(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2005/0075701 A1
`(43) Pub. Date:
`Apr. 7, 2005
`Shafer
`
`US 20050075701A1
`
`(54) DEVICE AND METHOD FOR ATTENUATING
`AN IMMUNE RESPONSE
`(75) Inventor: Lisa Lynn Shafer, Stillwater, MN (US)
`Correspondence Address:
`MEDTRONIC, INC.
`710 MEDTRONIC PARKWAYNE
`MS-LC340
`MINNEAPOLIS, MN 55432-5604 (US)
`(73) Assignee: Medtronic, Inc., Minneapolis, MN
`(21) Appl. No.:
`10/820,677
`(22) Filed:
`Apr. 8, 2004
`Related U.S. Application Data
`(60) Provisional application No. 60/507,855, filed on Oct.
`1, 2003.
`
`Publication Classification
`
`(51) Int. Cl." ....................................................... A61N 1/18
`(52) U.S. Cl. ................................................................ 607/72
`
`(57)
`
`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 instruc
`tions. 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.
`
`
`
`SYMPATHETIC
`NERWOUS
`SYSTEM
`1O
`
`SYMPATHETIC
`
`IMMUNE
`RESPONSE
`2O
`
`LUMENIS EX1042
`Page 1
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`Patent Application Publication Apr. 7, 2005 Sheet 1 of 26
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`US 2005/0075701 A1
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`
`
`SYMPATHETIC
`NERWOUS
`SYSTEM
`1O
`
`IMMUNE
`RESPONSE
`2O
`
`FIG. 1
`
`
`
`SYMPATHETIC
`NERVOUS
`SYSTEM
`1O
`
`SYMPATHETIC
`NT
`154
`
`IMMUNE
`RESPONSE
`2O
`
`FG. 3
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`SYMPATHETIC
`NERWOUS
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`IMMUNE
`RESPONSE
`2O
`
`FG. A.
`
`LUMENIS EX1042
`Page 2
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`Patent Application Publication Apr. 7, 2005 Sheet 2 of 26
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`US 2005/0075701 A1
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`WEIS?S
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`LUMENIS EX1042
`Page 3
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`Patent Application Publication Apr. 7, 2005 Sheet 3 of 26
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`US 2005/0075701 A1
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`LUMENIS EX1042
`Page 4
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`Patent Application Publication Apr. 7, 2005 Sheet 4 of 26
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`US 2005/0075701 A1
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`LUMENIS EX1042
`Page 5
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`Patent Application Publication Apr. 7, 2005 Sheet 5 of 26
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`LUMENIS EX1042
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`Patent Application Publication Apr. 7, 2005 Sheet 6 of 26
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`LUMENIS EX1042
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`Patent Application Publication Apr. 7, 2005 Sheet 7 of 26
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`US 2005/0075701 A1
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`LUMENIS EX1042
`Page 8
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`

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`Patent Application Publication Apr. 7, 2005 Sheet 8 of 26
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`US 2005/0075701 A1
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`LUMENIS EX1042
`Page 9
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`Patent Application Publication Apr. 7, 2005 Sheet 9 of 26
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`US 2005/0075701 A1
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`TEMPORARY
`CONNECTORS
`
`TEMPORARY
`CONNECTORS
`
`
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`TEMPORARY TESTING WIRES
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`(CATHODE)
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`
`LUMENIS EX1042
`Page 10
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`Patent Application Publication Apr. 7, 2005 Sheet 10 of 26
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`US 2005/0075701 A1
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`
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`POWER
`SOURCE
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`32
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`MEMORY
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`34
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`LUMENIS EX1042
`Page 11
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`Patent Application Publication Apr. 7, 2005 Sheet 11 of 26
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`LUMENIS EX1042
`Page 12
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`LUMENIS EX1042
`Page 12
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`Patent Application Publication Apr. 7, 2005 Sheet 12 of 26
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`LUMENIS EX1042
`Page 13
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`Patent Application Publication Apr. 7, 2005 Sheet 13 of 26
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`US 2005/0075701 A1
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`DAGNOSE
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`2OO
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`STIMULATE
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`F.G. 11
