Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23).

Abstract

The observation that overt type I diabetes is often preceded by the appearance of insulin autoantibodies and the reports that prophylactic administration of insulin to biobreeding diabetes-prone (BB-DP) rats, nonobese diabetic (NOD) mice, and human subjects results in protection from diabetes suggest that an immune response to insulin is involved in the process of beta cell destruction. We have recently reported that islet-infiltrating cells isolated from NOD mice are enriched for insulin-specific T cells, that insulin-specific T cell clones are capable of adoptive transfer of diabetes, and that epitopes present on residues 9-23 of the B chain appear to be dominant in this spontaneous response. In the experiments described in this report, the epitope specificity of 312 independently isolated insulin-specific T cell clones was determined and B-(9-23) was found to be dominant, with 93% of the clones exhibiting specificity toward this peptide and the remainder to an epitope on residues 7-21 of the A chain. On the basis of these observations, the effect of either subcutaneous or intranasal administration of B-(9-23) on the incidence of diabetes in NOD mice was determined. The results presented here indicate that both subcutaneous and intranasal administration of B-(9-23) resulted in a marked delay in the onset and a decrease in the incidence of diabetes relative to mice given the control peptide, tetanus toxin-(830-843). This protective effect is associated with reduced T-cell proliferative response to B-(9-23) in B-(9-23)-treated mice.It is now well established that insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder in which the insulin-producing beta cells are specifically destroyed. Although the available data indicate that T cells are the predominant mediators of beta cell destruction (1-4), overt diabetes is often preceded by the appearance of circulating antibodies specific to a number of beta cell products, among which is insulin (5). Insulin autoantibodies (IAAs) have been found in many new onset diabetic subjects prior to the administration of exogenous insulin (5) and have been found to precede the onset of diabetes by many years in certain individuals. The nonobese diabetic (NOD) mouse, which develops IDDM with many similarities to the human disease, is considered to be a good model of type I diabetes (6, 7), and IAAs have also been found to be present in NOD mice prior to the onset of diabetes (8-10). The presence of IAAs implies that there is also a T-cell response to this antigen, and although NOD mice can respond to insulin when immunized with insulin (11), attempts to demonstrate spontaneous T-cell responses to insulin in NOD mice have failed (12). In contrast, results from our laboratory indicate that T-cell responses to insulin arise spontaneously in NOD mice but that insulinspecific T cells are sequestered within the islet infiltrates characteristic of the disease process in these mice (13). More detailed investigations have revealed that insulin-specific T The publicatio...

Key Sequences Involved in the Spreading of the Systemic Autoimmune Response to Spliceosomal Proteins

“…In the case of chromatin, Datta et al have shown that a brief therapy of 3-month-old prenephritic SNF1 mice with peptide 16±39 from histone H4 (a peptide that contains a Th epitope recognized by CD4 1 T cells from SNF1 mice) had a tolerogenic effect on autoimmune T and B cells, and markedly delayed the onset of severe lupus nephritis [68]. Other examples have been described in EAE and type I diabetes [69,70]. These results are of considerable interest because it was not expected that a single peptide could control the diversified autoimmune response observed in such diseases.…”

Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase

“…In Type I diabetes, GAD and insulin have been identified as major autoantigens and tolerisation against these autoantigens has been attempted as a method for the prevention of the disease [14,32]. It has been reported that administration of purified GAD protein or peptide or insulin protein or peptide to NOD mice by a variety of routes can tolerise the T cell-mediated immune response against pancreatic beta cells, resulting in the prevention or delay of the development of insulitis and diabetes [28,29,33,34,35,36,37,38,39]. In many cases, the preventive effect was found to be associated with a Th2 shift [14,32].…”

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

“…In NOD mice, several peptides from these autoantigens have been identified as targets of T cell responses. These include GAD65 p524-543 and p246-266 [1, 2], GAD65 p206-220 and p286-300 [3], insulin B chain p9-23 [4,5], proinsulin p24-33 (proinsulin II p48-57) [6],, and insulin-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) p206-214 [8]. Extensive analysis of TCR BV gene usage and CDR3 sequences have demonstrated that the early islet-infiltrating T cell clonal expansion is restricted to distinct BV families, e.g., BV4 [9], BV2, BV12, BV14 [10], BV13 [11], BV8.2 [12], and BV1 [13].…”