RGD Reference Report - Human LT-alpha-mediated resistance to autoimmune diabetes is induced in NOD, but not NOD-scid, mice and abrogated by IL-12. - Rat Genome Database

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Human LT-alpha-mediated resistance to autoimmune diabetes is induced in NOD, but not NOD-scid, mice and abrogated by IL-12.

Authors: Miyaguchi, S  Satoh, J  Takahashi, K  Sakata, Y  Nakazawa, T  Miyazaki, J  Toyota, T 
Citation: Miyaguchi S, etal., Clin Immunol. 2001 Jan;98(1):119-24.
RGD ID: 2313263
Pubmed: PMID:11141334   (View Abstract at PubMed)
DOI: DOI:10.1006/clim.2000.4954   (Journal Full-text)

Systemic administration of human lymphotoxin-alpha (hLT-alpha) made NOD mice resistant not only to spontaneous autoimmune type 1 diabetes mellitus but also to cyclophosphamide (CY)-induced diabetes and diabetes transfer by diabetic NOD spleen cells (triple resistance). In this study we analyzed the mechanisms of hLT-alpha-induced resistance, focusing on (1) hLT-alpha-induced resistance in the pancreatic beta cell, (2) CY-resistant suppressor cells, (3) suppression of induction or function of effector cells for beta cell destruction, or (4) others. To examine the first possibility in vitro, a NOD-derived beta cell line (MIN6N) was pretreated with hLT-alpha and then mixed with diabetic NOD spleen cells and MIN6N cell viability was measured. Treatment with hLT-alpha did not protect MIN6N cells but rather enhanced cytotoxicity. Next NOD-scid mice were pretreated with hLT-alpha and then transferred with diabetic NOD spleen. All the recipients developed diabetes. These results excluded the first possibility. The second possibility was also excluded by a cotransfer experiment, in which diabetic NOD spleen cells were cotransferred to NOD-scid mice with nontreated or hLT-alpha-treated nondiabetic NOD spleens. There was no significant difference in diabetes incidence between the two groups. To observe the third possibility, spleen cells of hLT-alpha-treated triple-resistant NOD mice were transferred to NOD-scid mice. Diabetes developed in the recipients, although the onset of diabetes was slightly delayed. Finally, hLT-alpha-treated triple-resistant NOD mice developed diabetes 1 week after daily IL-12 treatment. In summary, hLT-alpha administration made NOD mice resistant to effector cells for beta cell destruction. This resistance was induced in NOD, but not in NOD-scid, mice, indicating that lymphocytes were obligatory for the resistance. However, it was not mediated by transferable suppressor cells. Because effector cells were present in hLT-alpha-treated NOD spleen and the resistance was abrogated by IL-12 treatment, it is speculated that hLT-alpha treatment may have changed a local cytokine balance protective from beta cell destruction.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
LTAHumantype 1 diabetes mellitus  IMP  RGD 
LtaRattype 1 diabetes mellitus  ISOLTA (Homo sapiens) RGD 
LtaMousetype 1 diabetes mellitus  ISOLTA (Homo sapiens) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Lta  (lymphotoxin alpha)

Genes (Mus musculus)
Lta  (lymphotoxin A)

Genes (Homo sapiens)
LTA  (lymphotoxin alpha)


Additional Information