stimulate the sympathetic neuron in an amount effective to attenuate the immune response;
sensing a condition of the subject; and
modifying a parameter of at least one of the plurality of electrical pulses based on the sensed condition,wherein the sympathetic neuron is a neuron of a splenic nerve, splenic neurovascular bundle, a periarterial splenic nerve, splenic peritoneum, splenic tissue, celiac plexus surrounding the celiac artery, a celiac ganglion, an aorticorenal ganglion, a greater thoracic splanchnic nerve, a lesser thoracic splanchnic nerve, or a least thoracic splanchinc nerve,wherein the disease or disorder is selected from the group consisting of allergy, anaphylactic shock, immune complex disease, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pelvic inflammatory disease, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, urticaria, warts, wheals, vasulitis, rheumatoid arthritis, Alzheimer'"'"'s disease, meningitis, encephalitis, multiple sclerosis, Guillane-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget'"'"'s disease, gout, periodontal disease, synovitis, Sjogren'"'"'s syndrome, myasthenia gravis, thryoiditis, systemic lupus erythematosus, lupus erythematosus, Addison'"'"'s disease, pernicious anemia, Goodpasture'"'"'s syndrome, Behcets'"'"'s syndrome, allograft rejection, graft-versus-host disease, Berger'"'"'s disease, Type I diabetes, ankylosing spondylitis, Retier'"'"'s syndrome, Graves disease, and Hodgkins disease,wherein sensing the condition comprises detecting a characteristic or symptom associated with a disorder or disease associated with the immune response or stimulation of the one or more neurons,wherein the characteristic or symptom is selected from the group consisting of (i) presence of an immune mediator, (ii) an amount of an immune mediator, (iii) an objective symptom of the subject, and (iv) presence or amount of transforming growth factor (TGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF), fibroblast growth factor (FGF), intracellular adhesion molecule (I-CAM), subtypes thereof, nitric oxide, nuclear factor kappa B (NFκ
-B), early growth response protein (ERG-1), a mitogen-activated protein (MAP) kinase, toll-like receptors (TLRs), or a SMAD transcription factor, andwherein the immune mediator is selected from the group consisting of a cytokine receptor, a chemokine, a chemokine receptor, a cell type involved in an immune respone, a cell surface molecule involved in an immune response, an exogenous antigen, a cytokine.
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Abstract
Stimulation of one or more neurons of the sympathetic nervous system, including the splenic nerve, to attenuate an immune response, including an inflammatory immune response, is discussed. Devices and systems to stimulate the sympathetic nervous system to attenuate an immune response are also discussed. Devices discussed include pulse generators and drug pumps. Systems are described as optionally having one or more sensors and operator instructions. In specific examples, stimulation of the splenic nerve of pigs with a pulse generator is shown to be safe and effective in attenuating a lipopolysaccharide-induced immune response.
194 Citations
106 Claims
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1. A method for attenuating an immune response, comprising:
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identifying a subject suffering from or at risk of a disease or disorder mediated by the immune response; placing at least a portion of a lead comprising an electrode within a tissue of the subject at a location in which stimulation of the tissue by the electrode is capable of stimulating a sympathetic neuron; applying a plurality of electrical stimulation pulses to the tissue via the electrode to stimulate the sympathetic neuron in an amount effective to attenuate the immune response; sensing a condition of the subject; and modifying a parameter of at least one of the plurality of electrical pulses based on the sensed condition, wherein the sympathetic neuron is a neuron of a splenic nerve, splenic neurovascular bundle, a periarterial splenic nerve, splenic peritoneum, splenic tissue, celiac plexus surrounding the celiac artery, a celiac ganglion, an aorticorenal ganglion, a greater thoracic splanchnic nerve, a lesser thoracic splanchnic nerve, or a least thoracic splanchinc nerve, wherein the disease or disorder is selected from the group consisting of allergy, anaphylactic shock, immune complex disease, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pelvic inflammatory disease, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, urticaria, warts, wheals, vasulitis, rheumatoid arthritis, Alzheimer'"'"'s disease, meningitis, encephalitis, multiple sclerosis, Guillane-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget'"'"'s