Nasal Tolerance in Experimental Autoimmune Myasthenia Gravis (EAMG): Induction of Protective Tolerance in Primed Animals

Overview

Journal Clin Exp Immunol

Publisher Oxford University Press

Specialty Allergy & Immunology

Date 1998 Apr 7

PMID 9528890

Citations 12

Authors

F D Shi

X F Bai

H L Li

Y M Huang

P H van der Meide

H Link

Affiliations

Soon will be listed here.

Abstract

Nasal administration of microg doses of acetylcholine receptor (AChR) is effective in preventing the development of B cell-mediated EAMG in the Lewis rat, a model for human MG. In order to investigate whether nasal administration of AChR modulates ongoing EAMG, Lewis rats were treated nasally with AChR 2 weeks after immunization with AChR and Freund's complete adjuvant. Ten-fold higher amounts of AChR given nasally (600 microg/rat) were required to ameliorate the manifestations of EAMG compared with the amounts necessary for prevention of EAMG. In lymph node cells from rats receiving 600 microg/rat of AChR, AChR-induced proliferation and interferon-gamma (IFN-gamma) secretion were reduced compared with control EAMG rats receiving PBS only. The anti-AChR antibodies in rats treated nasally with 600 microg/rat of AChR had lower affinity, reduced proportion of IgG2b and reduced capacity to induce AChR degradation. Numbers of AChR-reactive IFN-gamma and tumour necrosis factor-alpha (TNF-alpha) mRNA-expressing lymph node cells from rats treated nasally with 600 microg/rat of AChR were suppressed, while IL-4, IL-10 and transforming growth factor-beta (TGF-beta) mRNA-expressing cells were not affected. Collectively, these data indicate that nasal administration of AChR in ongoing EAMG induced selective suppression of Th1 functions, i.e. IFN-gamma and IgG2b production, but no influence on Th2 cell functions. The impaired Th1 functions may result in the production of less myasthenic anti-AChR antibodies and contribute to the amelioration of EAMG severity in rats treated with AChR 600 microg/rat by the nasal route.

Citing Articles

A Recombinant Acetylcholine Receptor α1 Subunit Extracellular Domain Is a Promising New Drug Candidate for Treatment Of Myasthenia Gravis.

Lazaridis K, Fernandez-Santoscoy M, Baltatzidou V, Andersson J, Christison R, Grunberg J Front Immunol. 2022; 13:809106.

PMID: 35720339 PMC: 9204200. DOI: 10.3389/fimmu.2022.809106.

Engineered agrin attenuates the severity of experimental autoimmune myasthenia gravis.

Li Z, Li M, Wood K, Hettwer S, Muley S, Shi F Muscle Nerve. 2017; 57(5):814-820.

PMID: 29193204 PMC: 5910282. DOI: 10.1002/mus.26025.

A Sensitive Method for Detecting Peptide-specific CD4 T Cell Responses in Peripheral Blood from Patients with Myasthenia Gravis.

Sharma S, Malmestrom C, Lindberg C, Meisel S, Schon K, Verolin M Front Immunol. 2017; 8:1370.

PMID: 29114250 PMC: 5660702. DOI: 10.3389/fimmu.2017.01370.

A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1-T146.

Consonni A, Sharma S, Schon K, Lebrero-Fernandez C, Rinaldi E, Lycke N Front Immunol. 2017; 8:1133.

PMID: 28959261 PMC: 5604076. DOI: 10.3389/fimmu.2017.01133.

Current and emerging treatments for the management of myasthenia gravis.

Sathasivam S Ther Clin Risk Manag. 2011; 7:313-23.

PMID: 21845054 PMC: 3150477. DOI: 10.2147/TCRM.S14015.

References

Link J, Soderstrom M, Ljungdahl A, Hojeberg B, Olsson T, Xu Z . Organ-specific autoantigens induce interferon-gamma and interleukin-4 mRNA expression in mononuclear cells in multiple sclerosis and myasthenia gravis. Neurology. 1994; 44(4):728-34. DOI: 10.1212/wnl.44.4.728. View

Zhang G, Xiao B, Bai X, van der Meide P, Orn A, Link H . Mice with IFN-gamma receptor deficiency are less susceptible to experimental autoimmune myasthenia gravis. J Immunol. 1999; 162(7):3775-81. View

