1. A method of assessing whether a subject comprises CD4+, CD25+high T cells that have been activated to a specific non-self antigen, and is therefore tolerant, or capable of becoming tolerant, to the specific non-self antigen, the method of comprising:
(a) in a first culture, incubating a first portion of a population of T lymphocytes comprising, CD4+, CD25+high T cells obtained from the subject in the presence of (i) one or more cytokines selected from the group consisting of IL-5, IL-12 and IFN-\u03b3, wherein the one of more cytokines are isolated or purified proteins or are contained in supernatant from a CHO\u2014K1 cell transfected with a nucleic acid which expresses the one or more cytokines in the CHO\u2014K1 cell so that the transfected CHO\u2014K1 cell produces the one or more cytokines, and (ii) the specific non-self antigen bound to the surface of an antigen presenting cell, wherein the proliferation of the antigen presenting cell has been impaired, or the specific non-self antigen bound to a synthetic antigen presenting system;
(b) in a second culture, incubating a second portion of a population of T lymphocytes comprising CD4+, CD25+high T cells obtained from the subject in the presence of (i) one or more cytokines selected from the group consisting of IL-5, IL-12 and IFN-\u03b3, wherein the one or more cytokines are isolated or purified proteins or are contained in supermatant from a CHO\u2014K1 cell transfected with a nucleic acid which expresses the one or more cytokines in the CHO\u2014K1 cell so that the transfected CHO\u2014K1 cell produces the one or more cytokines, and (ii) a self antigen bound to the surface of an antigen presenting cell, wherein the proliferation of the antigen presenting cell has been impaired, or a self antigen bound to a synthetic antigen presenting system; and
(c) detecting proliferation or survival of CD4+CD25+high T cells in the first culture and the second culture, wherein when the CD4+CD25+high T cell proliferation or survival in the fast culture exceeds the CD4+CD25+high T cell proliferation or survival the second culture, wherein said subject comprises CD4+CD25+high T cells that have been activated to the specific non-self antigen, and is therefore tolerant, or capable of becoming tolerant, to the specific non-self antigen, when the CD4+CD25+high T cell proliferation or survival in the first culture exceeds the CD4+CD25+high T cell proliferation or survival in the second culture.
2. The method of claim 1, wherein the cytokine is IL-5.
3. The method of claim 1, wherein the cytokine is IL-12.
4. The method claim 1, wherein the cytokine is IFN-\u03b3.
5. The method of claim 1, wherein the population of lymphocytes is isolated CD4+lymphocytes.
6. The method of claim 1, wherein the population of lymphocytes is at least 96% CD4+and at least 85% CD4+CD25+high.
7. The method of claim 1, wherein the specific non-self antigen is selected from the group consisting of alloantigen, xenoantigen, allergen and an antigen from an infectious disease.
8. The method of claim 1, wherein the subject is a human.
9. The method of claim 1, wherein the one or more cytokines selected from the group consisting of IL-5, IL-12 and IFN-\u03b3 is a purified protein.
10. The method of claim 1, wherein the one or more cytokines selected from the group consisting of IL-5, IL-12 and IFN-\u03b3 is contained in the supernatant from a CHO\u2014K1 cell producing the cytokine.
11. The method of claim 6, wherein (c) comprises detecting proliferation of CD4+CD25+high T cells in the first culture and the second culture, and wherein the subject comprises CD4+, CD25+high T cells that have been activated to the specific non-self antigen when the CD4+, CD25+high T cell proliferation in the first culture exceeds the CD4+, CD25+high T cell proliferation in the second culture.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of treating a headache in a patient, the method comprising:
positioning a device adjacent to a skin surface of a neck of the patient;
generating one or more electrical impulses with the device; and
transmitting, via the device, the electrical impulses to a vagus nerve of the patient, wherein the electrical impulses are sufficient to generate action potentials within fibers of the vagus nerve responsible for activating neural pathways causing a release of GABA within a brain of the patient to at least partially relieve a pain associated with the headache.
2. The method of claim 1, wherein a sufficient level of GABA is released in the brain of the patient to reduce a level of glutamate in the brain.
3. The method of claim 1, wherein the electrical impulses are sufficient to at least partially relieve said pain within about 5 minutes of the transmitting.
4. The method of claim 1, wherein the electrical impulses are generated exterior to the patient and transmitted transcutaneously through an outer skin surface of the patient to generate an electrical impulse at or near the fibers of the vagus nerve.
5. The method of claim 1, further comprising:
generating an electric field at or near the device; and
shaping the electric field such that the electric field is sufficient to modulate the vagus nerve; and wherein the electric field is not sufficient to substantially modulate a nerve or a muscle between the skin surface and a target region within the patient.
6. The method of claim 1, wherein the transmitting is carried out by generating a magnetic field exterior to the patient, wherein the magnetic field is sufficient to induce an electrical impulse at or near the vagus nerve within the patient.
