Immunomodulatory roles of VIP and PACAP in models of multiple sclerosis

Current Pharmaceutical Design

Volumn 17, Issue 10, 2011, Pages 1025-1035

  Abad, Catalina ^a   Waschek, James A ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

EAE; Multiple sclerosis; Neuroimmunomodulation; PACAP; VIP

Indexed keywords

ALEMTUZUMAB; DEXAMETHASONE; ENDOTOXIN; GLATIRAMER; GLUCOCORTICOID; HYPOPHYSIS ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE; MYELIN OLIGODENDROCYTE GLYCOPROTEIN; MYELIN PROTEIN; NATALIZUMAB; OXAZOLONE; PERTUSSIS TOXIN; PROTEOLIPID PROTEIN; RECOMBINANT BETA INTERFERON; VASOACTIVE INTESTINAL POLYPEPTIDE;

ACTIVE IMMUNIZATION; ALLERGIC ENCEPHALOMYELITIS; ANTIINFLAMMATORY ACTIVITY; BONE MARROW CELL; CD4+ T LYMPHOCYTE; CENTRAL NERVOUS SYSTEM; CYTOKINE PRODUCTION; CYTOTOXICITY; DISEASE SEVERITY; DRUG BINDING; DRUG EFFICACY; DRUG MEGADOSE; HISTOPATHOLOGY; HUMAN; IMMUNE SYSTEM; IMMUNOCOMPETENT CELL; IMMUNOHISTOCHEMISTRY; IMMUNOMODULATION; IN VITRO STUDY; IN VIVO STUDY; INNATE IMMUNITY; LYMPHOCYTE PROLIFERATION; LYMPHOID CELL; MULTIPLE SCLEROSIS; NERVE DEGENERATION; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; PASSIVE IMMUNIZATION; PATHOGENESIS; PREVALENCE; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; STROKE;

ANIMALS; DISEASE MODELS, ANIMAL; HUMANS; IMMUNOMODULATION; MULTIPLE SCLEROSIS; PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE; VASOACTIVE INTESTINAL PEPTIDE;

EID: 79958149534     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161211795589364     Document Type: Review

References (158)

1. Atlasz T, Szabadfi K, Kiss P, et al. Pituitary adenylate cyclase activating polypeptide in the retina: focus on the retinoprotective effects. Ann N Y Acad Sci 2010; 1200: 128-39.
2. Hill JM. Vasoactive intestinal peptide in neurodevelopmental disorders: therapeutic potential. Curr Pharm Des 2007; 13: 1079-89.
3. Bourgault S, Vaudry D, Dejda A, Doan ND, Vaudry H, Fournier A. Pituitary adenylate cyclase-activating polypeptide: focus on structure-activity relationships of a neuroprotective Peptide. Curr Med Chem 2009; 16: 4462-80.
4. Ohtaki H, Nakamachi T, Dohi K, Shioda S. Role of PACAP in ischemic neural death. J Mol Neurosci 2008; 36: 16-25.
5. Gozes I, Brenneman DE. A new concept in the pharmacology of neuroprotection. J Mol Neurosci 2000; 14: 61-8.
6. Gozes I. VIP, from gene to behavior and back: summarizing my 25 years of research. J Mol Neurosci 2008; 36: 115-24.
7. Vaudry D, Falluel-Morel A, Bourgault S, et al. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 2009; 61: 283-357.
8. Fahrenkrug J. VIP and PACAP. Results Probl Cell Differ 2010; 50: 221-34.
9. Dickson L, Finlayson K. VPAC and PAC receptors: From ligands to function. Pharmacol Ther 2009; 121: 294-316.
10. Laburthe M, Couvineau A, Tan V. Class II G protein-coupled receptors for VIP and PACAP: structure, models of activation and pharmacology. Peptides 2007; 28: 1631-9.
11. Lutz EM, Ronaldson E, Shaw P, Johnson MS, Holland PJ, Mitchell R. Characterization of novel splice variants of the PAC1 receptor in human neuroblastoma cells: consequences for signaling by VIP and PACAP. Mol Cell Neurosci 2006; 31: 193-209.