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`LUMENIS EX1042
`Page 14
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`Patent Application Publication Apr. 7, 2005 Sheet 14 of 26
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`US 2005/0075701 A1
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`
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`DEVICE
`1OO
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`
`CONDITION
`
`LUMENIS EX1042
`Page 15
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`Patent Application Publication Apr. 7, 2005 Sheet 15 of 26
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`US 2005/0075701 A1
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`1OO
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`LUMENIS EX1042
`Page 16
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`

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`Patent Application Publication Apr. 7, 2005 Sheet 16 of 26
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`US 2005/0075701 A1
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`7OO
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`LUMENIS EX1042
`Page 17
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`Patent Application Publication Apr. 7, 2005 Sheet 17 of 26
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`US 2005/0075701 A1
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`
`
`
`
`
`
`
`
`OPERATOR
`900
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`DEVICE
`1OO
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`SENSOR
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`INSTRUCTIONS
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`SYMPATHETIC
`NERVOUS
`SYSTEM
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`F.G. 15
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`LUMENIS EX1042
`Page 18
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`US 2005/0075701 A1
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`
`
`FG. 16A
`
`LUMENIS EX1042
`Page 19
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`

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`Patent Application Publication Apr. 7, 2005 Sheet 19 of 26
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`US 2005/0075701 A1
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`
`
`FIG. 16B
`
`LUMENIS EX1042
`Page 20
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`

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`Patent Application Publication Apr. 7, 2005 Sheet 20 of 26
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`US 2005/0075701 A1
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`
`
`FIG. 17A
`
`LUMENIS EX1042
`Page 21
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`
`
`FIG. 17B
`
`LUMENIS EX1042
`Page 22
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`
`
`FIG. 17C
`
`LUMENIS EX1042
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`Apr. 7, 2005 Sheet 23 of 26
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`
`
`FIG. 17D
`
`LUMENIS EX1042
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`Patent Application Publication Apr. 7, 2005 Sheet 24 of 26
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`US 2005/0075701 A1
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`g
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`
`
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`
`60 90 120 150 180 20 240 270 300 330 360
`TIME
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`
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`Patent Application Publication Apr. 7, 2005 Sheet 25 of 26
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`
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`
`LUMENIS EX1042
`Page 26
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`Patent Application Publication Apr. 7, 2005 Sheet 26 of 26
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`US 2005/0075701 A1
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`2 O
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`LUMENIS EX1042
`Page 27
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`US 2005/0075701 A1
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`Apr. 7, 2005
`
`DEVICE AND METHOD FOR ATTENUATING AN
`IMMUNE RESPONSE
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`0001. This application claims priority to U.S. Provisional
`Application No. 60/507,855, filed Oct. 1, 2003, which
`provisional application is hereby incorporated herein by
`reference in its entirety.
`
`FIELD OF THE INVENTION
`0002 The invention relates to medical devices and meth
`ods for modulating neurons and modulating an immune
`response.
`
`BACKGROUND
`0003. The use of electrical stimulation to attenuate an
`immune response has only recently been described and has
`been limited to Stimulation of a parasympathetic nerve. U.S.
`Pat. No. 6,610,713 (Tracey) demonstrated that stimulation
`of the parasympathetic vagus nerve prior to bacterial chal
`lenge resulted in a weakened Systemic inflammatory
`response and was associated with greater Survivability.
`0004. While intriguing, stimulation of the vagus nerve to
`attenuate an immune response presents Several concerns.
`Because the vagus nerve is comprised predominantly of
`afferent fibers, stimulation of the vagus nerve can produce
`undesired, non-specific CNS effects. While U.S. Pat. No.
