Antigen-specific tolerance inhibits autoimmune uveitis in pre-sensitized animals by deletion and CD4+CD25+ T-regulatory cells.
The objective of this study was to inhibit experimental autoimmune anterior uveitis (EAAU) by establishing antigen-specific immune tolerance in animals pre-sensitized with melanin-associated antigen (MAA). Intravenous administration of MAA on days 6, 7, 8 and 9 post-immunization induced tolerance and inhibited EAAU in all Lewis rats. The number of cells (total T cells, CD4(+) T cells and CD8(+) T cells) undergoing apoptosis dramatically increased in the popliteal lymph nodes (LNs) of the tolerized animals compared with non-tolerized animals. In addition, Fas ligand (FasL), TNF receptor 1 (TNFR1) and caspase-8 were upregulated in tolerized rats. Proliferation of total lymphocytes, CD4(+)T cells and CD8(+) T cells (harvested from the popliteal LNs) in response to antigenic stimulation was drastically reduced in the state of tolerance compared with the cells from non-tolerized animals. The level of interferon (IFN)-gamma and IL-2 decreased, whereas TGF-beta2 was elevated in the state of tolerance. Furthermore, the number of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) increased in the popliteal LNs of tolerized animals compared with non-tolerized animals. In conclusion, our results suggest that deletion of antigen-specific T cells by apoptosis and active suppression mediated by Tregs has an important role in the induction of antigen specific immune tolerance in animals with an established immune response against MAA.
Matta
Bharati
B
Department of Ophthalmology, Jones Eye Institute, Little Rock, AR 72205, USA.
Jha
Purushottam
P
Bora
Puran S
PS
Bora
Nalini S
NS
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002417:Cattle; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D000939:Epitopes / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D007114:Immunization; D007275:Injections, Intravenous; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014605:Uveitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*
D001324:Autoantigens; D016207:Cytokines; D000939:Epitopes; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D053645:Interleukin-2 Receptor alpha Subunit