Tolerance to Melanin-Associated Antigen in Autoimmune Uveitis Is Mediated by CD4+CD25+ T-Regulatory Cells

Abstract

Experimental autoimmune anterior uveitis (EAAU)serves as an animal model for human idiopathic AU, the most common form of intraocular inflammation of significant morbidity whose recurrence can lead to permanent vision loss. This study was undertaken to inhibit EAAU by inducing tolerance to melanin-associated antigen (MAA) and to investigate the underlying mechanisms responsible for tolerance induction. Intravenous administration of MAA both induced tolerance and inhibited EAAU in Lewis rats. Flow cytometric analysis revealed that the proliferation of lymph node cells in response to antigenic stimulation was drastically reduced in the state of tolerance both in vivo and in vitro. Our results from co-culture experiments demonstrated that intravenous administration of MAA led to the generation of T-regulatory cells that suppress T-cell proliferative responses and induce tolerance. Expression levels of both interleukin-10 and transforming growth factor-␤2 were elevated whereas reduced levels of tumor necrosis factor-␣, interferon-␥, and interleukin-2 were detected in tolerance-induced animals. Tolerance was reversed by replenishing these animals with recombinant interleukin-2. Tolerance could be adoptively transferred by removing lymph node cells from tolerance-induced donors and giving them to recipient rats. Interestingly, adoptive transfer of tolerance failed when lymph nodes cells were depleted of Uveitis is broadly defined as inflammation of the uvea and is responsible for more than 2.8% of blindness in the US.Each year, 17.6% of active uveitis patients experience a transient or permanent loss of vision. A recent report from the Northern California Epidemiology Study suggested a higher disease rate for the older population in the US.

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).…”

“…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).…”

“…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).…”