`6,610713 discusses selective stimulation of the efferent
`vagus, selective efferent stimulation will be difficult to
`achieve in a predominantly afferent nerve Such as the vagus.
`Further, the vagus nerve is a “wandering nerve that inner
`Vates Several tissues in addition to the Spleen, including the
`heart, liver and gastrointestinal tract. Accordingly, Stimula
`tion of the vagus nerve to attenuate an immune response may
`result in many undesired and non-specific effects.
`0005 Further, due to the complex mechanisms underly
`ing control of an immune response, Stimulation of the vagus
`nerve may not produce a complete or effective attenuation of
`a systemic inflammatory response. U.S. Pat. No. 6,610,713
`Suggested that the weakened Systemic inflammatory
`response following vagus nerve Stimulation was due to
`inhibition of pro-inflammatory cytokines through a nicotinic
`cholinergic receptor-mediated response. However, the para
`Sympathetic cholinergic aspect of regulation of an inflam
`matory response is only one aspect of Such regulation. For
`example, the Sympathetic noradrenergic nervous System
`may also play a role in regulating an inflammatory immune
`response.
`0006 Like the parasympathetic nervous system, the sym
`pathetic nervous System innervates the Spleen, which is a
`major lymphoid organ. The efferent fibers of the Sympathetic
`Splenic nerve include noradrenergic neurons. Some main
`targets of noradrenergic innervation of the Spleen include
`immature and mature immune cells, Such as T lymphocytes,
`macrophages, mast cells, and plasma cells. In a normal
`healthy individual, the immune cells maintain a homeostasis
`with regard to the various factors released by the immune
`cells. Dysfunction of these cell types can lead to increased
`release of pro-inflammatory cytokines resulting in inflam
`mation and an excessive immune response. Similarly, dyS
`
`function in these cell types can lead to a Suppressed immune
`response Such as that observed in immunocompromised
`patients.
`0007 Noradrenergic agonists appear to play a role in the
`regulation of Such cell-types. For example, norepinephrine
`and b-adrenergic agonists have been shown to be involved
`in the elimination of bacteria and may act as endogenous
`regulators of cytokine production in Sepsis. In addition,
`enhanced norepinephrine levels and b-adrenergic receptor
`activation can decrease pro-inflammatory cytokine levels,
`increase anti-inflammatory cytokine levels, and alter
`immune effector functions during bacterial infection.
`0008. The use of electrical stimulation of a nerve or tissue
`asSociated with the Sympathetic nervous System to control
`an immune response in Vivo has not previously been
`described.
`0009. However, as presented herein, stimulation of the
`Sympathetic nervous System, particularly the Splenic nerve,
`the fibers of which are predominantly efferent, may serve to
`attenuate an inflammatory immune response while provid
`ing less potentially undesired effects than would stimulation
`of the parasympathetic nervous System, particularly the
`vagus nerve. Furthermore, inhibition of the Sympathetic
`nervous System may be used to Strengthen an immune
`response when the endogenous immune response is not
`Sufficient. Taken as a whole, varying the output of the
`Sympathetic nervous system can serve to modulate an
`immune response for a desired effect thereby allowing for
`fine adjustments.
`
`SUMMARY OF THE INVENTION
`0010. An embodiment of the invention provides a system
`for attenuating an inflammatory immune response. The
`System includes a device capable of Stimulating a sympa
`thetic nervous System of a Subject. In an embodiment, the
`System includes (a) a pulse generator adapted for stimulation
`of the sympathetic nervous System and (b) one or more leads
`connected to the pulse generator and adapted to being
`positioned to apply a Stimulus to the Sympathetic nervous
`System. In an embodiment, the one or more leads are adapted
`to being positioned to apply a Stimulus to the Splenic nerve.
