Prevention of Autoimmune Destruction of Syngeneic Islet Grafts in Spontaneously Diabetic Nonobese Diabetic Mice by a Combination of Avitamin D3 Analog and Cyclosporine1

Casteels, Kristina; Waer, Mark; Laureys, Jozef; Valckx, Dirk; Depovere, Jos; Bouillon, Roger; Mathieu, Chantal

doi:10.1097/00007890-199805150-00014

Cited by 101 publications

(81 citation statements)

References 26 publications

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“…Diabetic NOD mice transplanted with syngeneic islets show early recurrence of the disease [38,39]. Histological analysis indicates severe infiltration and destruction of more than 50% of the grafts already 6 days after transplantation [38].…”

Section: Discussionmentioning

confidence: 99%

“…Histological analysis indicates severe infiltration and destruction of more than 50% of the grafts already 6 days after transplantation [38]. Both CD4+ and CD8+ T-cells producing Th1-type cytokines (principally IFN-γ), are involved in the destruction of beta cells [39].…”

Section: Discussionmentioning

confidence: 99%

“…For mRNA analysis in islets from native pancreases, islets were prepared from 2-to 12-week-old male and female NOD mice as well as from 4-week-old male and female BALB/c mice [38]. Islets were isolated from the pancreas by collagenase digestion in cold Hank's salt solution followed by hand picking under a stereomicroscope.…”

Section: Isolation and Transplantation Of Islets From Nod Micementioning

confidence: 99%

“…For syngeneic islet transplantation into diabetic NOD mice (an experimental model for the recurrence of autoimmune beta-cell destruction, [38,39]), 2-or 3-week-old NOD islets (n=500) were grafted after avertin anesthaesia under the left kidney capsule of both male and female spontaneously diabetic NOD recipients, ranging in age from 4 to 6 months. Note that 2-or 3-week-old NOD mice from our colony were normoglycaemic and did not have detectable insulitis [8].…”

Section: Isolation and Transplantation Of Islets From Nod Micementioning

confidence: 99%

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IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

et al. 2003

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Aims/hypothesis. Cytokines and chemokines are important mediators of immune responses due to their ability to recruit and activate leukocytes. Using microarray analysis we observed that rat beta cells exposed to IL-1β and IFN-γ have increased mRNA levels of chemokines and IL-15. The aim of this study was to characterize the expression of IP-10, MIP-3α, fractalkine and IL-15 in rat beta cells, human pancreatic islets, and in islets isolated from NOD mice, both during the pre-diabetic period and following islet transplantation. Methods. FACS-purified rat beta cells and human islets were cultured with IL-1β, IFN-γ and/or TNF-α. Islets were isolated from NOD or BALB/c mice at different ages. For syngeneic islet transplantation, 2-or 3-week-old NOD islets were grafted under the kidney capsule of spontaneously diabetic NOD recipients. Chemokine and IL-15 mRNA expression and protein release were evaluated, respectively, by RT-PCR and ELISA.Results. Human islets and rat beta cells express IP-10, MIP-3α, fractalkine and IL-15 mRNAs upon exposure to cytokines. The expression of IL-15, IP-10 and fractalkine is regulated by IFN-γ, while the expression of MIP-3α is IL-1β-dependent. Moreover, cytokines induced IL-15, IP-10, Mig, I-TAC and MIP-3α protein accumulation in culture medium from human islets. In vivo, there was an age-related increase in IL-15, IP-10 and MIP-3α expression in islets isolated from NOD mice. Following syngeneic islet transplantation, increased expression of IL-1β, IFN-γ, fractalkine, IP-10, MCP-1 and MIP-3α mRNAs were observed in the grafts. Conclusion/interpretation. Cytokine-exposed islets or beta cells express chemokines and IL-15. This could contribute to the recruitment and activation of mononuclear cells and development of insulitis in early Type 1 diabetes and during graft destruction. [Diabetologia (2003) 46:255-266] Keywords Type 1 diabetes mellitus, chemokines, IL-15, NOD mice, beta cells, interferon-γ, interleukin-1β, pancreatic islets, islet transplantation, insulitis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Isolation and Transplantation Of Islets From Nod Micementioning

confidence: 99%

Section: Isolation and Transplantation Of Islets From Nod Micementioning

confidence: 99%

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IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

et al. 2003

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“…Our group has previously demonstrated that both insulitis and diabetes can be prevented or arrested in NOD mice by administration of 1␣,25(OH) 2 D 3 (26) or its nonhypercalcemic analogs (29). Moreover, recurrence of disease after syngeneic islet transplantation can be prevented by administration of these nonhypercalcemic analogs in combination with low doses of cyclosporin A (30). These studies also demonstrate that 1␣,25(OH) 2 D 3 induces an immune shift locally in the pancreas as well as in transplanted islet grafts that is characterized by downregulation of the Th1 cytokines and upregulation of Th2 cytokines.…”

mentioning

confidence: 99%

1alpha,25-dihydroxyvitamin D3 induces an autoantigen-specific T-helper 1/T-helper 2 immune shift in NOD mice immunized with GAD65 (p524-543).

