Abstract
Optimal immune-based therapies for type 1 diabetes (T1D) should restore self-tolerance without inducing chronic immunosuppression. CD4
Foxp3
regulatory T cells (T
) are a key cell population capable of facilitating durable immune tolerance. However, clinical trials with expanded T
in T1D and solid-organ transplant recipients are limited by poor T
engraftment without host manipulation. We showed that T
engraftment and therapeutic benefit in nonautoimmune models required ablative host conditioning. Here, we evaluated T
engraftment and therapeutic efficacy in the nonobese diabetic (NOD) mouse model of autoimmune diabetes using nonablative, combinatorial regimens involving the anti-CD3 (αCD3), cyclophosphamide (CyP), and IAC (IL-2/JES6-1) antibody complex. We demonstrate that αCD3 alone induced substantial T-cell depletion, impacting both conventional T cells (T
) and T
, subsequently followed by more rapid rebound of T
Despite robust depletion of host T
and host T
, donor T
failed to engraft even with interleukin-2 (IL-2) support. A single dose of CyP after αCD3 depleted rebounding host T
and resulted in a 43-fold increase in donor T
engraftment, yet polyclonal donor T
failed to reverse diabetes. However, infusion of autoantigen-specific T
after αCD3 alone resulted in robust T
engraftment within the islets and induced remission in all mice. This novel combinatorial therapy promotes engraftment of autoantigen-specific donor T
and controls islet autoimmunity without long-term immunosuppression.