`The System may also include operator instructions for how
`to operate the device and/or System. For example, the System
`may include operator instructions indicating that the device
`or System may be used for purposes of Stimulating a neuron
`asSociated with the Sympathetic nervous System to attenuate
`an immune response, instructions regarding parameters for
`Setting a pulse generator to Stimulate the Sympathetic ner
`Vous System, instructions for how to position a lead to
`Stimulate the Sympathetic nervous System, etc. The System
`may also include a Sensor. The Senor may be coupled to a
`Stimulator to adjust one or more Stimulation parameter. The
`Sensor may be capable of detecting a dysfunctional immune
`or sickness response, detecting whether a neuron has been
`Stimulated or whether an immune response has been attenu
`ated or enhanced, and the like.
`0011. In an embodiment, the invention provides a method
`for attenuating an immune response through Stimulation of
`the Sympathetic nervous System. The immune response may
`be an inflammatory immune response. The Sympathetic
`nervous System can be Stimulated electrically with, for
`
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`
`Apr. 7, 2005
`
`example, a pulse generator. In an embodiment, Stimulation
`of the Sympathetic nervous System includes Stimulation of
`the Splenic nerve.
`0012. In an embodiment, the invention provides a method
`for enhancing an immune response through modulation of
`the Sympathetic nervous System.
`0013 In another embodiment, the invention provides a
`method for modulating an immune response through the
`combined Stimulation of the parasympathetic and Sympa
`thetic nervous Systems. The immune response may be an
`inflammatory immune response or an immunosuppressive
`response. Both the parasympathetic and Sympathetic ner
`Vous Systems may be Stimulated electrically with, for
`example, a pulse generator. In an embodiment, Stimulation
`of the parasympathetic nervous System may include Stimu
`lation of the vagus nerve. In an embodiment, Stimulation of
`the Sympathetic nervous System may include Stimulation of
`the splenic nerve. The stimulation may be delivered at the
`Same time or at alternating times to allow for finer control of
`an immune response.
`0.014.
`In another embodiment, the invention is directed to
`a computer-readable medium comprising program instruc
`tions. The program instructions cause a programmable pro
`ceSSor to quantify one or more conditions of a Subject to
`establish a health State of the Subject, the one or more
`condition being associated with an immune response;
`instruct a medical device to provide a Stimulatory Signal
`having stimulation parameters to a neuron; determine
`whether the health state of the subject improved based on
`changes in one or more of the one or more conditions, and
`modify the Stimulation parameters based the determination
`of whether the health state of the subject improved. A
`medical device may comprise the computer-readable
`medium.
`0.015 The invention can provide a number of advantages.
`For example, by Stimulating the Sympathetic nervous SyS
`tem, which innervates all primary and Secondary lymphoid
`organs, the invention provides for great flexibility for con
`trolling an inflammatory immune response. By Stimulating
`one or more Sympathetic nerves that innervate one or more
`lymphoid organs, an inflammatory immune response can be
`attenuated at one or more levels. In addition, the invention
`provides for greater specificity with reduced potential undes
`ired, non-specific effects. For example, Stimulating the
`Splenic nerve, which is comprised primarily of efferent
`fibers, can attenuate an immune response while minimizing
`direct CNS effects due to the stimulation. Other advantages
`will also be evident based on the disclosure herein.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`0016 FIG. 1 is a diagrammatic illustration of stimulation
`of a Sympathetic nervous System attenuating an immune
`response,
`0017 FIG. 2 is a diagrammatic illustration of a sympa
`thetic nervous System;
`0.018
`FIG. 3 is a diagrammatic illustration of stimulation
`of a Sympathetic nervous System producing Sympathetic
`neurotransmitters attenuating an immune response;
`0.019
`FIG. 4 is a diagrammatic illustration of a device
`Stimulating a sympathetic nervous System attenuating an
