Costimulation and autoimmune diabetes in BB rats

Area of Science:

• Immunology
• Autoimmunity
• Transplantation Immunology

Background:

• T-cell activation is regulated by costimulatory signals.
• The BB rat model is used to study type 1 diabetes and transplantation.

Purpose of the Study:

• To investigate the role of costimulation in autoimmunity and transplantation using the BB rat model.
• To evaluate the efficacy of different costimulation blockade strategies in type 1 diabetes.

Main Methods:

• Utilized diabetes-prone (BBDP) and diabetes-resistant (BBDR) BB rats.
• Administered various monoclonal antibodies (mAbs) targeting costimulatory molecules like CD28, CD154, CTLA4-Ig, CD80, CD86, and CD134L.
• Induced diabetes in BBDR rats using polyinosinic-polycytidylic acid and Treg cell depletion.

Main Results:

• Two anti-CD28 mAbs completely prevented diabetes in BBDP rats.
• Anti-CD154 mAb delayed diabetes in BBDP rats, while CTLA4-Ig and anti-CD80 mAbs accelerated it.
• In the induced BBDR model, anti-CD154 mAb delayed diabetes, whereas CTLA4-Ig, anti-CD134L, and anti-CD28 mAbs had minimal effect.
• Blockade of CD134-CD134L and CD40-CD154 pathways was effective in preventing autoimmune recurrence in syngeneic islet grafts.

Conclusions:

• The effectiveness of costimulation blockade for type 1 diabetes treatment depends on the targeted pathway.
• Treatment efficacy is influenced by the mechanism of induction, disease stage, intensity, and duration.
• Different costimulatory pathways play distinct roles in the pathogenesis of type 1 diabetes.