The Effect of Local Production of Cytokines in the Pathogenesis of Insulin-Dependent Diabetes Mellitus

Falcone, Marika; Sarvetnick, Nora

doi:10.1006/clim.1998.4619

Cited by 31 publications

(13 citation statements)

References 98 publications

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“…Studies in nonobese diabetic (NOD) mice, an animal model for the human disease, have shown that they develop spontaneous proliferative T cell response to several ␤ cell autoantigens and resulted in ␤ islet destruction (1, 2, 4 -8). It is hypothesized that diabetes development in NOD mice is due to the loss of tolerance to autoantigens and a biased activation of Th1 cells may enhance diabetes, whereas Th2 cells inhibit the disease (2,5,9). Therefore, inhibition of Th1 cell-mediated immune response and restoration of tolerance to autoantigens and induction of Th2 cell differentiation may prevent disease development (5,10).…”

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confidence: 99%

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

Chen

Lee

Yun

et al. 2003

The Journal of Immunology

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Autoantigen-based immunotherapy can modulate autoimmune diabetes, perhaps due to the activation of Ag-specific regulatory T cells. Studies of these regulatory T cells should help us understand their roles in diabetes and aid in designing a more effective immunotherapy. We have used class II MHC tetramers to isolate Ag-specific T cells from nonobese diabetic (NOD) mice and BALB/c mice treated with glutamic acid decarboxylase 65 peptides (p206 and p221). Based on their cytokine secretion profiles, immunization of NOD mice with the same peptide induced different T cell subsets than in BALB/c mice. Treatment of NOD mice induced not only Th2 cells but also IFN-γ/IL-10-secreting T regulatory type 1 (Tr1) cells. Adoptive transfer experiments showed that isolated tetramer+ T cells specific for p206 or p221 could inhibit diabetes development. These cells were able to suppress the in vitro proliferation of other NOD mouse T cells without cell-cell contact. They performed their regulatory functions probably by secreting cytokines, and Abs against these cytokines could block their suppressive effect. Interestingly, the presence of both anti-IL-10 and anti-IFN-γ could enhance the target cell proliferation, suggesting that Tr1 cells play an important role. Further in vivo experiments showed that the tetramer+ T cells could block diabetogenic T cell migration into lymph nodes. Therefore, treatment of NOD mice with autoantigen could induce Th2 and Tr1 regulatory cells that can suppress the function and/or block the migration of other T cells, including diabetogenic T cells, and inhibit diabetes development.

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confidence: 99%

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

Chen

Lee

Yun

et al. 2003

The Journal of Immunology

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“…T cell loss by activation-induced cell death did not occur in the spleen or in vitro. A number of investigators using Tg nonobese diabetic mice, constitutively expressing a variety of cytokines under the control of the insulin promoter, have demonstrated that the determination of immunity vs peripheral tolerance does not take place in the islet, but within the draining LNs of the pancreas (12). Tg expression of TNF-␣, LT␣, or LT␤ in the pancreas results in lymphocyte accumulation and lymphoid neogenesis, through regulation of secondary lymphoid tissue chemokine, EBV-induced molecule 1 ligand chemokine, B lymphocyte chemoattractant, and secondary lymphoid organ development.…”

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confidence: 99%

L-Selectin-Dependent Lymphoid Occupancy Is Required to Induce Alloantigen-Specific Tolerance