disease, gout, periodontal disease, synovitis, Sjogren'"'"'s syndrome, myasthenia gravis, thryoiditis, systemic lupus erythematosus, lupus erythematosus, Addison'"'"'s disease, pernicious anemia, Goodpasture'"'"'s syndrome, Behcets'"'"'s syndrome, allograft rejection, graft-versus-host disease, Berger'"'"'s disease, Type I diabetes, ankylosing spondylitis, Retier'"'"'s syndrome, Graves disease, and Hodgkins disease, wherein sensing the condition comprises detecting a characteristic or symptom associated with a disorder or disease associated with the immune response or stimulation of the one or more neurons, wherein the characteristic or symptom is selected from the group consisting of (i) presence of an immune mediator, (ii) an amount of an immune mediator, (iii) an objective symptom of the subject, and (iv) presence or amount of transforming growth factor (TGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF), fibroblast growth factor (FGF), intracellular adhesion molecule (I-CAM), subtypes thereof, nitric oxide, nuclear factor kappa B (NFκ
-B), early growth response protein (ERG-1), a mitogen-activated protein (MAP) kinase, toll-like receptors (TLRs), or a SMAD transcription factor, andwherein the immune mediator is selected from the group consisting of a cytokine receptor, a chemokine, a chemokine receptor, a cell type involved in an immune respone, a cell surface molecule involved in an immune response, an exogenous antigen, a cytokine. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 38, 39, 40, 41, 42, 43, 44, 45, 46)
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25. A method for attenuating an immune response, comprising:
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identifying a mammalian subject suffering from or at risk of a disease or disorder mediated by the immune response; placing at least a portion of a lead comprising an electrode within a tissue of the mammalian subject at a location in which stimulation of the tissue by the electrode is capable of stimulating a sympathetic neuron; and applying a plurality of electrical stimulation pulses to the tissue via the electrode to stimulate the sympathetic neuron in an amount effective to attenuate the immune response; sensing a condition of the subject; and modifying a parameter of at least one of the plurality of electrical pulses based on the sensed condition, wherein the disease or disorder mediated by the immune response is selected from the group consisting of allergy, anaphylactic shock, immune complex disease, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pelvic inflammatory disease, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, urticaria, warts, wheals, vasulitis, rheumatoid arthritis, Alzheimer'"'"'s disease, meningitis, encephalitis, multiple sclerosis, Guillane-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget'"'"'s disease, gout, periodontal disease, synovitis, Sjogren'"'"'s syndrome, myasthenia gravis, thryoiditis, systemic lupus erythematosus, lupus erythematosus, Addison'"'"'s disease, pernicious anemia, Goodpasture'"'"'s syndrome, Behcets'"'"'s syndrome, allograft rejection, graft-versus-host disease, Berger'"'"'s disease, Type I diabetes, ankylosing spondylitis, Retier'"'"'s syndrome, Graves disease, and Hodgkins disease, wherein sensing the condition comprises detecting a characteristic or symptom associated with a disorder or disease associated with the immune response or stimulation of the one or more neurons, wherein the characteristic or symptom is selected from the group consisting of (i) presence of an immune mediator, (ii) an amount of an immune mediator, (iii) an objective symptom of the subject, and (iv) presence or amount of transforming growth factor (TGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF), fibroblast growth factor (FGF), intracellular adhesion molecule (I-CAM), subtypes thereof, nitric oxide, nuclear factor kappa B (NFκ
-B), early growth response protein (ERG-1), a mitogen-activated protein (MAP) kinase, toll-like receptors (TLRs), or a SMAD transcription factor, andwherein the immune mediator is selected from the group consisting of a cytokine receptor, a chemokine, a chemokine receptor, a cell type involved in an immune respone, a cell surface molecule involved in an immune response, an exogenous antigen, a cytokine. - View Dependent Claims (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104)
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105. A method for inhibiting release of a proinflammatory mediator from a mammalian cell, comprising:
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identifying a mammalian subject suffering from, or at risk for, a disease or disorder mediated by a proinflammatory mediator; and applying a plurality of electrical stimulation pulses to a sympathetic neuron of the subject in an amount effective to inhibit the release of the proinflammatory mediator; sensing a condition of the subject; and modifying a parameter of at least one of the plurality of electrical pulses based on the sensed condition, wherein the disease or disorder mediated by a proinflammatory mediator is selected from the group consisting of allergy, anaphylactic shock, immune complex disease, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pelvic inflammatory disease, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, urticaria, warts, wheals, vasulitis, rheumatoid arthritis, Alzheimer'"'"'s disease, meningitis, encephalitis, multiple sclerosis, Guillane-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget'"'"'s disease, gout, periodontal disease, synovitis, Sjogren'"'"'s syndrome, myasthenia gravis, thryoiditis, systemic lupus erythematosus, lupus erythematosus, Addison'"'"'s disease, pernicious anemia, Goodpasture'"'"'s syndrome, Behcets'"'"'s syndrome, allograft rejection, graft-versus-host disease, Berger'"'"'s disease, Type I diabetes, ankylosing spondylitis, Retier'"'"'s syndrome, Graves disease, and Hodgkins disease, wherein sensing the condition comprises detecting a characteristic or symptom associated with a disorder or disease associated with the immune response or stimulation of the one or more neurons, wherein the characteristic or symptom is selected from the group consisting of (i) presence of an immune mediator, (ii) an amount of an immune mediator, (iii) an objective symptom of the subject, and presence or amount of transforming growth factor (TGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF), fibroblast growth factor (FGF), intracellular adhesion molecule (I-CAM), subtypes thereof, nitric oxide, nuclear factor kappa B (NFκ
-B), early growth response protein (ERG-1), a mitogen-activated protein (MAP) kinase, toll-like receptors (TLRs), or a SMAD transcription factor, andwherein the immune mediator is selected from the group consisting of a cytokine receptor, a chemokine, a chemokine receptor, a cell type involved in an immune respone, a cell surface molecule involved in an immune response, an exogenous antigen, a cytokine.
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106. A method of inhibiting an inflammatory cytokine cascade in a patient, comprising:
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applying a plurality of electrical stimulation pulses to a sympathetic neuron in the patient in an amount sufficient to inhibit the inflammatory cytokine cascade, wherein the patient is diagnosed as suffering from, or at risk for, a disease or disorder mediated by the inflammatory cytokine cascade; sensing a condition of the subject; and modifying a parameter of at least one of the plurality of electrical pulses based on the sensed condition, wherein the disease or disorder mediated by a proinflammatory mediator is selected from the group consisting of allergy, anaphylactic shock, immune complex disease, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pelvic inflammatory disease, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, urticaria, warts, wheals, vasulitis, rheumatoid arthritis, Alzheimer'"'"'s disease, meningitis, encephalitis, multiple sclerosis, Guillane-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget'"'"'s disease, gout, periodontal disease, synovitis, Sjogren'"'"'s syndrome, myasthenia gravis, thryoiditis, systemic lupus erythematosus, lupus erythematosus, Addison'"'"'s disease, pernicious anemia, Goodpasture'"'"'s syndrome, Behcets'"'"'s syndrome, allograft rejection, graft-versus-host disease, Berger'"'"'s disease, Type I diabetes, ankylosing spondylitis, Retier'"'"'s syndrome, Graves disease, and Hodgkins, wherein sensing the condition comprises detecting a characteristic or symptom associated with a disorder or disease associated with the immune response or stimulation of the one or more neurons, wherein the characteristic or symptom is selected from the group consisting of (i) presence of an immune mediator, (ii) an amount of an immune mediator,m (iii) an objective symptom of the subject, and (iv) presence or amount of transforming growth factor (TGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF), fibroblast growth factor (FGF), intracellular adhesion molecule (I-CAM), subtypes thereof, nitric oxide, nuclear factor kappa B (NFκ
-B), early growth response protein (ERG-1), a mitogen-activated protein (MAP) kinase, toll-like receptors (TLRs), or a SMAD transcription factor, andwherein the immune mediator is selected from the group consisting of a cytokine receptor, a chemokine, a chemokine receptor, a cell type involved in an immune respone, a cell surface molecule involved in an immune response, an exogenous antigen, a cytokine.
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Specification