Curing CNS autoimmune disease with myelin-reactive Foxp3+ Treg.
The potential use of CD4(+)Foxp3(+) Treg as a cellular therapy for autoimmune disease is of great interest. For clinical translation, the key objective is to reverse established disease. Here we demonstrate that myelin basic protein (MBP)-reactive CD4(+)CD25(+) Treg from TCR Tg mice, but not polyclonal (non-MBP-reactive) Treg, can transfer efficient protection against MBP-induced EAE when used either directly from donor mice, or after in vitro expansion. MBP-reactive Treg transfer also showed some ability to improve recovery from EAE initiated by T cells recognizing a distinct CNS autoantigen, proteolipid protein. Importantly, we also demonstrate for the first time in the context of EAE that in vitro-expanded naturally occurring MBP-reactive Treg can prevent disease relapse when given after the onset of clinical EAE. Our study also contains data pertaining to the most effective Treg sub-population in vivo (CD4(+)CD25(+)CD62L(hi)) and shows that their potent suppressive effects reflect stable expression of Foxp3, although not CD25 or CD62L. Our data provide proof of the principle that Treg-based therapies can cure CNS autoimmune disease, highlight the challenges for clinical translation and open new avenues for assessing how changing immune function via Treg activity might impact on neurodegeneration and repair.
Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Ashworth Laboratories, Edinburgh, UK.
Leigh A
LA
Stephens
Katy H
KH
Malpass
Stephen M
SM
Anderton
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D002469:Cell Separation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control / Q000628:therapy*; D051858:Forkhead Transcription Factors / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D019041:L-Selectin / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology*; D018991:Myelin Proteolipid Protein / Q000276:immunology*; D009186:Myelin Sheath / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C074815:myelin basic protein 1-9; C435023:myelin proteolipid protein (139-151); D019041:L-Selectin