GSBS Student Publications

Title

CD28/CD154 blockade prevents autoimmune diabetes by inducing nondeletional tolerance after effector t-cell inhibition and regulatory T-cell expansion

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Pediatrics

Date

5-22-2008

Document Type

Article

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

OBJECTIVE: Blocking T-cell signaling is an effective means to prevent autoimmunity and allograft rejection in many animal models, yet the clinical translation of many of these approaches has not resulted in the success witnessed in experimental systems. Improved understanding of these approaches may assist in developing safe and effective means to treat disorders such as autoimmune diabetes.

RESEARCH DESIGN AND METHODS: We studied the effect of anti-CD154 and CTLA4-Ig on diabetes development, and the requirements to induce tolerance in nod.scid mice after transfer of transgenic beta-cell reactive BDC2.5.NOD T-cells. RESULTS: Nod.scid recipients of diabetogenic BDC2.5.NOD cells were protected indefinitely from diabetes by a short course of combined costimulation blockade, despite the continued diabetogenic potential of their T-cells. The presence of pathogenic T-cells in the absence of disease indicates peripheral immune tolerance. T-cell maturation occurred in protected recipients, yet costimulation blockade temporarily blunted early T-cell proliferation in draining pancreatic nodes. Tolerance required preexisting regulatory T-cells (Tregs), and protected recipients had greater numbers of Tregs than diabetic recipients. Diabetes protection was successful in the presence of homeostatic expansion and high T-cell precursor frequency, both obstacles to tolerance induction in other models of antigen-specific immunity.

CONCLUSIONS: Immunotherapies that selectively suppress effector T-cells while permitting the development of natural regulatory mechanisms may have a unique role in establishing targeted long-standing immune protection and peripheral tolerance. Understanding the mechanism of these approaches may assist in the design and use of therapies for human conditions, such as type 1 diabetes.

Rights and Permissions

Citation: Diabetes. 2008 Oct;57(10):2672-83. Epub 2008 May 20. Link to article on publisher's site

DOI of Published Version

10.2337/db07-1712

Related Resources

Link to Article in PubMed

Journal Title

Diabetes

PubMed ID

18492787