Publications & Reports

Remission and pancreas isograft survival in recent onset diabetic NOD mice after treatment with low-dose anti-CD3 monoclonal antibodies.

Mottram PL, Murray-Segal LJ, Han W, Maguire J, Stein-Oakley AN
The Austin Research Institute, Heidelberg, Victoria, Australia. [email protected]

Abstract

Diabetes in NOD mice is an autoimmune disease similar to Type I diabetes in humans. Prior to hypoglycemia, changes in the islet infiltrate led to autoreactive T cell activation and destruction of the insulin-producing beta cells. If T cell activation can be inhibited before beta cell destruction is complete, islet cell rescue and regeneration can occur. Female NOD mice > 100 days old with blood glucose levels > 20 mM/l for less than 7 days were selected as ‘recent onset’ mice. Untreated, all of these animals would die of diabetes in < 40 days. Mice treated with anti-CD4 (GK1.5) achieved 14.3% permanent remission, while those treated with anti-CD8 (53.6.7) showed 33.3% permanent remission. Mice treated with anti-CD3 (145-2C1) also achieved 33.3% permanent remission, but 14% of these died of first dose syndrome. In mice treated with a low dose of anti-CD3 (10 microg KT3), which did not induce first dose syndrome, 50% remained in remission for > 100 days. This dose of mAb reduced insulitis but did not deplete splenic CD3 cells. When mice in remission were challenged with a vascularized pancreas isograft at 50 days, 9/22 remained normal and 13/22 had recurrent disease in both transplanted and native pancreas. Of the long-surviving isografts 7/9 were in KT3 treated recipients. Histology showed activated T cell infiltration in the native and transplanted pancreases of mice with transient remission. Benign insulitis with macrophages, B cells, CD4 > CD8 T cells and low levels of IL-2R, IL-2, IFN-gamma and IL-4 was seen in islets from the native pancreas and in long surviving pancreas isografts in mice that remained in remission. Thus, using low dose KT3, it was possible to halt the development of diabetes in 50% of animals treated soon after diagnosis, despite significant islet cell destruction at this stage. Of the KT3 treated mice in permanent remission, 70% had re-established tolerance to autoantigen and did not destroy vascularized pancreas isografts.

Publication

  • Journal: Transplant Immunology
  • Published: 01/06/2002
  • Volume: 10
  • Issue: 1
  • Pagination: 63-72

Author