12. Pilzer I, Gozes I. VIP provides cellular protection through a specific splice variant of the PACAP receptor: a new neuroprotection target. Peptides 2006; 27: 2867-76.
13. Bellinger DL, Lorton D, Horn L, Brouxhon S, Felten SY, Felten DL. Vasoactive intestinal polypeptide (VIP) innervation of rat spleen, thymus, and lymph nodes. Peptides 1997; 18: 1139-49.
14. Gomariz RP, Lorenzo MJ, Cacicedo L, Vicente A, Zapata AG. Demonstration of immunoreactive vasoactive intestinal peptide (IR-VIP) and somatostatin (IR-SOM) in rat thymus. Brain Behav Immun 1990; 4: 151-61.
15. Gomariz RP, De La Fuente M, Hernanz A, Leceta J. Occurrence of vasoactive intestinal peptide (VIP) in lymphoid organs from rat and mouse. Ann N Y Acad Sci 1992; 650: 13-8.
16. Leceta J, Martinez MC, Delgado M, Garrido E, Gomariz RP. Lymphoid cell subpopulations containing vasoactive intestinal peptide in the rat. Peptides 1994; 15: 791-7.
17. Martinez C, Delgado M, Abad C, Gomariz RP, Ganea D, Leceta J. Regulation of VIP production and secretion by murine lymphocytes. J Neuroimmunol 1999; 93: 126-38.
18. Danek A, O'Dorisio MS, O'Dorisio TM, George JM. Specific binding sites for vasoactive intestinal polypeptide on nonadherent peripheral blood lymphocytes. J Immunol 1983; 131: 1173-7.
19. Waschek JA, Bravo DT, Richards ML. High levels of vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor mRNA expression in primary and tumor lymphoid cells. Regul Pept 1995; 60: 149-57.
20. Delgado M, Martinez C, Johnson MC, Gomariz RP, Ganea D. Differential expression of vasoactive intestinal peptide receptors 1 and 2 (VIP-R1 and VIP-R2) mRNA in murine lymphocytes. J Neuroimmunol 1996; 68: 27-38.
21. Delgado M, Martinez C, Leceta J, Garrido E, Gomariz RP. Differential VIP and VIP1 receptor gene expression in rat thymocyte subsets. Peptides 1996; 17: 803-7.
22. Delgado M, Pozo D, Martinez C, et al. Characterization of gene expression of VIP and VIP1-receptor in rat peritoneal lymphocytes and macrophages. Regul Pept 1996; 62: 161-6.
23. Pozo D, Delgado M, Martinez C, Gomariz RP, Guerrero JM, Calvo JR. Functional characterization and mRNA expression of pituitary adenylate cyclase activating polypeptide (PACAP) type I receptors in rat peritoneal macrophages. Biochim Biophys Acta 1997; 1359: 250-62.
24. Gozes Y, Brenneman DE, Fridkin M, Asofsky R, Gozes I. A VIP antagonist distinguishes VIP receptors on spinal cord cells and lymphocytes. Brain Res 1991; 540: 319-21.
25. Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D. VIP and PACAP inhibit IL-12 production in LPS-stimulated macrophages. Subsequent effect on IFNgamma synthesis by T cells. J Neuroimmunol 1999; 96: 167-81.
26. Herrera JL, Gonzalez-Rey E, Fernandez-Montesinos R, Quintana FJ, Najmanovich R, Pozo D. Toll-like receptor stimulation differentially regulates vasoactive intestinal peptide type 2 receptor in macrophages. J Cell Mol Med 2009; 13: 3209-17.
27. Lara-Marquez M, O'Dorisio M, O'Dorisio T, Shah M, Karacay B. Selective gene expression and activation-dependent regulation of vasoactive intestinal peptide receptor type 1 and type 2 in human T cells. J Immunol 2001; 166: 2522-30.
28. Paladini F, Cocco E, Cauli A, et al. A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of HLA-B*2705 in Sardinia. Genes Immun 2008; 9: 659-67.
29. Cocco E, Paladini F, Macino G, Fulci V, Fiorillo MT, Sorrentino R. The expression of vasoactive intestinal peptide receptor 1 is negatively modulated by microRNA 525-5p. PLoS One 2010; 5: e12067.
