Bystander suppression was described during the investigation of regulatory cells induced by oral administration of low doses of MBP. It solves a major conceptual problem in designing antigen- or T cell-specific therapy for inflammatory autoimmune diseases such as multiple sclerosis, type 1 diabetes and rheumatoid arthritis, in which the autoantigen is unknown or where there are reactivities to multiple autoantigens in the target tissue. During the course of chronic inflammatory autoimmune process in animals there is intra- and interantigenic spread of auto-reactivity at the target organ. Similarly, in human autoimmune diseases there are reactivities to multiple autoantigens in the target tissue. For example, in multiple sclerosis there is immune reactivity to at least three myelin antigens, myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG). In type 1 diabetes, there are multiple islet cell antigens that could be the target of autoreactivity, including glutamate decarboxylase (GAD), insulin and heat shock proteins. Because regulatory cells induced by oral antigen secrete antigen-nonspecific cytokines after being triggered by the fed antigen, they suppress inflammation in the microenvironment where the orally administered antigen is localized. Thus, for a human organ-specific inflammatory disease, one need not know the specific antigen that is the target of an autoimmune response but only orally administer an antigen capable of producing regulatory cells which then migrate to the target tissue and suppress inflammation.
Bystander suppression was demonstrated in vitro when it was shown that cells from MBP-fed animals suppressed proliferation of an ovalbumin line across a transwell, but only when triggered by the fed antigen. The soluble factor was identified as TGF[3. Bystander suppression has been demonstrated in a number of autoimmune disease models (Table 2). PLP peptide-induced EAE can be suppressed by oral administration of MBP, and MBP-specific T cell clones from orally tolerized animals which secrcte TGF(3 also suppress PLP-induced disease. In the Lewis rat EAE model, MBP peptide 71-90-induced disease can be suppressed by oral administration of peptide 21-40. In arthritis models, adjuvant- and antigen-induced arthritis can be suppressed with oral type II collagen. A viral-induced model of diabetes was developed by expressing a lymphocytic choriomeningitis virus (LCMV) protein on the insulin promoter and then infecting animals with the LCMV virus. In this model, the viral-triggered diabetes can be suppressed by oral administration of insulin. Bystander suppression in vitro has recently been shown in humans using common dietary proteins m 11 _i
Table 2 Bystander suppression immunizing antigen
Proteolipid protein BSA, mycobacteria Lymphocytic choriomeningitis virus MBP peptide 71-90
Myelin basic protein Collagen type II Insulin
MBP peptide 21-40
(OVA, bovine gammaglobulin) to stimulate cells in vitro which then suppressed in vitro tetanus toxoid responses. Bystander suppression may be more difficult to induce in uveitis models and feeding OVA has been reported to induce bystander suppression in adult animals but anergy in young animals.
Bystander suppression theoretically could be applied for the treatment of organ-specific inflammatory conditions which are not classic autoimmune diseases, such as psoriasis, or to target anti-inflam-matory cytokines to an organ where inflammation may play a role in disease pathogenesis even if the disease is not primarily inflammatory in nature. Although initially described in association with regulatory cells induced by oral antigen, bystander suppression could in principle be induced by any immune manipulation that induces TH2- or Tn3-type regulatory cells.
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