Vincent A, Jacobson L, Shillito P . Response to human acetylcholine receptor alpha 138-199: determinant spreading initiates autoimmunity to self-antigen in rabbits. Immunol Lett. 1994; 39(3):269-75. DOI: 10.1016/0165-2478(94)90168-6. View

Wang Z, Link H, Ljungdahl A, Hojeberg B, Link J, He B . Induction of interferon-gamma, interleukin-4, and transforming growth factor-beta in rats orally tolerized against experimental autoimmune myasthenia gravis. Cell Immunol. 1994; 157(2):353-68. DOI: 10.1006/cimm.1994.1233. View

Melamed D, Friedman A . In vivo tolerization of Th1 lymphocytes following a single feeding with ovalbumin: anergy in the absence of suppression. Eur J Immunol. 1994; 24(9):1974-81. DOI: 10.1002/eji.1830240906. View

Okumura S, McIntosh K, Drachman D . Oral administration of acetylcholine receptor: effects on experimental myasthenia gravis. Ann Neurol. 1994; 36(5):704-13. DOI: 10.1002/ana.410360504. View

Gu D, Wogensen L, Calcutt N, Xia C, Zhu S, Merlie J . Myasthenia gravis-like syndrome induced by expression of interferon gamma in the neuromuscular junction. J Exp Med. 1995; 181(2):547-57. PMC: 2191877. DOI: 10.1084/jem.181.2.547. View

Krolick K, Zoda T, Thompson P . Examination of characteristics that may distinguish disease-causing from benign AChR-reactive antibodies in experimental autoimmune myasthenia gravis. Adv Neuroimmunol. 1994; 4(4):475-93. DOI: 10.1016/0960-5428(94)00033-k. View

Ma C, Zhang G, Xiao B, Link J, Olsson T, Link H . Suppression of experimental autoimmune myasthenia gravis by nasal administration of acetylcholine receptor. J Neuroimmunol. 1995; 58(1):51-60. DOI: 10.1016/0165-5728(94)00187-s. View

10.

DEIBLER G, Martenson R, KIES M . Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species. Prep Biochem. 1972; 2(2):139-65. DOI: 10.1080/00327487208061467. View

11.

Lennon V, Lindstrom J, Seybold M . Experimental autoimmune myasthenia gravis: cellular and humoral immune responses. Ann N Y Acad Sci. 1976; 274:283-99. DOI: 10.1111/j.1749-6632.1976.tb47693.x. View

12.

Lindstrom J, Seybold M, Lennon V, Whittingham S, Duane D . Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology. 1976; 26(11):1054-9. DOI: 10.1212/wnl.26.11.1054. View

13.

Kao I, Drachman D . Myasthenic immunoglobulin accelerates acetylcholine receptor degradation. Science. 1977; 196(4289):527-9. DOI: 10.1126/science.850793. View

14.

Lindstrom J, Einarson B, Tzartos S . Production and assay of antibodies to acetylcholine receptors. Methods Enzymol. 1981; 74 Pt C:432-60. DOI: 10.1016/0076-6879(81)74031-x. View

15.

Sidman C, Marshall J, Shultz L, Gray P, Johnson H . Gamma-interferon is one of several direct B cell-maturing lymphokines. Nature. 1984; 309(5971):801-4. DOI: 10.1038/309801a0. View

16.

Christadoss P, Lindstrom J, Munro S, Talal N . Muscle acetylcholine receptor loss in murine experimental autoimmune myasthenia gravis: correlated with cellular, humoral and clinical responses. J Neuroimmunol. 1985; 8(1):29-41. DOI: 10.1016/s0165-5728(85)80045-x. View

17.

Derynck R, Jarrett J, Chen E, EATON D, Bell J, Assoian R . Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985; 316(6030):701-5. DOI: 10.1038/316701a0. View

18.

Dijkema R, van der Meide P, Dubbeld M, Caspers M, Wubben J, Schellekens H . Cloning, expression, and purification of rat IFN-gamma. Methods Enzymol. 1986; 119:453-64. DOI: 10.1016/0076-6879(86)19065-3. View

19.

Jelinek D, Lipsky P . Enhancement of human B cell proliferation and differentiation by tumor necrosis factor-alpha and interleukin 1. J Immunol. 1987; 139(9):2970-6. View

20.

Macdonald R, Hosking C, Jones C . The measurement of relative antibody affinity by ELISA using thiocyanate elution. J Immunol Methods. 1988; 106(2):191-4. DOI: 10.1016/0022-1759(88)90196-2. View