Antigen‐specific tolerance inhibits autoimmune uveitis in pre‐sensitized animals by deletion and CD4⁺CD25⁺ T‐regulatory cells

Abstract

The objective of the present 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 day 6, 7, 8 and 9 post-immunization induced tolerance and inhibited EAAU in all Lewis rats. 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 to non-tolerized animals. Additionally, FasL, 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 to the cells from non-tolerized animals. Level of IFN-γ and IL-2 decreased while TGF-β2 was elevated in the state of tolerance. Furthermore, the number of CD4+CD25+FoxP3+ Tregs increased in the popliteal LNs of tolerized animals compared to non-tolerized animals. In conclusion, our results suggest that deletion of antigen specific T cells via apoptosis and active suppression mediated by Tregs plays an important role in the induction of antigen specific immune tolerance in animals with an established immune response against MAA.

Inhibition of Complement Alternative Pathway Suppresses Experimental Autoimmune Anterior Uveitis by Modulating T Cell Responses

“…Specific experiments were carried out to determine whether the presence of factor B, an essential element of the alternative pathway, is crucial for the stimulation and/or function of T cells that are present in the draining (popliteal) LNs of MAA-sensitized Lewis rats. EAAU is a T cell-mediated autoimmune disease of the eye where a CD4 ϩ T cell-mediated immune response is initiated in the popliteal LNs of Lewis rats after footpad injection of MAA (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…Experimental autoimmune anterior uveitis (EAAU) is an organ-specific autoimmune disease of the eye that serves as an animal model of noninfectious autoimmune idiopathic AU (4 -15). The EAAU model has been extensively used in our laboratory to understand the underlying mechanisms involved in the pathogenesis of idiopathic AU (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). In this experimental model, inbred Lewis rats are subcutaneously immunized in the footpad with melanin-associated antigen (MAA) isolated from the iris and the CB, and EAAU is induced in these animals by an antigen-specific CD4 ϩ T cell response to MAA (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…The EAAU model has been extensively used in our laboratory to understand the underlying mechanisms involved in the pathogenesis of idiopathic AU (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). In this experimental model, inbred Lewis rats are subcutaneously immunized in the footpad with melanin-associated antigen (MAA) isolated from the iris and the CB, and EAAU is induced in these animals by an antigen-specific CD4 ϩ T cell response to MAA (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The hallmark pathologic features of EAAU include lymphocytic infiltration in the iris, the CB, and the anterior segment of the eye with no inflammation of the retina (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…In this experimental model, inbred Lewis rats are subcutaneously immunized in the footpad with melanin-associated antigen (MAA) isolated from the iris and the CB, and EAAU is induced in these animals by an antigen-specific CD4 ϩ T cell response to MAA (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The hallmark pathologic features of EAAU include lymphocytic infiltration in the iris, the CB, and the anterior segment of the eye with no inflammation of the retina (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Antigen-specific CD4 ϩ T cells can adoptively transfer disease into naïve syngenic recipients (7,8,13) and are the predominant inflammatory cells within the uvea (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…The hallmark pathologic features of EAAU include lymphocytic infiltration in the iris, the CB, and the anterior segment of the eye with no inflammation of the retina (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Antigen-specific CD4 ϩ T cells can adoptively transfer disease into naïve syngenic recipients (7,8,13) and are the predominant inflammatory cells within the uvea (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”