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


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.
Rigby
Mark R
MR
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA. mrigby@emory.edu
Trexler
Alison M
AM
Pearson
Thomas C
TC
Larsen
Christian P
CP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D016207:Cytokines; D023201:CD40 Ligand