30. Delgado M, Pozo D, Martinez C, et al. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit endotoxin-induced TNF-alpha production by macrophages: in vitro and in vivo studies. J Immunol 1999; 162: 2358-67.
31. Martinez C, Delgado M, Pozo D, et al. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide modulate endotoxin-induced IL-6 production by murine peritoneal macrophages. J Leukoc Biol 1998; 63: 591-601.
32. Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide enhance IL-10 production by murine macrophages: in vitro and in vivo studies. J Immunol 1999; 162: 1707-16.
33. Delgado M, Ganea D. Inhibition of endotoxin-induced macrophage chemokine production by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide in vitro and in vivo. J Immunol 2001; 167: 966-75.
34. Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide prevent inducible nitric oxide synthase transcription in macrophages by inhibiting NF-kappa B and IFN regulatory factor 1 activation. J Immunol 1999; 162: 4685-96.
35. Gonzalez-Rey E, Delgado M. Vasoactive intestinal peptide inhibits cyclooxygenase-2 expression in activated macrophages, microglia, and dendritic cells. Brain Behav Immun 2008; 22: 35-41.
36. Arranz A, Androulidaki A, Zacharioudaki V, et al. Vasoactive intestinal peptide suppresses toll-like receptor 4 expression in macrophages via Akt1 reducing their responsiveness to lipopolysaccharide. Mol Immunol 2008; 45: 2970-80.
37. Delgado M, Leceta J, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the production of inflammatory mediators by activated microglia. J Leukoc Biol 2003; 73: 155-64.
38. Kim WK, Kan Y, Ganea D, Hart RP, Gozes I, Jonakait GM. Vasoactive intestinal peptide and pituitary adenylyl cyclaseactivating polypeptide inhibit tumor necrosis factor-alpha produc tion in injured spinal cord and in activated microglia via a cAMPdependent pathway. J Neurosci 2000; 20: 3622-30.
39. Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev 2004; 56: 249-90.
40. Delgado M, Ganea D. Inhibition of IFN-gamma-induced janus kinase-1-STAT1 activation in macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. J Immunol 2000; 165: 3051-7.
41. Delgado M, Gomariz RP, Martinez C, Abad C, Leceta J. Antiinflammatory properties of the type 1 and type 2 vasoactive intestinal peptide receptors: role in lethal endotoxic shock. Eur J Immunol 2000; 30: 3236-46.
42. Martinez C, Abad C, Delgado M, et al. Anti-inflammatory role in septic shock of pituitary adenylate cyclase-activating polypeptide receptor. Proc Natl Acad Sci U S A 2002; 99: 1053-8.
43. Delgado M. VIP: a very important peptide in T helper differentiation. Trends Immunol 2003; 24: 221-4.
44. Kodali S, Ding W, Huang J, Seiffert K, Wagner JA, Granstein RD. Vasoactive intestinal peptide modulates Langerhans cell immune function. J Immunol 2004; 173: 6082-8.
45. Xin Z, Sriram S. Vasoactive intestinal peptide inhibits IL-12 and nitric oxide production in murine macrophages. J Neuroimmunol 1998; 89: 206-12.
46. Delgado M, Gonzalez-Rey E, Ganea D. VIP/PACAP preferentially attract Th2 effectors through differential regulation of chemokine production by dendritic cells. FASEB J 2004; 18: 1453-5.
47. Delgado M, Ganea D. VIP and PACAP enhance the in vivo generation of memory TH2 cells by inhibiting peripheral deletion of antigen-specific effectors. Arch Physiol Biochem 2001; 109: 372-6.
48. Sharma V, Delgado M, Ganea D. VIP protects Th2 cells by downregulating granzyme B expression. Ann N Y Acad Sci 2006; 1070: 540-4.
49. Sharma V, Delgado M, Ganea D. Granzyme B, a new player in activation-induced cell death, is down-regulated by vasoactive intestinal peptide in Th2 but not Th1 effectors. J Immunol 2006; 176: 97-110.
50. Delgado M, Chorny A, Gonzalez-Rey E, Ganea D. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J Leukoc Biol 2005; 78: 1327-38.
