Orally Induced Tolerance

314

153

Although oral administration of protein antigens may lead to specific immunologic unresponsiveness, this method of immunoregulation has not been applied to models of autoimmune disease. Type II collagen-induced arthritis is an animal model of polyarthritis induced in susceptible mice and rats by immunization with type II collagen, a major component of cartilage. Intragastric administration of soluble type II collagen, prior to immunization with type II collagen in adjuvant, suppresses the incidence of collagen-induced arthritis. Administration of denatured type II collagen has no observable effect on the incidence or severity of the disease. The overall magnitude of the antibody response is not significantly reduced in collagen-fed mice as compared to controls. While the isotype distribution of the anti-collagen antibodies is similar in the two groups, there is a tendency toward reduced IgG2 responses in the collagen-fed mice.Type II collagen-induced arthritis (CIA) is an animal model of polyarthritis induced in susceptible mice and rats by immunization with type II collagen (1, 2). Type II collagen is the major matrix protein of hyaline cartilage. The similarity of the histopathologic changes observed in CIA to those seen in human rheumatoid arthritis has centered interest on the contribution of collagen autoimmunity to the pathogenesis of the human disease. Although humoral and cellular immunity to type II collagen have been shown in CIA, the precise contribution of each to the development of disease has not been established. While T cells have been shown to recognize undenatured and denatured type II collagen (3), the humoral response is restricted to the undenatured, nonrepeating helical antigenic determinants of the collagen molecule (3, 4

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confidence: 78%

Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen.

Nagler‐Anderson¹,

Bober²,

Robinson³

et al. 1986

314

153

“…This finding is especially important since (i) oral tolerance, to be broadly applicable, must be effective in situations where potentially pathogenic lymphocytes exist and (ii) conventional oral tolerization protocols are less efficient at suppressing immune responses in systematically immune animals than in naive animals (19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, unless tolerogens are administered repeatedly and in large doses, tolerance is usually modest and of short duration (17,18), being rather difficult to induce in an already-immune host (19)(20)(21)(22).…”

mentioning

confidence: 99%

“…In contrast, feeding mice 1 or up to 10 daily consecutive doses of unconjugated SRBCs given alone or with free CTB, or of GM1-derivatized SRBCs alone (without CTB), had no appreciable effects on subsequent DTH reactivity. Daily oral administration of SRBCs 5 days per week for 3-4 weeks (i.e., [15][16][17][18][19][20] doses) was required to suppress the 24-hr DTH reaction to a level comparable to that achieved by a single dose of CTB-SRBCs, while as many as 20 consecutive feedings with unconjugated SRBCs had no effect on the early (2 hr) swelling reaction (Fig. 1) (Table 4) but was in fact effective at priming animals for systemic DTH responses to SRBCs (data not shown).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cholera toxin B subunit: an efficient transmucosal carrier-delivery system for induction of peripheral immunological tolerance.