7. The method of claim 1 wherein the electrical impulses have a frequency of about 1000 Hz to about 10,000 Hz and a duty cycle of about 1% to about 10%.
8. The method of claim 7 wherein the frequency is about 4000 Hz to about 6000 Hz.
9. The method of claim 7 wherein the frequency is about 5000 Hz.
10. The method of claim 7 wherein the duty cycle is about 2% to about 5%.
11. The method of claim 7 wherein the duty cycle is about 2.5%.
12. The method of claim 7 wherein the electrical impulses comprise bursts of pulses having a burst duration of about 0.1 to about 10 milliseconds and a burst frequency of about 5 Hz to about 100 Hz.
13. The method of claim 12 wherein the burst duration is about 2 to about 6 milliseconds.
14. The method of claim 12 wherein the burst frequency is about 10 Hz to about 35 Hz.
15. The method of claim 1, wherein the electrical impulses are sufficient to cause dopaminergic neurons originating in a ventral tegmental area of the brain to stimulate neurons or tissue to which said dopaminergic neurons project.
16. The method of claim 1, wherein the electrical impulses are sufficient to modulate serotonergic neurons in a raphe nucleus within the patient.
17. The method of claim 1 wherein the headache is a migraine headache.
18. The method of claim 1 wherein the headache is a cluster headache.
19. The method of claim 1 wherein the headache is a tension headache.
20. The method of claim 1 wherein the headache is a sinus headache.
21. A method of treating a headache in a patient, the method comprising:
positioning a device adjacent to a skin surface of a neck of the patient;
generating one or more electrical impulses with the device; and
transmitting, via the device, the electrical impulses to a vagus nerve of the patient, wherein the electrical impulses are sufficient to generate action potentials within fibers of the vagus nerve responsible for activating neural pathways causing a release of a sufficient level of inhibitory neurotransmitters within a brain of the patient to reduce a level of glutamate in the brain and at least partially relieve a pain associated with the headache.
22. The method of claim 21, wherein the inhibitory neurotransmitters comprise GABA.
23. The method of claim 21, wherein the inhibitory neurotransmitters comprise serotonin.
24. The method of claim 21, wherein the inhibitory neurotransmitters comprise norepinephrine.
25. The method of claim 21, wherein the electrical impulses are sufficient to at least partially relieve said pain within 5 minutes of the transmitting.
26. The method of claim 21, wherein the electrical impulses are generated exterior to the patient and transmitted transcutaneously through an outer skin surface of the patient to generate an electrical impulse at or near the fibers of the vagus nerve.
27. The method of claim 21, further comprising:
generating an electric field at or near the device; and
shaping the electric field such that the electrical field is sufficient to modulate the vagus nerve, wherein the electric field is not sufficient to substantially modulate a nerve or a muscle between the skin surface and a target region within the patient.
28. The method of claim 21, wherein the transmitting is carried out by generating a magnetic field exterior to the patient, wherein the magnetic field is sufficient to induce an electrical impulse at or near the vagus nerve within the patient.
29. The method of claim 21, wherein the electrical impulses have a frequency from about 1,000 Hz to about 10,000 Hz and a duty cycle from about 1% to about 10%.
30. The method of claim 29, wherein the frequency is from about 4,000 Hz to about 6,000 Hz.
31. The method of claim 29, wherein the frequency is about 5,000 Hz.
32. The method of claim 29, wherein the duty cycle is from about 2% to about 5%.
33. The method of claim 29, wherein the duty cycle is 2.5%.
34. The method of claim 21, wherein the electrical impulses comprise bursts of pulses having a burst duration from about 0.1 milliseconds to about 10 milliseconds and a burst frequency from about 5 Hz to about 100 Hz.
35. The method of claim 34, wherein the burst duration is from about 2 milliseconds to about 6 milliseconds.
36. The method of claim 34, wherein the burst frequency is from about 10 Hz to about 35 Hz.
37. The method of claim 21, wherein the headache is a migraine headache.
38. The method of claim 21, wherein the headache is a cluster headache.
39. The method of claim 21, wherein the headache is a tension headache.
40. The method of claim 21, wherein the headache is a sinus headache.
41. A method of treating a headache in a patient, the method comprising:
positioning a device adjacent to a skin surface of a neck of the patient;
generating one or more electrical impulses with the device; and
transmitting, via the device, the electrical impulses to a vagus nerve of the patient, wherein the electrical impulses are sufficient to generate action potentials within fibers of the vagus nerve responsible for activating neural pathways causing a release of inhibitory neurotransmitters within a brain of the patient to at least partially relieve a pain associated with the headache, wherein the electrical impulses are sufficient to cause dopaminergic neurons originating in a ventral tegmental area of the brain to stimulate neurons or tissue to which said dopaminergic neurons project.
42. The method of claim 41, wherein the inhibitory neurotransmitters comprise serotonin.
43. The method of claim 41, wherein the inhibitory neurotransmitters comprise norepinephrine.