Diabetes, Vol 57, pp 405-414, 2008
Murine Antithymocyte Globulin Therapy Alters Disease Progression in NOD Mice by a Time-Dependent Induction of Immunoregulation
Simon G, et al
OBJECTIVE—Antilymphocyte serum can reverse overt type1 diabetes in NOD mice; yet, the therapeutic parameters andimmunological mechanisms underlying the ability for this agentto modulate autoimmune responses against β-cells are unclear,forming the rationale for this investigation.
RESEARCH DESIGN AND METHODS—A form of antilymphocyte serum,rabbit anti-mouse thymocyte globulin (mATG), was utilized ina variety of in vivo and in vitro settings, each for the purposeof defining the physiological, immunological, and metabolicactivities of this agent, with particular focus on actions influencingdevelopment of type 1 diabetes.
RESULTS—We observed that mATG attenuates type 1 diabetesdevelopment in an age-dependent fashion, only proving efficaciousat disease onset or in the late pre-diabetic phase (12 weeksof age). When provided at 12 weeks of age, mATG reversed pancreaticinsulitis, improved metabolic responses to glucose challenge,and rapidly increased frequency of antigen-presenting cellsin spleen and pancreatic lymph nodes. Surprisingly, mATG therapydramatically increased, in an age-dependent fashion, the frequencyand the functional activity of CD4+CD25+ regulatory T-cells.Adoptive transfer/cotransfer studies of type 1 diabetes alsosupport the concept that mATG treatment induces a stable andtransferable immunomodulatory repertoire in vivo.
CONCLUSIONS—These findings indicate that an inductionof immunoregulation, rather than simple lymphocyte depletion,contributes to the therapeutic efficacy of antithymocyte globulinand suggest that time-dependent windows for the ability to delayor reverse type 1 diabetes exist based on the capacity to enhancethe functional activity of regulatory T-cells.