51. Delgado M, Gonzalez-Rey E, Ganea D. The neuropeptide vasoactive intestinal peptide generates tolerogenic dendritic cells. J Immunol 2005; 175: 7311-24.
52. Gonzalez-Rey E, Chorny A, Fernandez-Martin A, Ganea D, Delgado M. Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells. Blood 2006; 107: 3632-8.
53. Delgado M, Martinez C, Pozo D, et al. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activation polypeptide (PACAP) protect mice from lethal endotoxemia through the inhibition of TNF-alpha and IL-6. J Immunol 1999; 162: 1200-5.
54. Delgado M, Ganea D. Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson's disease by blocking microglial activation. FASEB J 2003; 17: 944-6.
55. Ohtaki H, Nakamachi T, Dohi K, et al. Pituitary adenylate cyclaseactivating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Proc Natl Acad Sci U S A 2006; 103: 7488-93.
56. Fernandez-Martin A, Gonzalez-Rey E, Chorny A, et al. VIP prevents experimental multiple sclerosis by downregulating both inflammatory and autoimmune components of the disease. Ann N Y Acad Sci 2006; 1070: 276-81.
57. Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP. Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med 2001; 7: 563-8.
58. Abad C, Martinez C, Leceta J, Gomariz RP, Delgado M. Pituitary adenylate cyclase-activating polypeptide inhibits collagen-induced arthritis: an experimental immunomodulatory therapy. J Immunol 2001; 167: 3182-9.
59. Abad C, Martinez C, Juarranz MG, et al. Therapeutic effects of vasoactive intestinal peptide in the trinitrobenzene sulfonic acid mice model of Crohn's disease. Gastroenterology 2003; 124: 961-71.
60. Jimeno R, Gomariz RP, Gutierrez-Canas I, Martinez C, Juarranz Y, Leceta J. New insights into the role of VIP on the ratio of T-cell subsets during the development of autoimmune diabetes. Immunol Cell Biol; 88: 734-45.
61. Kato H, Ito A, Kawanokuchi J, et al. Pituitary adenylate cyclaseactivating polypeptide (PACAP) ameliorates experimental autoimmune encephalomyelitis by suppressing the functions of antigen presenting cells. Mult Scler 2004; 10: 651-9.
62. Gonzalez-Rey E, Fernandez-Martin A, Chorny A, et al. Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses. Am J Pathol 2006; 168: 1179-88.
63. Rola-Pleszczynski M, Bolduc D, St-Pierre S. The effects of vasoactive intestinal peptide on human natural killer cell function. J Immunol 1985; 135: 2569-73.
64. Ichinose M, Asai M, Imai K, Sawada M. Enhancement of phagocytosis in mouse macrophages by pituitary adenylate cyclase activating polypeptide (PACAP) and related peptides. Immunopharmacology 1995; 30: 217-24.
65. Delgado M, Garrido E, de la Fuente M, Gomariz RP. Pituitary adenylate cyclase-activating polypeptide (PACAP-38) stimulates rat peritoneal macrophage functions. Peptides 1996; 17: 1097-105.
66. De la Fuente M, Delgado M, del Rio M, Martinez C, Hernanz A, Gomariz RP. Stimulation by vasoactive intestinal peptide (VIP) of phagocytic function in rat macrophages. Protein kinase C involvement. Regul Pept 1993; 48: 345-53.
67. de la Fuente M, Delgado M, del Rio M, et al. Vasoactive intestinal peptide modulation of adherence and mobility in rat peritoneal lymphocytes and macrophages. Peptides 1994; 15: 1157-63.
68. Xia M, Leppert D, Hauser SL, et al. Stimulus specificity of matrix metalloproteinase dependence of human T cell migration through a model basement membrane. J Immunol 1996; 156: 160-7.
69. Xia M, Sreedharan SP, Dazin P, Damsky CH, Goetzl EJ. Integrindependent role of human T cell matrix metalloproteinase activity in chemotaxis through a model basement membrane. J Cell Biochem 1996; 61: 452-8.
70. Goetzl EJ, Pankhaniya RR, Gaufo GO, Mu Y, Xia M, Sreedharan SP. Selectivity of effects of vasoactive intestinal peptide on macrophages and lymphocytes in compartmental immune responses. Ann N Y Acad Sci 1998; 840: 540-50.
