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Title: Studies on the pathogenesis and prevention of insulin-dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse
Author: O'Reilly, Lorraine Ann
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1993
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The Non-obese Diabetic Mouse (NOD) spontaneously develops diabetes with many similarities to the human autoimmune disease insulin dependent diabetes mellitus (IDDM). The studies outlined in this thesis attempted to a) determine the cellular constitution of the pancreatic infiltrate (insulitis) which results in beta (β) cell destruction and insulin insufficiency b) modulate the disease by a plethora of strategies either in the adoptive transfer model (irradiated NOD males reconstituted with diabetic spleen cells, producing diabetes) or by transgenesis. Immunohistochemical analysis of transfer recipient pancreata at weekly time intervals before diabetes onset revealed a progressive influx of both the CD4+ and CD8+ T cell subpopulations with no unusual bias in T cells bearing Vβ6, Vβ8.1, Vβ8.2, or Vβ11. Class II major histocompatibility antigen (H-2) positive cells, macrophages and hyperexpression of class I MHC antigens on both pancreatic endocrine and exocrine tissues were also observed. Two subpopulations of pancreatic macrophages could be identified, one recently recruited and actively phagocytic and the other a fixed tissue population. In vivo depletion of transfer recipients with rat anti-mouse monoclonal antibodies (Mo.Ab) was used to assess the role of each particular cell type in the inflammatory process. Depletion with anti-CD4 at the time of transfer or non-depleting anti-CD4 up to 12 days after transfer was still able to arrest the infiltration of islets and prevent further β cell destruction. Administration of anti-CD8 within 2 weeks of transfer was able to prevent diabetes and halt the massive pancreatic infiltration by T cells and inflammatory macrophages. However, depletion of Vβ8-positive cells in transfer recipients showed that these T cells are not necessary for the effector phase of β cell destruction in NOD mice. Treatment of transfer recipients with 5C6,(a Mo.Ab against the CR3 receptor which prevents macrophage adhesion and migration), was able to prevent disease. This suggested an essential contribution of macrophages either as antigen presenting cells or as effector cells in the destruction of the β cell or both, although both CD4 and CDS T cells were necessary for disease manifestation. One of the cytocidal activities of macrophages is mediated by nitric oxide synthesised from L-arginine. However inhibition of this pathway with an analogue of L- arginine (L-NMMA), was unable to prevent IDDM in either transfer recipients or cyclophosphamide induced diabetes, suggesting that macrophage involvement in IDDM is not through this pathway. IDDM is under polygenic control in both man and the NOD mouse. The NOD mouse does not express the class II MHC molecule I-E and the sequence of the I-Aβ chain is unique. Introduction of an Ead transgene or of a modified I-Aβ chain prevented diabetes, hyperexpression of class I MHC antigens, pancreatic infiltration by T cells and macrophages but had no effect on submandibular gland infiltration. Thymus immunohistochemical analysis showed hyperexpression of MHC class II and germinal centres composed of B220+(B lymphocyte) CD5- cells present in abnormally large perivascular spaces in the epithelial cell matrix of NOD mice. These thymic abnormalities were not found in the CBA mouse strain, but were present in diabetes non-susceptible NOD-E transgenics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available