et al. 2000

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Prevention of type 1 diabetes in NOD mice by 1,25-dihydroxyvitamin D 3 [1␣,25(OH) 2 D 3 ] is accompanied by a T-helper (Th) 1/Th2 cytokine shift in the pancreas. The aim of this study was to investigate whether this immune shift also occurs outside of the pancreas and whether it is limited to autoantigen-specific immune responses. NOD mice treated with 1␣,25(OH) 2 D 3 (5 µg/kg every 2 days) or control vehicle were immunized with GAD65 (p524-543) or ovalbumin (OVA) in the rear footpads. First, we examined T-cell proliferation and cytokine production (via enzyme-linked immunosorbent assay) of draining lymph node cells in vitro with or without peptide rechallenge. Although no differences in proliferation were measured between control and 1␣,25(OH) 2 D 3 -treated mice after in vitro GAD65 rechallenge, a marked shift in cytokine secretion profile was seen in 1␣,25(OH) 2 D 3 -treated mice: interleukin-4 was increased (37 ± 5 vs. 21 ± 12 pg/ml in controls, P < 0.005), whereas ␥-interferon levels were decreased (6 ± 3 vs. 9 ± 3 ng/ml in controls, P < 0.05). This shift was absent in OVA-primed mice. Second, we measured cytokine profiles by reverse transcriptase-polymerase chain reaction in popliteal lymph nodes at different time points after priming with GAD65 or OVA in vivo. A marked Th1/Th2 shift occurred in 1␣,25(OH) 2 D 3 -treated mice after in vivo priming with GAD65. Again, this shift was absent after OVA immunization. Finally, we measured cytokine profiles after rechallenge with a panel of autoantigens (GAD65, heat shock protein 65, insulin Bchain) and control antigens (OVA, keyhole limpet hemocyanine, myelin proteolipid protein, tetanus toxin) and confirmed the Th1/ Th2 shift in autoantigen-injected mice but not in control antigen-injected mice. In conclusion, the immune deviation induced by 1␣,25(OH) 2 D 3 in NOD mice can also be induced in the peripheral immune system but is limited to pancreatic autoantigens.

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1,25‐Dihydroxyvitamin D ₃ and its Dissociated Analogs as Modulators of Vitamin D Receptor Action

May

Steinmeyer

Asadullah

et al. 2008

Methods and Principles in Medicinal Chemistry

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Prevention of Autoimmune Destruction of Syngeneic Islet Grafts in Spontaneously Diabetic Nonobese Diabetic Mice by a Combination of Avitamin D3 Analog and Cyclosporine1

Abstract: KH1060, an analog of 1,25(OH)2D3, delays autoimmune disease recurrence after syngeneic islet transplantation in NOD mice, both alone and especially in combination with CsA, possibly restoring tolerance to beta cells in 30% of cases.

Cited by 101 publications

References 26 publications

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

1alpha,25-dihydroxyvitamin D3 induces an autoantigen-specific T-helper 1/T-helper 2 immune shift in NOD mice immunized with GAD65 (p524-543).

1,25‐Dihydroxyvitamin D ₃ and its Dissociated Analogs as Modulators of Vitamin D Receptor Action

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Prevention of Autoimmune Destruction of Syngeneic Islet Grafts in Spontaneously Diabetic Nonobese Diabetic Mice by a Combination of Avitamin D3 Analog and Cyclosporine1

Abstract: KH1060, an analog of 1,25(OH)2D3, delays autoimmune disease recurrence after syngeneic islet transplantation in NOD mice, both alone and especially in combination with CsA, possibly restoring tolerance to beta cells in 30% of cases.

Cited by 101 publications

References 26 publications

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

1alpha,25-dihydroxyvitamin D3 induces an autoantigen-specific T-helper 1/T-helper 2 immune shift in NOD mice immunized with GAD65 (p524-543).

1,25‐Dihydroxyvitamin D 3 and its Dissociated Analogs as Modulators of Vitamin D Receptor Action

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1,25‐Dihydroxyvitamin D ₃ and its Dissociated Analogs as Modulators of Vitamin D Receptor Action