`immune response;
`
`0020 FIGS.5A and 5B are diagrammatic illustrations of
`an external system (5A) and an implantable system (5B)
`capable of Stimulating a Sympathetic nervous System;
`0021 FIGS. 6A-6C are diagrammatic illustrations of (A)
`a Suitable arrangement for implanting one embodiment of a
`electrical stimulation System of the present invention; (B)
`components of one embodiment of an electric Stimulation
`System of the present invention; and (C) an pulse generator
`and associated medical electrical leads according to one
`embodiment of the present invention;
`0022 FIGS. 7A-7F are diagrammatic illustrations of
`various embodiments of medical electrical leads Suitable for
`use in various embodiments of a System or method of the
`present invention;
`0023 FIG. 8 is diagrammatic illustration of a block
`diagram of one embodiment of the present invention;
`0024 FIG. 9 is a diagrammatic illustration of a neuro
`Stimulatory device adapted to Stimulate a splenic nerve
`according to an embodiment of the invention;
`0025 FIG. 10 is a drug pump system that may be used
`to Stimulate a Sympathetic nervous System according to an
`embodiment of the invention;
`0026 FIG. 11 is a flow chart illustrating how stimulation
`of a Sympathetic nervous System may be modified according
`to an embodiment of the invention;
`0027 FIG. 12 is diagrammatic illustration of an embodi
`ment of the invention including a Sensor;
`0028 FIGS. 13A-13C are block diagrams of (A) one
`embodiment of an open-loop Stimulation System of the
`present invention; (B) one closed-loop embodiment of a
`Stimulation System of the present invention; and (C) another
`embodiment of a closed loop electric Stimulation System of
`the present invention;
`0029 FIG. 14 is a schematic block diagram of a micro
`processor and related circuitry for utilizing a Sensor to
`control Stimulation administration to a Sympathetic nervous
`System according to an embodiment of the invention;
`0030 FIG. 15 is a diagrammatic illustration of a system
`according to an embodiment of the invention;
`0031
`FIG. 16 is a photograph of the cuff electrode used
`to Stimulate the Splenic nerve in one embodiment;
`0032 FIG. 17 is a photograph showing A) Simple Sur
`gical approach-lateral flank incision, cuff electrode was
`attached in the vicinity of scissor tips. B) Tissue reflected
`upon necropsy to show electrode placement. C) Higher
`magnification of B, to demonstrade the branches of nerve
`and artery within cuff electrode. D) Histology of tissue under
`the cuff electrode after Stimulation of various frequencies
`(1-120 Hz);
`0033 FIG. 18 is a graph demonstrating the effects of
`electrical stimulation of the splenic nerve on LPS-induced
`mean arterial blood pressure (MABP);
`0034 FIGS. 19 A-C are graphs demonstrating the effects
`of electrical stimulation of the splenic nerve on LPS-induced
`pro inflammatory cytokine production; and
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`
`0035 FIG. 20 is a graph demonstrating the effect of
`electrical stimulation of the splenic nerve on the LPS
`induced reduction in white blood cell (WBC) count.
`0.036 The drawings are not necessarily to scale. Like
`numbers refer to like parts or Steps throughout the drawings.
`
`DETAILED DESCRIPTION
`0037. In the following descriptions, reference is made to
`the accompanying drawings that form a part hereof, and in
`which are shown by way of illustration several specific
`embodiments of the invention. It is to be understood that
`other embodiments of the present invention are contem
`plated and may be made without departing from the Scope or
`spirit of the present invention. The following detailed
`description, therefore, is not to be taken in a limiting Sense.
`0038) Definitions
`0.039
`All scientific and technical terms used in this
`application have meanings commonly used in the art unless
`otherwise specified. The definitions provided herein are to
`facilitate understanding of certain terms used frequently
`herein and are not meant to limit the Scope of the present
`disclosure.
`0040 AS used herein, “subject” means a living being
`having an autonomic nervous System. “Subject' includes
`mammals. Such as mice, rats, pigs, cats, dogs, horses, non
`human primates and humans. “Autonomic nervous System”
`collectively refers to the sympathetic and parasympathetic
`nervous System.
