Ex vivo generated regulatory T cells modulate experimental autoimmune myasthenia gravis.
Naturally occurring CD4(+)CD25(+) regulatory T (Treg) cells are key players in immune tolerance and have therefore been suggested as potential therapeutic tools for autoimmune diseases. In myasthenia gravis (MG), reduced numbers or functionally impaired Treg cells have been reported. We have observed that PBL from myasthenic rats contain decreased numbers of CD4(+)CD25(high)Foxp3(+) cells as compared with PBL from healthy controls, and we have tested whether Treg cells from healthy donors can suppress experimental autoimmune MG in rats. Because the number of naturally occurring Treg cells is low, we used an approach for a large-scale ex vivo generation of functional Treg cells from CD4(+) splenocytes of healthy donor rats. Treg cells were generated ex vivo from CD4(+) cells by stimulation with anti-CD3 and anti-CD28 Abs in the presence of TGF-beta and IL-2. The obtained cells expressed high levels of CD25, CTLA-4, and Foxp3, and they were capable of suppressing in vitro proliferation of T cells from myasthenic rats in response to acetylcholine receptor, the major autoantigen in myasthenia. Administration of ex vivo-generated Treg cells to myasthenic rats inhibited the progression of experimental autoimmune MG and led to down-regulation of humoral acetylcholine receptor-specific responses, and to decreased IL-18 and IL-10 expression. The number of CD4(+)CD25(+) cells in the spleen of treated rats remained unchanged, but the subpopulation of CD4(+)CD25(+) cells expressing Foxp3 was significantly elevated. Our findings imply that Treg cells play a critical role in the control of myasthenia and could thus be considered as potential agents for the treatment of MG patients.
Aricha
Revital
R
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Feferman
Tali
T
Fuchs
Sara
S
Souroujon
Miriam C
MC
D000818:Animals; D051927:CD24 Antigen / Q000096:biosynthesis / Q000097:blood; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000097:blood; D008231:Lymphopenia / Q000276:immunology / Q000473:pathology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D051381:Rats; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D051927:CD24 Antigen; D016207:Cytokines; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D053645:Interleukin-2 Receptor alpha Subunit