Insulin prevents adoptive cell transfer of diabetes in the autoimmune non-obese diabetic mouse

Thivolet, Charles; Goillot, Evelyne; Bédossa, Pierre; Durand, Annie; Bonnard, Maurice; Orgiazzi, Jacques

doi:10.1007/bf00405002

Cited by 58 publications

(30 citation statements)

References 22 publications

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“…With regard to the progression of insulitis in the NOD mouse, we confirmed the effect of prophylactic insulin treatment in lowering the severity of destructive insulitis [13,14]. Moreover, we showed that if the effect of the treatment on the infiltrative lymphocytic insulitis, as assessed by H+E staining, was not detectable at 9 weeks of age, it became clearly visible and significant at 13 weeks of age.…”

Section: Discussionsupporting

confidence: 63%

“…The same improvement was observed in different animal models of type 1 diabetes, either induced by neonatal streptozotocin [9], or the spontaneous models, the BB rat [10][11][12] and the NOD mouse [13]. In both the BB rat and the NOD mouse prophylactic insulin treatment not only prevented spontaneous disease, but transfer of diabetes to young pre-diabetic animals was also inhibited [14,15].…”

Section: Introductionsupporting

confidence: 58%

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Effect of Prophylactic Insulin Treatment on the Number of ER-MP23+Macrophages in the Pancreas of NOD Mice. Is the Prevention of Diabetes Based on β-cell Rest?

Jansen

Rosmalen

Homo‐Delarche

et al. 1996

Journal of Autoimmunity

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Prophylactic insulin treatment has been shown to have beneficial effects in type 1 diabetes, both in humans and in various animal models of the disease. In experimental models, the protective effect of prophylactic insulin treatment was observed in two parameters: (1) progression of insulitis and (2) diabetes incidence. The mechanism of protection still remains to be investigated. We therefore analysed by immunohistochemistry the effect of prophylactic insulin treatment vs placebo treatment (from 4 to 13 weeks of age) on ER-MP23 + macrophage infiltration in and around pancreatic islets in the non-obese diabetic (NOD) mouse, a spontaneous model for type 1 diabetes. BALB/c mice were used as diabetes-free controls. Using conventional haematoxylin-eosin staining, we detected a protective effect of prophylactic insulin treatment in NOD females on the lymphocytic insulitis, significant at 13 weeks, but not at 9 weeks of age. However, when assessed by immunostaining for early infiltration of ER-MP23 + macrophages around islets, the reduction in severity of insulitis could already be detected as early as 9 weeks of age. With regard to the early accumulation of ER-MP23 + cells, we observed that their numbers per mm 2 surface area of the exocrine pancreas and per m at the circumference of the islet were higher in placebo-treated NODs (197±13.8 and 14±0.9, respectively) as compared to age-matched BALB/c mice (123.1±7.1 and 3.5±0.9, respectively). Prophylactic insulin treatment of NODs lowered the attraction of ER-MP23 + macrophages to the exocrine pancreas and to the circumference of the islets (156.3±8.5 and 7.9±1, respectively). Interestingly also, the islet size was found to be larger in placebo-treated NODs (51% was larger than 10 m 2 ) than in age-matched BALB/c mice (9% larger than 10 m 2 ). Prophylactic insulin treatment of NODs reduced their islet size to sizes found in the control BALB/c strain. In conclusion, the decrease in islet size by early insulin administration, and the lower attraction of ER-MP23 + macrophages to the islets are morphological indications that prevention of diabetes development by prophylactic insulin treatment results from a downregulation of islet metabolism and growth, with a concomitant decline in the release of islet factors attracting macrophages.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionsupporting

confidence: 58%

Effect of Prophylactic Insulin Treatment on the Number of ER-MP23+Macrophages in the Pancreas of NOD Mice. Is the Prevention of Diabetes Based on β-cell Rest?

Jansen

Rosmalen

Homo‐Delarche

et al. 1996

Journal of Autoimmunity

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“…The same caveat applies to mouse adoptive transfer models, which documented a similar protective effect, but with no off-treatment follow-up period [25,26]. Indeed, in the study by Thivolet et al [26] protection was associated with significant hypoglycaemia, similar to the values we observed, and was lost upon early treatment discontinuation.One major question remains unanswered: by which mechanisms does β-cell rest exert its protective effect? Two major hypotheses can be proposed.…”