`0041 AS used herein, “mediator of an immune response
`means a molecule that affects an immune response in a
`Subject and includes proinflammatory and anti-inflammatory
`cytokines and chemokines and their respective receptors, as
`well as Signal transduction molecules involved in transmit
`ting a signal associated with interaction of a cytokine or
`chemokine with a receptor.
`0.042
`Attenuation of an Immune Response
`0.043
`FIG. 1 illustrates an embodiment of the invention,
`where a Sympathetic nervous System 10 of a Subject is
`Stimulated to attenuate an immune response 20. It is under
`stood that any means capable of Stimulating a Sympathetic
`nervous System 10, or one or more neurons thereof, may be
`employed. AS used herein, “attenuating an immune
`response'20 means to reduce the ability of a subject to
`produce an immune response 20, reduce the ability of a
`Subject to produce mediators of an immune response 20,
`increase the ability of a Subject to produce an anti-immune
`response, and/or increase the ability of a Subject to produce
`mediators of an anti-immune response. Attenuation of an
`immune response 20 may be detected by measuring a
`reduction in a deleterious characteristic associated with an
`immune response 20, a reduction in a quantified Symptom of
`a deleterious characteristic, disease, and/or disorder associ
`ated with an immune response 20, a reduction in the level of
`a mediator of an immune response 20, an increase in the
`level of a mediator of an anti-immune response, and the like,
`or a combination thereof.
`0044) In an embodiment, the immune response 20 may be
`an inflammatory immune response 20. An inflammatory
`immune response 20 can be mediated by an inflammatory
`cytokine cascade and can be alleviated by an anti-inflam
`
`matory cytokine cascade. Attenuation of an inflammatory
`immune response 20 may be detected by measuring a
`decrease in one or more proinflammatory cytokines. Non
`limiting examples of proinflammatory cytokines include
`tumor necrosis factor (TNF; also known as TNFC. or cachec
`tin), interleukin (IL)-1C, IL-1 B, IL-2, IL-5, IL-6, IL-8,
`IL-15, IL-18, interferon Y (IFN-Y); platelet-activating factor
`(PAF), thromboxane; soluble adhesion molecules; vasoac
`tive neuropeptides, phospholipase A2; plasminogen activa
`tor inhibitor (PAI-1); free radical generation; neopterin;
`CD14, proStacyclin; neutrophil elastase; protein kinase;
`monocyte chemotactic proteins 1 and 2 (MCP-1, MCP-2);
`macrophage migration inhibitory factor (MIF), high mobil
`ity group box protein 1 (HMGB-1), and other known factors.
`Attenuation of an inflammatory immune response may also
`be detected by measuring an increase in one or more
`anti-inflammatory cytokines. Non-limiting examples of anti
`inflammatory cytokines include IL-4, IL-10, IL-17, IL-13,
`IL-1 alpha, and TNFalpha receptor. It will be recognized that
`Some of proinflammatory cytokines may act as anti-inflam
`matory cytokines in certain circumstances, and Vice-versa.
`Such cytokines are typically referred to as plieotropic cytok
`ines. Attenuation of an inflammatory response may also be
`detected by measuring changes (baseline versus during
`therapy delivery, a first point in therapy verSuS a Second
`point in therapy, etc.) in the presence of other factors
`involved in an immune response. Non-limiting examples of
`Such other factors include TGF, PDGF, VEGF, EGF, FGF,
`I-CAM, nitric oxide, and other known factors. In addition,
`an attenuated immune response may be detected by changes
`in chemokines, such as 6cKine and MIP3beta, and chemok
`ine receptors, including CCR7 receptor. Further, attenuation
`of an immune response may be measured by changes in
`immune cell population (upregulated Langerhans cells, den
`dritic cells, lymphocytes), or immune cell Surface co-stimu
`latory molecules (Major Histocompatibility, CD80, CD86,
`CD28, CD40). Attenuation of an inflammatory response
`may also be detected by measuring changes in other factors
`involved in the inflammatory cascade, for example in the
`Signal transduction cascades including factorS Such as NFK
`B, Egr-1, Smads, toll-like receptors, and MAP kinases.
