Improvement of Islet Engrafts via Treg Induction Using Immunomodulating Polymeric Tolerogenic Microparticles

Type1 diabetes (T1D) is a life-threatening condition for whichislet transplantation offers a way to extend longevity and vastlyimprove quality of life, but the degree and duration of success canvary greatly due to the patient's protective immunity againstforeign material. The field is in need of cellular engineering modalitiesto promote a localized, tolerogenic environment to protect transplantedislet tissue. Artificial antigen-presenting cells (aAPCs) can be designedexogenously to mimic immune cells, such as dendritic cells, and administeredto patients, allowing greater control over T cell differentiation.As regulatory T cell (Treg) modulation can reduce the activity ofcytotoxic T-effector populations, this strategy can be used to promoteimmune acceptance of both biomaterials and cellular transplants, suchas islets. A new class of poly-(lactic-co-glycolicacid) (PLGA) and PLGA/PBAE-blend aAPCs containing transforming growthfactor beta and conjugated with anti-CD3 and anti-CD28 antibodies,called tolerogenic aAPCs (TolAPCs), are specifically designed to generatea tolerogenic response by inducing Tregs. We characterized TolAPCs'physical and chemical properties via advanced particle imaging andsizing modalities and investigated their impact on the local and systemicimmune system across BALB/c and C57BL/6 mouse strains as well as healthymale and female mice via histologic, gene expression, and immunofluorescencestaining methods. Strain-specific differences were observed, whereassex made no difference in the TolAPC response. TolAPCs stimulatedthe expansion of FOXP3(+) Tregs and provided islet cell protection,maintaining improved glucose-stimulated insulin secretion in vitrowhen co-cultured with cytotoxic CD8(+) T cells. We also exploredthe ability of this TolAPC platform to promote tolerance in a streptozotocin-inducedmurine T1D C57BL/6 mouse model. We achieved partial islet protectionover the first few days following co-injection with PLGA/PBAE TolAPCs;however, grafts failed soon thereafter. Analysis of the local injectionsite demonstrated that other immune cell types, including APCs andcytotoxic natural killer cells, increased in the islet injection site.While we aimed to promote a localized tolerogenic microenvironmentinvivo using biodegradable TolAPCs to induce Tregs and extend islettransplant durability, further TolAPC improvements will be requiredto both elongate efficacy and control additional immune cell responders.

Automated summary

Type 1 diabetes (T1D) is a life-threatening condition that can be improved by islet transplantation, but the success can vary due to the patient's immune response. Artificial antigen-presenting cells (aAPCs) can promote immune acceptance and generate a tolerogenic response by inducing regulatory T cells (Tregs). The study investigated the properties of a specific type of aAPCs (TolAPCs) and their impact on the immune system in mice, showing potential for islet protection and glucose-stimulated insulin secretion. However, further improvements are needed for long-term efficacy and control of other immune cell responses.