Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects

Schloot, Nanette C.; Roep, Bart O.; Wegmann, Dale; Yu, Liping; Chase, H. Peter; Wang, T.; Eisenbarth, George S.

doi:10.1007/s001250050716

Cited by 73 publications

(99 citation statements)

References 69 publications

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“…Our data extend these findings by demonstrating that soluble self-antigens can engage Th2 responses in the presence of an established Th1 autoimmune response±allowing that the antigens used in our study be considered self-antigens since they differ from their murine counterparts by only a one amino acid conservative substitution in a region which does not comprise a T-cell determinant ( [6] and references therein). While these data Responses to control PPD (10 mg/ml) were similar in both experimental and control groups.…”

Section: Resultssupporting

confidence: 77%

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Insulin selectively primes Th2 responses and induces regulatory tolerance to insulin in pre-diabetic mice

1998

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There is conflicting information as to the existence, prevalence and phenotype of cellular immune responses to insulin in pre-diabetic rodents and humans [1±6]. Furthermore, little is known about the immunological impact of insulin administration, other than it can boost insulin autoantibody levels ([7] and references therein). The subcutaneous administration of soluble antigen has been traditionally thought to be only weakly immunogenic in naive animals, necessitating the use of adjuvants to prime significant immune responses. However, it has recently been shown that the subcutaneous administration of prototypic soluble foreign antigens can prime naive T cells toward a Th2 phenotype [8]. This finding raises the question whether the subcutaneous administration of self-antigens, such as insulin to pre-diabetic and diabetic individuals, also induces Th2 responses. If insulin administration does have an immunological impact, the nature of this response (Th1/ Th2) may depend on whether an autoimmune response to insulin is already established and the phenotype of this response. If a memory Th1 response to insulin is present in pre-diabetic and diabetic animals, insulin injection may boost this pro-inflammatory response. On the other hand, if insulin adminis- Diabetologia (1998) Summary Little is known about the immunological impact of insulin administration other than it can boost insulin autoantibody levels. In particular, while the subcutaneous administration of a soluble foreign antigen (without adjuvant) is generally only weakly immunogenic in a naive animal, it is unknown what effect the subcutaneous administration of a soluble self-antigen has in animals with established autoimmune responses to the antigen. Addressing these questions in pre-diabetic nonobese diabetic (NOD) mice, we examined the effects of administering insulin, as well as the metabolically inactive B-chain of insulin, on insulin-specific cellular and humoral immune responses. We show that pre-diabetic NOD mice have a spontaneous Th1-biased response against insulin. Administering insulin, or the insulin B-chain, rather than boosting the established Th1 response, primed Th2 cellular and humoral immunity to insulin, shifting the predominant insulin response toward a Th2 phenotype. Despite the presence of a Th1 response against insulin, insulin treated mice failed to mount proliferative T-cell responses following immunization and challenge with insulin, demonstrating that the treatment induced an active form of tolerance to this autoantigen. Thus, the subcutaneous administration of a soluble antigen can engage Th2 responses and induce self-tolerance, even after the establishment of autoreactive Th-1 responses. Such immune deviation and induced regulatory tolerance may contribute to the protective effects of prophylactic insulin therapy, as well as the establishment of a ªhoneymoonº phase in new-onset insulin-dependent diabetic patients. [Diabetologia (1998) 41: 237±240]

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Section: Resultssupporting

confidence: 77%

“…Using a high resolution ELISPOT assay we examined the nature of the spontaneous cellular autoimmune response to insulin and the immunological impact of administering insulin, as well as the metabolically inactive insulin B-chain (which contains insulin's dominant determinant ( [6] and references therein) in pre-diabetic NOD mice.…”

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confidence: 99%

Insulin selectively primes Th2 responses and induces regulatory tolerance to insulin in pre-diabetic mice

1998

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“…For instance, provided that prophylactic insulin therapy as tested in the Diabetes Prevention Trial-1 in NorthAmerica has an immunological component, in addition to a metabolic effect, there is no immunological evidence that the approach chosen in the clinical trial was appropriate [97,98,99,100,101]. Alterations in autoimmune T-cell responses to insulin can be detected following initiation of insulin therapy at diagnosis of Type 1 diabetes that suggest suppression of T-cell reactivity or induction of tolerance to insulin [22], indicating a potential benificial immunological effect of insulin therapy. Unfortunately, there are too few data on T-cell autoreactivity collected in the clinical trial to allow determining whether the dosage regimen was appropriate to generate this immunological effect.…”