`Attenuation of an immune response may also be detected by
`a change in the presence of, or the clearance of, an exog
`enous antigen believed to have caused an inflammatory
`response, Such as e.g. a bacteria, a Virus, or a fungus.
`Further, cell types involved in an immune response, Such as
`Langerhans cells, dendritic cells, T lymphocytes, and B
`lymphocytes may be detected. In addition, cell Surface
`molecules involved in an immune response, Such as major
`histocompatibility complex (MHC), CD80, CD86, CD28,
`and CD40 may be detected.
`0045 Attenuation of an inflammatory immune response
`20 includes attenuation of a deleterious characteristic of a
`disorder and/or disease State associated with a heightened
`inflammatory immune response 20. Deleterious character
`istics include inflammation and apoptosis. Disorders or
`disease States associated with an inflammatory immune
`response 20 are described in U.S. Pat. No. 6,610,713 and
`include disorders characterized by both localized and Sys
`temic reactions, including, diseases involving the gas
`trointestinal tract and associated tissues (such as appendici
`tis, peptic, gastric and duodenal ulcers, peritonitis,
`pancreatitis, ulcerative, pseudomembranous, acute and
`ischemic colitis, inflammatory bowel disease, diverticulitis,
`
`LUMENIS EX1042
`Page 30
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`US 2005/0075701 A1
`
`Apr. 7, 2005
`
`epiglottitis, achalasia, cholangitis, coeliac disease, cholecys
`titis, hepatitis, Crohn's disease, enteritis, and Whipple's
`disease); Systemic or local inflammatory diseases and con
`ditions (such as asthma, allergy, anaphylactic shock,
`immune complex disease, organ ischemia, reperfusion
`injury, organ necrosis, hay fever, Sepsis, Septicemia, endot
`oxic shock, cachexia, hyperpyrexia, eosinophilic granuloma,
`granulomatosis, and Sarcoidosis); diseases involving the
`urogential System and associated tissues (Such as Septic
`abortion, epididymitis, vaginitis, prostatitis and urethritis);
`diseases involving the respiratory System and associated
`tissues (such as bronchitis, emphysema, rhinitis, cystic
`fibrosis, adult respiratory distress Syndrome, pneumonitis,
`pneumoultramicroscopicsilicovolcanoconiosis,
`alvealitis,
`bronchiolitis, pharyngitis, pleurisy, and Sinusitis); diseases
`arising from infection by various viruses (such as influenza,
`respiratory Syncytial virus, HIV, hepatitis B virus, hepatitis
`C virus and herpes), bacteria (Such as disseminated bacter
`emia, Dengue fever), fungi (Such as candidiasis) and proto
`Zoal and multicellular parasites (such as malaria, filariasis,
`amebiasis, and hydatid cysts); dermatological diseases and
`conditions of the skin (Such as burns, dermatitis, dermato
`myositis, Sunburn, urticaria warts, and wheals); diseases
`involving the cardiovascular System and associated tissues
`(Such as vasulitis, angiitis, endocarditis, arteritis, atheroscle
`rosis, thrombophlebitis, pericarditis, myocarditis, myocar
`dial ischemia, congestive heart failure, periarteritis nodosa,
`and rheumatic fever); diseases involving the central or
`peripheral nervous system and associated tissues (such as
`Alzheimer's disease, meningitis, encephalitis, multiple Scle
`rosis, cerebral infarction, cerebral embolism, Guillame
`Barre Syndrome, neuritis, neuralgia, Spinal cord injury,
`paralysis, and uveitis); diseases of the bones, joints, muscles
`and connective tissues (such as the various arthritides and
`arthralgias, osteomyelitis, fasciitis, Paget's disease, gout,
`periodontal disease, rheumatoid arthritis, and Synovitis);
`other autoimmune and inflammatory disorders (such as
`myasthenia gravis, thryoiditis, Systemic lupus erythemato
`Sus, Goodpasture's Syndrome, Behcets's Syndrome,
`allograft rejection, graft-Versus-host disease, Type I diabe
`tes, ankylosing spondylitis, Berger's disease, diabetes
`including Type I diabetes, ankylosing spondylitis, Berger's
`disease, and Retier's Syndrome); as well as various cancers,
`tumors and proliferative disorders (Such as Hodgkins dis
`ease), nosicomal infection; and, in any case the inflamma
`tory or immune host response to any primary disease.