71. Schratzberger P, Geiseler A, Dunzendorfer S, Reinisch N, Kahler CM, Wiedermann CJ. Similar involvement of VIP receptor type I and type II in lymphocyte chemotaxis. J Neuroimmunol 1998; 87: 73-81.
72. Peuriere S, Susini C, Esteve JP, Vaysse N, Escoula L. Dual effect of vasoactive intestinal peptide on the mitogenic response of rabbit spleen lymphocytes. Regul Pept 1990; 27: 117-26.
73. Martinez C, Delgado M, Pozo D, et al. VIP and PACAP enhance IL-6 release and mRNA levels in resting peritoneal macrophages: in vitro and in vivo studies. J Neuroimmunol 1998; 85: 155-67.
74. Cai Y, Xin X, Shim GJ, et al. Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) stimulate interleukin-6 production through the third subtype of PACAP/VIP receptor in rat bone marrow-derived stromal cells. Endocrinology 1997; 138: 2515-20.
75. Maimone D, Cioni C, Rosa S, Macchia G, Aloisi F, Annunziata P. Norepinephrine and vasoactive intestinal peptide induce IL-6 secretion by astrocytes: synergism with IL-1 beta and TNF alpha. J Neuroimmunol 1993; 47: 73-81.
76. Matsumoto H, Koyama C, Sawada T, et al. Pituitary folliculostellate-like cell line (TtT/GF) responds to novel hypophysiotropic peptide (pituitary adenylate cyclase-activating peptide), showing increased adenosine 3',5'-monophosphate and interleukin-6 secretion and cell proliferation. Endocrinology 1993; 133: 2150-5.
77. Brenneman DE, Phillips TM, Hauser J, Hill JM, Spong CY, Gozes I. Complex array of cytokines released by vasoactive intestinal peptide. Neuropeptides 2003; 37: 111-9.
78. Yadav M, Rosenbaum J, Goetzl EJ. Cutting edge: vasoactive intestinal peptide (VIP) induces differentiation of Th17 cells with a distinctive cytokine profile. J Immunol 2008; 180: 2772-6.
79. Fong JS, Rae-Grant A, Huang D. Neurodegeneration and neuroprotective agents in multiple sclerosis. Recent Pat CNS Drug Discov 2008; 3: 153-65.
80. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683-747.
81. Rieckmann P. Socio-economic aspects of neuroimmunological diseases. J Neurol 2006; 253 Suppl 5: V87-90.
82. Zuvich RL, McCauley JL, Pericak-Vance MA, Haines JL. Genetics and pathogenesis of multiple sclerosis. Semin Immunol 2009; 21: 328-33.
83. Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev 2010; 9: A387-94.
84. Dyment DA, Ebers GC, Sadovnick AD. Genetics of multiple sclerosis. Lancet Neurol 2004; 3: 104-10.
85. Batchelor JR, Compston A, McDonald WI. The significance of the association between HLA and multiple sclerosis. Br Med Bull 1978; 34: 279-84.
86. Lincoln MR, Montpetit A, Cader MZ, et al. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet 2005; 37: 1108-12.
87. Munz C, Lunemann JD, Getts MT, Miller SD. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol 2009; 9: 246-58.
88. Soderstrom M, Link H, Sun JB, et al. T cells recognizing multiple peptides of myelin basic protein are found in blood and enriched in cerebrospinal fluid in optic neuritis and multiple sclerosis. Scand J Immunol 1993; 37: 355-68.
89. Ohashi T, Yamamura T, Inobe J, Kondo T, Kunishita T, Tabira T. Analysis of proteolipid protein (PLP)-specific T cells in multiple sclerosis: identification of PLP 95-116 as an HLA-DR2, w15-associated determinant. Int Immunol 1995; 7: 1771-8.
90. Benvenuto R, Paroli M, Buttinelli C, et al. Tumor necrosis factoralpha and interferon-gamma synthesis by cerebrospinal fluidderived T cell clones in multiple sclerosis. Ann N Y Acad Sci 1992; 650: 341-6.