Bai

Liu

Wang

et al. 2002

The Journal of Immunology

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Maneuvers that interfere with signals 1, 2, 3, or Ag processing can result in indefinite allograft survival. However, they are not applicable to all tissues, strains, or species, suggesting that there are additional levels of immune regulation. We hypothesized that secondary lymphoid organs are important for interactions among lymphocytes, alloantigen, and immunosuppressants that lead to tolerance. To explore this, cardiac allografts were performed with a tolerogenic immunosuppressive regimen. Concurrent administration of anti-L-selectin (CD62L) Ab, which prevents lymph node homing, prevents indefinite allograft survival and tolerance. Anti-CD62L Ab is not costimulatory, and Fab and F(ab′)2 anti-CD62L have similar activities. Flow cytometry and histologic examination show that Ab shifts T cells away from lymph nodes and into spleen, peripheral blood, and graft. Tolerance is not induced in CD62L−/− mice, and adoptive transfer of CD62L−/−, but not CD62L+/+, T cells prevents tolerization in wild-type recipients. FTY720, an immunosuppressant that promotes chemokine-dependent, but CD62L-independent, lymph node homing, reverses the Ab effect. Blockade of other homing receptors also prevents tolerization. These results indicate that T lymphocytes use CD62L-dependent migration for alloantigen-specific tolerance, and suggest that lymph nodes or other lymphoid tissues are an important site for peripheral tolerization to alloantigen.

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“…This early graft loss is most probably due to high inflammation levels locally in the is- Transplantation trauma is suggested to lead to some degree of organ injury and cell death, most often related to an acute storm of many macrophage-derived cytokines, reactive oxygen and nitrogen intermediates. All of these products have the potential of further damaging the grafted islet cells [24,25,26]. Additionally, autoimmune-prone diabetic mice are reported to have intrinsic defects in their macrophages, such as anomalies in cell maturation, antigen presentation, antigen processing and accessory cell function [14,27].…”

Section: Discussionmentioning

confidence: 99%

Prevention of primary non-function of islet xenografts in autoimmune diabetic NOD mice by anti-inflammatory agents

Gysemans¹,

Stoffels²,

Giulietti³

et al. 2003

Diabetologia

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Aims/hypothesis. High levels of inflammation locally in the graft during the initial days after transplantation can cause primary non-function (PNF) of grafted xenogeneic islets in NOD mice. The aim of this study was to explore in a model of spontaneous diabetes, the NOD mouse, the potential of anti-inflammatory agents in the prevention of PNF after xenogeneic islet transplantation. Methods. Spontaneously diabetic NOD mice were transplanted with 300 rat islets. Animals were treated with acetylsalicylic acid (AsA), rofecoxib, TGF-β or IL-1 receptor antagonist (IL-1ra). Intra-graft expression of inflammation-related molecules was measured by real time PCR 8 h post-transplantation. At the same time point, plasma nitrite levels were measured. Results. Xenogeneic islets transplanted in control spontaneously diabetic mice resulted in PNF in 16 out of 38 mice (42%). Initial graft loss was not altered by administration of rofecoxib (30%) or TGF-β (25%).AsA reduced the rate of rapid graft loss to 8% (p<0.05 vs controls) and administration of IL-1ra even totally prevented PNF (0%, p<0.05 vs controls). Furthermore, all therapies prolonged the mean survival time of xenogeneic islet grafts. The inhibition of PNF by AsA was associated with decreased intra-islet levels of inflammation-related molecules (IL-1, TNF-α, iNOS, COX-2) and chemokines (MCP-1 and MIP-3α). Finally, also a diminished production of systemic nitrite levels was observed in AsA-and IL-1ra-treated islet recipients. Conclusions/Interpretation. These data show that treatment with AsA or IL-1ra prevents PNF after islet transplantation in spontaneously diabetic NOD mice. Moreover, the involvement of non-specific inflammation is recognized in xenogeneic islet PNF in spontaneously diabetic NOD mice. [Diabetologia (2003[Diabetologia ( ) 46:1115[Diabetologia ( -1123

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The Effect of Local Production of Cytokines in the Pathogenesis of Insulin-Dependent Diabetes Mellitus

Cited by 31 publications

References 98 publications

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

L-Selectin-Dependent Lymphoid Occupancy Is Required to Induce Alloantigen-Specific Tolerance

Prevention of primary non-function of islet xenografts in autoimmune diabetic NOD mice by anti-inflammatory agents

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