A 1α,25-dihydroxyvitamin D3 analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice

被引:371
作者
Gregori, S
Giarratana, N
Smiroldo, S
Uskokovic, M
Adorini, L
机构
[1] BioXell, I-20132 Milan, Italy
[2] Hoffmann La Roche Inc, Dept Oncol, Nutley, NJ 07110 USA
关键词
D O I
10.2337/diabetes.51.5.1367
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Type 1 diabetes is a chronic progressive autoimmune disease characterized by mononuclear cell infiltration, dominated by interleukin-12 (IL-12)-dependent Th1 cells, of the pancreatic islets, with subsequent destruction of insulin-producing beta-cells. Here, we demonstrate that treatment of adult nonobese diabetic (NOD) mice with an analog of 1alpha,25-dihydroxyvitamin D-3, an immunomodulatory agent preventing dendritic cell maturation, decreases lipopolysaccharide-induced IL-12 and gamma-interferon production, arrests Th1 cell infiltration and progression of insulitis, and inhibits diabetes development at nonhypercalcemic doses. Arrest of disease progression is accompanied by an enhanced frequency in the pancreatic lymph nodes of CD4(+)CD25(+) regulatory T-cells that are able to inhibit the T-cell response to the pancreatic autoantigen insulinoma-associated protein 2 and to significantly delay disease transfer by pathogenic CD4(+)CD25(-) cells. Thus, a short treatment of adult NOD mice with an analog of 1,25-dihydroxyvitamin D3 inhibits IL-12 production, blocks pancreatic infiltration of Th1 cells, enhances CD4(+)CD25(+) regulatory cells, and arrests the progression of type I diabetes, suggesting its possible application in the treatment of human autoimmune diabetes.
引用
收藏
页码:1367 / 1374
页数:8
相关论文
共 51 条
[1]   Interleukin 12 and autoimmune diabetes [J].
Adorini, L .
NATURE GENETICS, 2001, 27 (02) :131-132
[2]   Checkpoints in the progression of autoimmune disease: Lessons from diabetes models [J].
Andre, I ;
Gonzalez, A ;
Wang, B ;
Katz, J ;
Benoist, C ;
Mathis, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (06) :2260-2263
[3]   The NOD mouse model of type 1 diabetes: As good as it gets? [J].
Atkinson, MA ;
Leiter, EH .
NATURE MEDICINE, 1999, 5 (06) :601-604
[4]   Cell death mediators in autoimmune diabetes - No shortage of suspects [J].
Benoist, C ;
Mathis, D .
CELL, 1997, 89 (01) :1-3
[5]   1,25-dihydroxyvitamin D3 inhibits dendritic cell differentiation and maturation in vitro [J].
Berer, A ;
Stöckl, J ;
Majdic, O ;
Wagner, T ;
Kollars, M ;
Lechner, K ;
Geissler, K ;
Oehler, L .
EXPERIMENTAL HEMATOLOGY, 2000, 28 (05) :575-583
[6]  
BHALLA AK, 1984, J IMMUNOL, V133, P1748
[7]   PARACRINE ROLE FOR CALCITRIOL IN THE IMMUNE-SYSTEM AND SKIN CREATES NEW THERAPEUTIC POSSIBILITIES FOR VITAMIN-D ANALOGS [J].
BOUILLON, R ;
GARMYN, M ;
VERSTUYF, A ;
SEGAERT, S ;
CASTEELS, K ;
MATHIEU, C .
EUROPEAN JOURNAL OF ENDOCRINOLOGY, 1995, 133 (01) :7-16
[8]  
Cantani A, 1998, J INVEST ALLERG CLIN, V8, P68
[9]   1,25-dihydroxyvitamin D-3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis [J].
Cantorna, MT ;
Hayes, CE ;
DeLuca, HF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (15) :7861-7864
[10]  
Casteels K, 1995, Curr Opin Nephrol Hypertens, V4, P313, DOI 10.1097/00041552-199507000-00005