Sun

Holmgren

Czerkinsky

1994

277

183

Oral administration of antigens, including allergens and autoantigens, may be an efficient way to prevent disease associated with untoward immune responses to self. and non-self-antigens. However, this approach has met with limitations because it usually requires repeated administrations of large doses of antigen and is less efficient in an already immune host, and the effect is ofshort duration. We report that a single oral adinistration ofminute Oral administration of antigens is a long-recognized method for inducing peripheral immunological tolerance (1, 2) and has been proposed as a means to prevent or treat allergic reactions (3,4), Rh alloimmunization (5), and experimental autoimmune diseases (6-13). Efforts to develop optimal tolerogenic formulations based on this strategy have been stimulated by recent studies reporting beneficial effects of oral administration of antigens in patients with autoimmune diseases (14)(15)(16).Although oral administration of antigens offers a convenient way to induce systemic tolerance, its therapeutic potential has been seriously limited. Indeed, unless tolerogens are administered repeatedly and in large doses, tolerance is usually modest and of short duration (17, 18), being rather difficult to induce in an already-immune host (19)(20)(21)(22).We now report that a single oral administration of a small dose of a soluble or particulate antigen conjugated to the B subunit of cholera toxin (CTB), rather than abrogating systemic tolerance to conjugated antigens, as generally assumed (23-25), can profoundly enhance it in naive as well as in immune animals.MATERIALS AND METHODS Animals. BALB/c and C57BL/6J female mice, 6-8 weeks old at the start of experiments, were used.Antigens. Purified human -y-globulin (HGG) was purchased from Pharmacia. Sheep red blood cells (SRBCs) and horse red blood cells (HRBCs) were obtained from the National Institute of Veterinary Medicine (HAtunaholm, Sweden).Cholera toxin (CT) was obtained from List Biological Laboratories (Campbell, CA).Preparation of CTB-Conjugated Antigens. CTB was purified from the culture supernatant of a mutant strain of Vibrio cholerae deleted of the CT genes and transfected with a plasmid encoding CTB (26, 27).To facilitate coupling to CTB, SRBCs and HRBCs were first derivatized with monosialoganglioside (GM1). A solution of GM1 (Sigma) [300 nmol/ml in phosphate-buffered saline (PBS)] was added to packed red cells at a ratio of 1:2 (vol/vol) and the mixture was incubated for 2 hr at 370C with shaking. After three washes with PBS, GM1-coated red cells were resuspended in PBS. CTB was added to the cell suspension in molar excess to the cell-bound GM1 (50 ,g of CTB per 5 x 109 GM1-SRBCs per ml). After 2 hr at 370C, the erythrocytes were washed twice with PBS to remove unbound CTB. A solid-phase hemadsorption assay using GM1 immobilized on plastic wells was employed to ascertain that the CTB molecules (pentamers) had bound to GM1-coupled SRBCs or HRBCs and were still able to bind additional GM1 molecules.HGG was covale...

“…This approach, however, requires administration of massive amounts of antigens or prolonged feeding of small amounts of antigens, which are then only effective in rather narrow dose ranges. Further, oral tolerance is especially difficult to induce in an already immunologically sensitized host (14)(15)(16)(17)(18), such as in patients harboring autoreactive T cells.…”

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confidence: 99%

A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes

Bergerot

Ploix

Petersen

et al. 1997

220

182

Mucosally induced immunological tolerance is an attractive strategy for preventing or treating illnesses resulting from untoward inf lammatory immune reactions against self-or non-self-antigens. Oral administration of relevant autoantigens and allergens has been reported to delay or suppress onset of clinical disease in a number of experimental autoimmune and allergic disorders. However, the approach often requires repeated feeding of large amounts of tolerogens over long periods and is only partly effective in animals already systemically sensitized to the ingested antigen such as in animals already harboring autoreactive T cells, and thus presumably also in humans with an autoimmune disease. We have recently shown that oral administration of microgram amounts of antigen coupled to cholera toxin B subunit (CTB), can effectively suppress systemic T cell reactivity in naive as well as in immune animals. We now report that feeding small amounts (2-20 g) of human insulin conjugated to CTB can effectively suppress beta cell destruction and clinical diabetes in adult nonobese diabetic (NOD) mice. The protective effect could be transferred by T cells from CTBinsulin-treated animals and was associated with reduced lesions of insulitis. Furthermore, adoptive co-transfer experiments involving injection of Thy-1,2 recipients with diabetogenic T cells from syngeneic mice and T cells from congenic Thy-1,1 mice fed with CTB-insulin demonstrated a selective recruitment of Thy-1,1 donor cells in the peripancreatic lymph nodes concomitant with reduced islet cell infiltration. These results suggest that protection against autoimmune diabetes can be achieved by feeding minute amounts of a pancreas islet cell autoantigen linked to CTB and appears to involve the selective migration and retention of protective T cells into lymphoid tissues draining the site of organ injury.