Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin.

Abstract

Nonobese diabetic (NOD) mice spontaneously develop an autoimmune form of diabetes associated with insulitis. A number of immunomodulatory therapies have been investigated as a treatment for the disease process. Oral administration of the autoantigens myelin basic protein and collagen type II suppresses experimental models of encephalomyelitis and arthritis. We have now found that oral administration of insulin delays the onset and reduces the incidence of diabetes in NOD mice over a 1-year period in animals administered 1 mg of porcine insulin orally twice a week for 5 weeks and then weekly until 1 year of age. As expected, orally administered insulin had no metabolic effect on blood glucose levels. The severity of lymphocytic infiltration of pancreatic islets was also reduced by oral administration of insulin. Furthermore, splenic T cells from animal orally treated with insulin adoptively transfer protection against diabetes, demonstrating that oral insulin administration generates active cellular mechanisms that suppress disease. These results show that oral insulin affects diabetes and the pancreatic cellular inflammatory process in the NOD mouse and raise the possibility that oral administration of insulin or other pancreatic autoantigens may provide a new approach for the treatment of autoimmune diabetes.

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

“…Further, oral CTB-INS treatment was effective at doses 500-5,000 times lower than those previously required to treat young (weaning) NOD mice with unconjugated insulin (23). Partial protection (48%) has previously been reported after feeding NOD mice at as early as 5 weeks of age with 1 mg of porcine insulin administered twice weekly for 5 weeks and weekly thereafter, whereas lower doses were ineffective (23).…”

“…Further, oral CTB-INS treatment was effective at doses 500-5,000 times lower than those previously required to treat young (weaning) NOD mice with unconjugated insulin (23). Partial protection (48%) has previously been reported after feeding NOD mice at as early as 5 weeks of age with 1 mg of porcine insulin administered twice weekly for 5 weeks and weekly thereafter, whereas lower doses were ineffective (23). The present study demonstrates that feeding minute amounts of insulin conjugated to CTB can significantly reduce the incidence of diabetes even when given as a single dose and that protection tends to be more durable when using five consecutive doses of conjugate.…”

“…Prolonged feeding of large (milligram) amounts of heterologous insulin has been shown to delay the onset of diabetes in NOD mice (23). However, the therapeutic potential of such treatment in humans appears to be limited by the dose and frequency of autoantigen administration and by the short duration of the protection.…”

Antigen-based vs. systemic immunomodulation in type 1 diabetes

“…As mentioned above, insulin is being regarded as possibly the major auto-Ag in T1D. In the NOD mouse model numerous studies could prevent or delay the onset and development of T1D by administering insulin or an insulin peptide, like B:9-23, orally, 110,111 subcutaneously, 80 intravenously 112 or intranasally. 80,113,114 Nakayama and colleagues made a double insulin knockout in combination with an altered insulin B:9-23 transgene to preserve the insulin metabolic activity while abrogating the NOD T-cell responsiveness.…”

Autoimmunity and Apoptosis - Therapeutic Implications

“…The basic concept of peptide-tolerance therapy is to educate immune system to tolerate these peptides by being exposed to them. This systemic exposure to autoantigens, although yielded encouraging results in some experiments [155][156][157], has not shown to be successful in established cases of autoimmune disorders [158] and even led to induction of autoimmunity in some experimental models [159].…”