91. Gallo P, Piccinno MG, Tavolato B, Siden A. A longitudinal study on IL-2, sIL-2R, IL-4 and IFN-gamma in multiple sclerosis CSF and serum. J Neurol Sci 1991; 101: 227-32.
92. Monteyne P, Sindic CJ. Data on cytokine mRNA expression in CSF and peripheral blood mononuclear cells from MS patients as detected by PCR. Mult Scler 1998; 4: 143-6.
93. Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123-32.
94. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133-41.
95. Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 2009; 132: 3329-41.
96. Fransson ME, Liljenfeldt LS, Fagius J, Totterman TH, Loskog AS. The T-cell pool is anergized in patients with multiple sclerosis in remission. Immunology 2009; 126: 92-101.
97. Khoury SJ, Guttmann CR, Orav EJ, Kikinis R, Jolesz FA, Weiner HL. Changes in activated T cells in the blood correlate with disease activity in multiple sclerosis. Arch Neurol 2000; 57: 1183-9.
98. Venken K, Hellings N, Thewissen M, et al. Compromised CD4+ CD25(high) regulatory T-cell function in patients with relapsingremitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology 2008; 123: 79-89.
99. Putheti P, Pettersson A, Soderstrom M, Link H, Huang YM. Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J Clin Immunol 2004; 24: 155-61.
100. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004; 199: 971-9.
101. Huan J, Culbertson N, Spencer L, Bartholomew R, Burrows GG, Chou YK, et al. Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res 2005; 81: 45-52.
102. Michel L, Berthelot L, Pettre S, et al. Patients with relapsingremitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor alpha-chain are excluded from the analysis. J Clin Invest 2008; 118: 3411-9.
103. Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN. Expression of monocyte chemoattractant protein-1 and other betachemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J Neuroimmunol 1998; 84: 238-49.
104. Li Y, Chu N, Hu A, Gran B, Rostami A, Zhang GX. Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain 2007; 130: 490-501.
105. Karni A, Abraham M, Monsonego A, et al. Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response. J Immunol 2006; 177: 4196-202.
106. Huang YM, Xiao BG, Ozenci V, et al. Multiple sclerosis is associated with high levels of circulating dendritic cells secreting proinflammatory cytokines. J Neuroimmunol 1999; 99: 82-90.
107. Vaknin-Dembinsky A, Balashov K, Weiner HL. IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol 2006; 176: 7768-74.
108. Bo L, Mork S, Kong PA, Nyland H, Pardo CA, Trapp BD. Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions. J Neuroimmunol 1994; 51: 135-46.
109. McRae BL, Semnani RT, Hayes MP, van Seventer GA. Type I IFNs inhibit human dendritic cell IL-12 production and Th1 cell development. J Immunol 1998; 160: 4298-304.
110. Kozovska ME, Hong J, Zang YC, et al. Interferon beta induces Thelper 2 immune deviation in MS. Neurology 1999; 53: 1692-7.
111. Stone LA, Frank JA, Albert PS, et al. The effect of interferon-beta on blood-brain barrier disruptions demonstrated by contrastenhanced magnetic resonance imaging in relapsing-remitting multiple sclerosis. Ann Neurol 1995; 37: 611-9.
112. Satoh J, Paty DW, Kim SU. Differential effects of beta and gamma interferons on expression of major histocompatibility complex antigens and intercellular adhesion molecule-1 in cultured fetal human astrocytes. Neurology 1995; 45: 367-73.
113. Ramgolam VS, Sha Y, Jin J, Zhang X, Markovic-Plese S. IFN-beta inhibits human Th17 cell differentiation. J Immunol 2009; 183: 5418-27.
114. Fridkis-Hareli M, Teitelbaum D, Gurevich E, et al. Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity and promiscuity. Proc Natl Acad Sci U S A 1994; 91: 4872-6.
115. Teitelbaum D, Meshorer A, Hirshfeld T, Arnon R, Sela M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol 1971; 1: 242-8.
116. Aharoni R, Teitelbaum D, Sela M, Arnon R. Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 1997; 94: 10821-6.
117. Aharoni R, Teitelbaum D, Leitner O, Meshorer A, Sela M, Arnon R. Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. Proc Natl Acad Sci U S A 2000; 97: 11472-7.