Section: Immunotherapymentioning

confidence: 99%

“…Intriguingly, although the initial report contained some flaws, several additional reports describe pronounced differences and inverse correlations between T-and B-cell responses to beta-cell autoantigens including insulin, GAD65, GAD67 and ICA69 [21,22]. The contribution of autoantibodies to development of Type 1 diabetes remains to be determined.…”

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confidence: 99%

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

2003

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“…Foxp3 ͉ HLA-DRB1*0401 ͉ type 1 diabetes P roinsulin (P-Ins) is considered an important autoantigen in type 1 diabetes (T1D), because it is the only truly ␤-cellspecific target, and because autoreactivity to P-Ins is very common in T1D patients with the HLA-DRB1*0401 (DR4) DQ8 haplotype (1)(2)(3)(4)(5)(6). The differences distinguishing autoreactive from foreign antigen reactive T cell responses to the same immunogenic epitope are still largely unknown (7).…”

mentioning

confidence: 99%

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

Durinovic‐Belló

Rosinger

Ja³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Recently, we have identified proinsulin (P-Ins)73-90 as an immunodominant T cell epitope of HLA-DRB1*0401 (DR4) subjects with ␤-islet cell autoimmunity and of HLA-DR4͞CD4 double-transgenic mice immunized with human P-Ins. We have compared the fine specificities of one human CD4 T cell clone and two mouse T cell hybridoma clones recognizing this epitope, and, although these three clones all recognized the same core region (LALEGSLQK), there were major differences in how they interacted with the peptide (p)͞HLA complex, reflecting the fact that human P-Ins is a foreign antigen in the mouse and an autoantigen in the type 1 diabetes patient. The human T cell clone was forkhead transcription factor 3 (Foxp3)-positive, a marker for regulatory T cell lineages, and secreted predominantly IL-5, IL-10, and low levels of IFN␥ in response to P-Ins73-90. This finding is compatible with the previously detected regulatory cytokine pattern in subjects with ␤-cell autoimmunity. However, added N-or C-terminal amino acids drastically changed HLA and tetramer binding capacity as well as T cell reactivity and the cytokine phenotype of the P-Ins 73-90-specific human CD4 T cell clone, suggesting a potential for this P-Ins epitope as a target for therapeutic intervention in HLA-DR4-positive humans with ␤-islet cell autoimmunity or recent-onset type 1 diabetes.Foxp3 ͉ HLA-DRB1*0401 ͉ type 1 diabetes P roinsulin (P-Ins) is considered an important autoantigen in type 1 diabetes (T1D), because it is the only truly ␤-cellspecific target, and because autoreactivity to P-Ins is very common in T1D patients with the HLA-DRB1*0401 (DR4) DQ8 haplotype (1-6). The differences distinguishing autoreactive from foreign antigen reactive T cell responses to the same immunogenic epitope are still largely unknown (7). To understand the structural requirements for activation of self-reactive P-Ins 73-90 -specific T cells in T1D autoimmunity, we have isolated a Foxp3-positive CD4 ϩ T cell clone from a DR4-homozygous T1D patient and compared the fine specificity of this T cell receptor to those of two murine T cell hybridoma clones derived from HLA-DR4 transgenic mice, in which this epitope is a foreign antigen (8). P-Ins 73-90 is situated at the C terminus of the C peptide and also covers the enzymatic cleavage site of the insulin A chain (8). This site is proteolytically destroyed during the maturation of insulin before secretion and is, therefore, an indication that Proinsulin and not Insulin may be the actual autoantigenic target in T1D.In human studies using purified CD4 ϩ T cells from HLA-DR4-positive subjects with islet autoimmunity, P-Ins 73-90 was also identified as an immunodominant epitope. This epitope was recognized by approximately two thirds of autoantibody-positive subjects, one third of recently diagnosed T1D patients, and a few control subjects (5, 9). The cytokines seen in response to P-Ins 73-90 were predominantly IL-4 and IL-10 in subjects with ␤-cell autoimmunity (9). Moreover, in a consecutive follow up of three high-risk individuals, ...

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Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects

Cited by 73 publications

References 69 publications

Insulin selectively primes Th2 responses and induces regulatory tolerance to insulin in pre-diabetic mice

Insulin selectively primes Th2 responses and induces regulatory tolerance to insulin in pre-diabetic mice

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

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