Antigen‐driven tissue‐specific suppression following oral tolerance: Orally administered myelin basic protein suppresses proteolipid protein‐induced experimental autoimmune encephalomyelitis in the SJL mouse

Abstract

Immunomodulatory treatment paradigms have been applied to animal models of T cell-mediated autoimmune diseases in an attempt to develop an immunospecific and non-toxic form of therapy which can be applied to humans. These treatment paradigms are often directed to T cells with a restricted T cell receptor repertoire or that react with dominant peptide determinants. Experimental data, however, suggests that even if the initial T cell response is restricted to a specific self-protein in the target organ, spreading autoimmunity may develop with broadening of T cell autoreactivity to additional epitopes of the same autoantigen or to different autoantigens in the target organ. Thus, multiple autoantigens may become targets of the autoimmune response. This makes immunotherapeutic strategies based on suppressing responses to restricted proteins or clones of cells problematic. We have previously shown that suppression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat by oral myelin basic protein (MBP) is mediated by the release of transforming growth factor-beta after triggering by the oral tolerogen. Here, we report that in the SJL model of EAE oral administration of an autoantigen from the target tissue suppresses disease independent of whether it is or is not the inciting antigen. Thus, orally administered MBP or MBP peptides suppress proteolipid protein (PLP)-induced EAE, whereas intravenously administered MBP does not. Both oral and intravenous PLP, however, suppressed PLP disease. These findings have important implications for the use of oral tolerance as a therapeutic approach for the treatment of T cell-mediated inflammatory autoimmune diseases in man in which the inciting autoantigen is unknown or in which there is autoreactivity to multiple autoantigens in the target tissue.

Proinsulin: a unique autoantigen triggering autoimmune diabetes

“…Results of mechanistic studies confirmed that the effective downregulation of the immune response specific to the therapeutic autoantigen rapidly extends to other candidate autoantigens (24,25) (Figure 1). A better understanding of the underlying molecular mechanisms of these interactions will be essential to expedite the transfer of autoantigen therapy to the clinic.…”

“…In fact, the molecular processes that spread pathogenic responses are probably similar to those operating to spread protection in the case of bystander suppression (24,25). It has been well established in different models of autoimmunity, including EAE (24) and type 1 diabetes, that protection from disease may be induced following delivery by various routes of any of the candidate autoantigens (in the case of autoimmune diabetes using proinsulin, insulin, heat shock protein 60, or glutamic acid decarboxylase).…”

MOG79–90 Peptide in Complex with Recombinant MHC Class II Molecules Ameliorates Experimental Autoimmune Encephalomyelitis

“…In similarity with our results, it has earlier been reported that MOG35-55 peptide covalently bound to recombinant 1-and 1-domains of the human DR2 molecule could induce efficient tolerance in DR2 transgenic mice (21). There have been many reports demonstrating tolerance induction by administration of antigenic proteins or peptides (2,15,17,18). However, a major disadvantage of these methods is the need for further processing and presentation by APCs, while the preformed MHC II/peptide complexes bind directly to the T cell receptor.…”

Antigen-based vs. systemic immunomodulation in type 1 diabetes

“…In several autoimmune disease models, like experimental autoimmune encephalomyelitis (EAE) and T1D, administration of an auto-Ag through a tolerogenic route drives the downregulation of the immune response to that specific auto-Ag, mostly through the induction of a Treg compartment. 94,95 The extension of this suppression to immune responses against other disease-related auto-Ags is a phenomenon referred to as bystander suppression. 93,94,96 This is made possible partly by the suppressive cytokines secreted by Ag-non-specific Tregs.…”

“…94,95 The extension of this suppression to immune responses against other disease-related auto-Ags is a phenomenon referred to as bystander suppression. 93,94,96 This is made possible partly by the suppressive cytokines secreted by Ag-non-specific Tregs. This phenomenon holds great promise for the future since any auto-Ag, capable of inducing a Treg compartment, could inhibit the destructive immunologic actions characteristic for an autoimmune disease when administered in a tolerogenic way.…”