118. Jee Y, Piao WH, Liu R, et al. CD4(+)CD25(+) regulatory T cells contribute to the therapeutic effects of glatiramer acetate in experimental autoimmune encephalomyelitis. Clin Immunol 2007; 125: 34-42.
119. Ziemssen T, Kumpfel T, Schneider H, Klinkert WE, Neuhaus O, Hohlfeld R. Secretion of brain-derived neurotrophic factor by glatiramer acetate-reactive T-helper cell lines: Implications for multiple sclerosis therapy. J Neurol Sci 2005; 233: 109-12.
120. Weber MS, Prod'homme T, Youssef S, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med 2007; 13: 935-43.
121. Stuve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006; 59: 743-7.
122. Dumont FJ. Alemtuzumab (Millennium/ILEX). Curr Opin Investig Drugs 2001; 2: 139-60.
123. Kong JS, Teuber SS, Gershwin ME. Potential adverse events with biologic response modifiers. Autoimmun Rev 2006; 5: 471-85.
124. Miller SD, Karpus WJ, Davidson TS. Experimental autoimmune encephalomyelitis in the mouse. Curr Protoc Immunol; Chapter 15: Unit 15 1.
125. Reboldi A, Coisne C, Baumjohann D, et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 2009; 10: 514-23.
126. El-behi M, Rostami A, Ciric B. Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol 2010; 5: 189-97.
127. Scheikl T, Pignolet B, Mars LT, Liblau RS. Transgenic mouse models of multiple sclerosis. Cell Mol Life Sci 2010; 67: 4011-34.
128. Quandt JA, Baig M, Yao K, et al. Unique clinical and pathological features in HLA-DRB1*0401-restricted MBP 111-129-specific humanized TCR transgenic mice. J Exp Med 2004; 200: 223-34.
129. Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell 1994; 78: 399-408.
130. Waldner H, Whitters MJ, Sobel RA, Collins M, Kuchroo VK. Fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin proteolipid protein-specific T cell receptor. Proc Natl Acad Sci U S A 2000; 97: 3412-7.
131. Bettelli E, Pagany M, Weiner HL, Linington C, Sobel RA, Kuchroo VK. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J Exp Med 2003; 197: 1073-81.
132. Oleszak EL, Chang JR, Friedman H, Katsetos CD, Platsoucas CD. Theiler's virus infection: a model for multiple sclerosis. Clin Microbiol Rev 2004; 17: 174-207.
133. Melvold RW, Jokinen DM, Knobler RL, Lipton HL. Variations in genetic control of susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. I. Differences between susceptible SJL/J and resistant BALB/c strains map near the T cell beta-chain constant gene on chromosome 6. J Immunol 1987; 138: 1429-33.
134. Rodriguez M, Leibowitz J, David CS. Susceptibility to Theiler's virus-induced demyelination. Mapping of the gene within the H-2D region. J Exp Med 1986; 163: 620-31.
135. Li H, Mei Y, Wang Y, Xu L. Vasoactive intestinal polypeptide suppressed experimental autoimmune encephalomyelitis by inhibiting T helper 1 responses. J Clin Immunol 2006; 26: 430-7.
136. Fernandez-Martin A, Gonzalez-Rey E, Chorny A, Ganea D, Delgado M. Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis. Eur J Immunol 2006; 36: 318-26.
137. Chorny A, Gonzalez-Rey E, Delgado M. Regulation of dendritic cell differentiation by vasoactive intestinal peptide: therapeutic applications on autoimmunity and transplantation. Ann N Y Acad Sci 2006; 1088: 187-94.
138. Chorny A, Gonzalez-Rey E, Fernandez-Martin A, Pozo D, Ganea D, Delgado M. Vasoactive intestinal peptide induces regulatory dendritic cells with therapeutic effects on autoimmune disorders. Proc Natl Acad Sci U S A 2005; 102: 13562-7.
139. Toscano MG, Delgado M, Kong W, Martin F, Skarica M, Ganea D. Dendritic cells transduced with lentiviral vectors expressing VIP differentiate into VIP-secreting tolerogenic-like DCs. Mol Ther 2010; 18: 1035-45.
