Pre-emptive targeting of the epitope spreading cascade with genetically modified regulatory T cells during autoimmune demyelinating disease.
Epitope spreading or endogenous self-priming has been implicated in mediating the progression of autoimmune disease. In the present study we created an immune-deviated, epitope spreading response in SWXJ mice after the onset of experimental autoimmune encephalomyelitis, a prototypic autoimmune animal model widely used in multiple sclerosis research. We established an immunoregulatory spreading repertoire by transferring T cells genetically modified to produce high levels of IL-10 in response to a dominant epitope spreading determinant. Installation of a Th2/Tr1-like spreading repertoire resulted in a marked and prolonged inhibition of disease progression and demyelination characterized by 1) bystander inhibition of the recall response to the priming immunogen, and 2) a Th1-->Tr1 immune-deviated spreading response involving a shift in the source of IL-10 production from the transferred regulatory population to the host-derived, endogenously primed repertoire. Thus, our data provide a rationale for cell-based therapeutic intervention in multiple sclerosis by showing that pre-emptive targeting of the epitope spreading cascade with regulatory T cells effectively induces an immune-deviated spreading response capable of inhibiting ongoing inflammatory autoreactivity and disease progression.
Yin
L
L
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Yu
M
M
Edling
A E
AE
Kawczak
J A
JA
Mathisen
P M
PM
Nanavati
T
T
Johnson
J M
JM
Tuohy
V K
VK
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000502:physiology; D005260:Female; D018390:Gene Targeting; D007156:Immunologic Memory / Q000235:genetics; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D014162:Transfection
D001324:Autoantigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C115314:myelin basic protein 87-99; D016753:Interleukin-10