Generating tolerance through in situ recruitment of regulatory T cells for allogeneic cell transplantation in a bioengineered lymphoid platform.

Abstract

Cellular therapies aim to treat or manage disease by introducing living cells that integrate into the host and restore or eliminate dysfunctional tissues. Despite their promise for clinical success, the host immune response to cellular treatments remains a challenge since traditional approaches for abrogating immune rejection involve systemic immunosuppression, which results in severe off-target toxicity. One alternate strategy for restraining immune responses involves harnessing the natural immunomodulatory capabilities of regulatory T cells (Tregs), a specialized subset of T cells that suppress inflammatory immune responses and can promote induction and maintenance of transplant tolerance. Here we propose using the NanoLymph platform, an implantable subcutaneous device for continuous localized recruitment of Tregs, to achieve immunological tolerance free of systemic immunosuppression. The NanoLymph features a dual-reservoir system for the sustained release of immunomodulatory agents through a nanoporous membrane and a vascularized compartment that supports cell homing and allograft integration with the host. This work demonstrates robust vascularization of the NanoLymph by four weeks post-implantation, along with sustained in vivo elution of immunomodulatory agents for up to one month that selectively recruit and expand Tregs. Finally, we demonstrate that NanoLymph prolongs cell persistence in a bioluminescent allogeneic transplant model. Overall, the NanoLymph represents a versatile platform to generate a safe and localized tolerogenic microenvironment relevant for cell transplant therapies.