140. Sun W, Hong J, Zang YC, Liu X, Zhang JZ. Altered expression of vasoactive intestinal peptide receptors in T lymphocytes and aberrant Th1 immunity in multiple sclerosis. Int Immunol 2006; 18: 1691-700.
141. Brandtzaeg P, Oktedalen O, Kierulf P, Opstad PK. Elevated VIP and endotoxin plasma levels in human gram-negative septic shock. Regul Pept 1989; 24: 37-44.
142. Delgado M, Abad C, Martinez C, et al. Vasoactive intestinal peptide in the immune system: potential therapeutic role in inflammatory and autoimmune diseases. J Mol Med 2002; 80: 16-24.
143. Hannibal J, Jessop DS, Fahrenkrug J, Harbuz MS, Larsen PJ. PACAP gene expression in neurons of the rat hypothalamopituitary-adrenocortical axis is induced by endotoxin and interleukin-1beta. Neuroendocrinology 1999; 70: 73-82.
144. Vizzard MA. Up-regulation of pituitary adenylate cyclaseactivating polypeptide in urinary bladder pathways after chronic cystitis. J Comp Neurol 2000; 420: 335-48.
145. Armstrong BD, Abad C, Chhith S, et al. Impaired nerve regeneration and enhanced neuroinflammatory response in mice lacking pituitary adenylyl cyclase activating peptide. Neuroscience 2008; 151: 63-73.
146. Ohtaki H, Satoh A, Nakamachi T, et al. Regulation of oxidative stress by pituitary adenylate cyclase-activating polypeptide (PACAP) mediated by PACAP receptor. J Mol Neurosci; 42: 397-403.
147. Mori H, Nakamachi T, Ohtaki H, et al. Cardioprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on Doxorubicin-induced cardiomyopathy in mice. Circ J; 74: 1183-90.
148. Kemeny A, Reglodi D, Cseharovszky R, et al. Pituitary adenylate cyclase-activating polypeptide deficiency enhances oxazoloneinduced allergic contact dermatitis in mice. J Mol Neurosci 2010; 42: 443-9.
149. Nemetz N, Abad C, Lawson G, et al. Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide PACAP. Int J Cancer 2008; 122: 1803-9.
150. Azuma YT, Hagi K, Shintani N, et al. PACAP provides colonic protection against dextran sodium sulfate induced colitis. J Cell Physiol 2008; 216: 111-9.
151. Voice JK, Grinninger C, Kong Y, Bangale Y, Paul S, Goetzl EJ. Roles of vasoactive intestinal peptide (VIP) in the expression of different immune phenotypes by wild-type mice and T cell-targeted type II VIP receptor transgenic mice. J Immunol 2003; 170: 308-14.
152. Tan YV, Abad C, Lopez R, et al. Pituitary adenylyl cyclaseactivating polypeptide is an intrinsic regulator of Treg abundance and protects against experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2009; 106: 2012-7.
153. Abad C, Tan YV, Lopez R, et al. Vasoactive intestinal peptide loss leads to impaired CNS parenchymal T-cell infiltration and resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2010; 107: 19555-60.
154. Lange C, Scholl M, Melms A, Bischof F. CD62L(high) Treg cells with superior immunosuppressive properties accumulate within the CNS during remissions of EAE. Brain Behav Immun 2011; 25: 120-6.
155. Zhang X, Reddy J, Ochi H, Frenkel D, Kuchroo VK, Weiner HL. Recovery from experimental allergic encephalomyelitis is TGFbeta dependent and associated with increases in CD4+LAP+ and CD4+CD25+ T cells. Int Immunol 2006; 18: 495-503.
156. Kieseier BC, Kiefer R, Clements JM, et al. Matrix metalloproteinase-9 and-7 are regulated in experimental autoimmune encephalomyelitis. Brain 1998; 121 (Pt 1): 159-66.
157. Buhler LA, Samara R, Guzman E, et al. Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis. BMC Neurosci 2009; 10: 17.
158. Lu J, Zheng MH, Yan J, Chen YP, Pan JP. Effects of vasoactive intestinal peptide on phenotypic and functional maturation of dendritic cells. Int Immunopharmacol 2008; 8: 1449-54.