supporting

confidence: 72%

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

2012

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Despite encouraging results in the NOD mouse, type 1 diabetes prevention trials using subcutaneous insulin have been unsuccessful. To explain these discrepancies, 3-weekold NOD mice were treated for 7 weeks with subcutaneous insulin at two different doses: a high dose (0.5 U/mouse) used in previous mouse studies; and a low dose (0.005 U/mouse) equivalent to that used in human trials. Effects on insulitis and diabetes were monitored along with immune and metabolic modifications. Low-dose insulin did not have any effect on disease incidence. High-dose treatment delayed but did not prevent diabetes, with reduced insulitis reappearing once insulin discontinued. This effect was not associated with significant immune changes in islet infiltrates, either in terms of cell composition or frequency and IFN-γ secretion of islet-reactive CD8 + T cells recognizing the immunodominant epitopes insulin B 15-23 and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) [206][207][208][209][210][211][212][213][214] . Delayed diabetes and insulitis were associated with lower blood glucose and endogenous C-peptide levels, which rapidly returned to normal upon treatment discontinuation. In conclusion, high-but not low-dose prophylactic insulin treatment delays diabetes onset and is associated with metabolic changes suggestive of β-cell "rest" which do not persist beyond treatment. These findings have important implications for designing insulin-based prevention trials.Keywords: Insulin r NOD mouse r Prevention r T cells r Type 1 diabetes IntroductionType 1 diabetes (T1D) is an autoimmune disease in which failures in central and peripheral tolerance mechanisms lead to T-cellmediated destruction of insulin-producing β cells. Several β-cell Ags have been identified, among which insulin and its precursor (pre)proinsulin ((pre)PI) are major targets of islet-reactive T cells, both in humans [1] and in NOD mice [2]. This led to the Correspondence: Dr. Roberto Mallone e-mail: roberto.mallone@inserm.fr hypothesis that subcutaneous insulin administration could prevent disease, the rationale of which is twofold. First, insulin administration could induce a state of "β-cell rest" that would make β cells less vulnerable to metabolic stress, apoptosis [3], and possibly to immune-mediated destruction [4]. Second, repeated subcutaneous insulin injections could act as a vaccination protocol potentially restoring immune tolerance [5]. The relative role of these two putative mechanisms remains unsettled.Studies in the NOD mouse showed that subcutaneously administered insulin, started prior to disease development, is capable of preventing insulitis and diabetes [6]. This observation prompted the Diabetes Prevention Trial-Type 1 (DPT-1) [7] Eur. J. Immunol. 2012. 42: 1553-1561 developing disease [8]. However, both trials were unsuccessful, as no difference in T1D incidence was observed between insulinand placebo-treated individuals [7,8].It is still not clear why this translation from animal studies to human clinical trials fail...

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“…Cell-mediated responses to insulin in peripheral blood are weak [6][7][8][9][10][11][12][13], but insulinspecific T cell clones isolated from animal models of diabetes have been shown to transfer disease [14]. Moreover, treatments with intravenous, subcutaneous, oral or intranasal insulin have been shown to prevent or delay disease onset in animals and in humans [15][16][17][18][19]. Thus insulin, or its prohormone proinsulin, is considered an important early autoimmune target in type 1 diabetes, and has therefore a potential role in antigen-specific immunotherapy [20].…”

Section: Introductionmentioning

confidence: 99%

Autoimmune responses to the β cell autoantigen, insulin, and the INS VNTR-IDDM2 locus

Sarugeri

Dozio²,

Belloni³

et al. 1998

Clinical and Experimental Immunology

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SUMMARYType 1 diabetes is associated with autoimmunity to insulin. Genetic susceptibility to type 1 diabetes is polygenic and includes the INS VNTR-IDDM2 locus which may regulate the expression of insulin in pancreas and thymus. In order to determine whether insulin autoimmunity could be attributed to a genetic susceptibility conferred by the INS VNTR-IDDM2 locus, peripheral blood T cell proliferation to human insulin and insulin autoantibodies (IAA) was measured in patients with new onset type 1 diabetes and control subjects. IAA were detected in 21 of 53 patients and in none of 25 control subjects, while T cell responses were low (stimulation index range 0·4-7·2) and similar in both groups. Both antibody and T cell responses were higher in younger subjects and IAA were more prevalent in patients with the HLA-DR4 allele. No relationship was observed between humoral and cellular responses to insulin. No association was found between the INS VNTR-IDDM2-susceptible allele and insulin autoimmunity. Increased T cell responses and IAA were found in patients with either the diabetes-susceptible or the diabetes-protective INS VNTR-IDDM2 locus genotypes, and increased T cell responses were also found in control subjects with either susceptible or protective INS VNTR-IDDM2 locus genotypes. This study confirms that primary T cell proliferative responses to insulin are low and detectable also in control subjects. The detection of T cell proliferation and autoantibodies to insulin in subjects with and without the protective INS VNTR-IDDM2 locus genotypes does not support the hypothesis of an allele-specific capacity for tolerance induction which could determine a susceptibility to develop autoimmunity against the insulin protein and subsequently diabetes.

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Insulin prevents adoptive cell transfer of diabetes in the autoimmune non-obese diabetic mouse

Cited by 58 publications

References 22 publications

Effect of Prophylactic Insulin Treatment on the Number of ER-MP23+Macrophages in the Pancreas of NOD Mice. Is the Prevention of Diabetes Based on β-cell Rest?

Effect of Prophylactic Insulin Treatment on the Number of ER-MP23+Macrophages in the Pancreas of NOD Mice. Is the Prevention of Diabetes Based on β-cell Rest?

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

Autoimmune responses to the β cell autoantigen, insulin, and the INS VNTR-IDDM2 locus

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