`0046. Other conditions associated with immune or
`inflammatory response include injury to nerves or other
`tissue and pain associated with nerve or other tissue. Injury
`may be due to a physical, chemical or mechanical trauma.
`Non-limiting examples of injury include acute trauma, burn,
`and whiplash. Conditions associated with a particular organ
`Such as eye or ear may also include an immune or inflam
`matory response.
`0047 Any method for measuring the level of a cytokine
`or chemokine in a Subject may be used to determine whether
`an inflammatory immune response 20 has been attenuated.
`Several methods are known and include commercially avail
`able kits. A cytokine or chemokine may be directly detected.
`Alternatively, the presence or amount of a nucleic acid, Such
`as a polyribonucleotide, encoding a polypeptide described
`herein may serve as a measure of the presence or amount of
`the polypeptide. Thus, it will be understood that detecting
`
`the presence or amount of a polypeptide will include detect
`ing the presence or amount of a polynucleotide encoding the
`polypeptide.
`0048 Any method for measuring a deleterious charac
`teristic, disorder and/or disease State associated with a
`heightened inflammatory immune response may be used.
`Several methods are known and include determining the
`level of inflammation in a Subject, determining the extent of
`apoptosis in a Subject, determining physiological changes
`characteristic of a particular disease State, and determining
`a subjects white blood cell count. Inflammation may be
`measured in vitro or in Vivo by analysis of inflammatory
`markers in the blood and fluorescence and histological
`evidence and physiological responses Such as body tempera
`ture. Apoptosis may be measured by dye uptake and circu
`lating levels of apoptosis markers, and tissue biopsy. These
`and other known methods may be used to measure an
`inflammatory immune response.
`0049 Further, any symptom associated with a deleterious
`characteristic, disease, or disorder of an inflammatory
`immune response 20 may be used to determine whether an
`inflammatory immune response 20 has been attenuated. A
`Symptom may be quantified either objectively or Subjec
`tively. Non-limiting examples of objective measures include
`decreased Swelling, decreased flushing, changes in ECG,
`EKG, changes in measures of total health, changes in
`response to pain tests, and decreased body temperature.
`Other objective measures of improvement in disorders or
`disease States associated with a heightened immune response
`20 are known and may be used to determine efficacy of the
`various embodiments of the invention. Subjective measures,
`e.g., the Subject's perception of the one or more Symptom of
`an inflammatory immune response may be quantified in any
`know manner. For example, the Subject may rank their
`perceived Severity of the Symptom on base on a numerical
`Scale. The Scale can be from, 1 to 2, from 1 to 3, from 1 to
`4, from 1 to 5, from 1 to 10, etc.
`0050) Sympathetic Nervous System
`0051 FIG. 1 illustrates an embodiment of the invention,
`where a Sympathetic nervous System 10 of a Subject is
`Stimulated to attenuate an immune response 20. The inven
`tion provides, in various embodiments, devices and methods
`for Stimulating a Sympathetic nervous System 10 of a Subject
`to attenuate an immune response 20. Sympathetic nervous
`System 10 is used herein in its broadest Sense and includes
`Stimulation of one or more neu