Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes

Abstract

The first signs of autoimmune activation leading to b-cell destruction in type 1 diabetes (T1D) appear during the first months of life. Thus, the perinatal period offers a suitable time window for disease prevention. Moreover, thymic selection of autoreactive T cells is most active during this period, providing a therapeutic opportunity not exploited to date. We therefore devised a strategy by which the T1D-triggering antigen preproinsulin fused with the immunoglobulin (Ig)G Fc fragment (PPI-Fc) is delivered to fetuses through the neonatal Fc receptor (FcRn) pathway, which physiologically transfers maternal IgGs through the placenta. PPI-Fc administered to pregnant PPI B15-23 T-cell receptor-transgenic mice efficiently accumulated in fetuses through the placental FcRn and protected them from subsequent diabetes development. Protection relied on ferrying of PPI-Fc to the thymus by migratory dendritic cells and resulted in a rise in thymic-derived CD4 + regulatory T cells expressing transforming growth factor-b and in increased effector CD8 + T cells displaying impaired cytotoxicity. Moreover, polyclonal splenocytes from nonobese diabetic (NOD) mice transplacentally treated with PPI-Fc were less diabetogenic upon transfer into NOD.scid recipients. Transplacental antigen vaccination provides a novel strategy for early T1D prevention and, further, is applicable to other immune-mediated conditions.Islet destruction by autoreactive T cells is the hallmark of type 1 diabetes (T1D). Intense research efforts are therefore ongoing to develop immunotherapies aimed at blunting islet autoimmunity. Antigen (Ag)-specific immunotherapies are particularly attractive due to their selectivity and safety (1) but have met with limited success. Several attempts have focused on tolerogenic vaccination with b-cell Ags derived from preproinsulin (PPI) (2), which is the target initiating the autoimmune cascade in nonobese diabetic (NOD) mice (3) and likely also in humans (2). A recent clinical trial employing intranasal insulin in slow-onset T1D patients did not result in C-peptide preservation, despite successful induction of insulin-specific immune tolerance (4). These results suggest that the timing of intervention may be too late and that the Ag spreading that follows early b-cell destruction leads to a diversification of autoimmune reactions beyond insulin, thus making tolerance restoration to this sole Ag insufficient. The same problem is encountered in prevention trials. Despite absence of clinical disease, selection of at-risk patients based on positivity for multiple autoantibodies (auto-Abs) underscores the presence of an autoimmune reaction that has already spread to several Ags (5). Prospective cohorts of genetically at-risk children further highlighted that b-cell autoimmunity initiates very early, possibly already during

Islet-reactive CD8 + T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors

“…Collectively, the present data pose new challenges toward development of circulating T-cell biomarkers for T1D staging and suggest novel therapeutic strategies based on mimicking ‘benign’ autoimmunity or complementing incomplete central tolerance (38). …”

Beta-cell Specific Autoantibodies: Are they Just an Indicator of Type 1 Diabetes?

“…Genetic abrogation of maternal AAb transmission in NOD mice protects the offspring from T1D development, suggesting that the maternal transmission of AAbs is a critical environmental component for T1D in mice [87–89]. Interestingly, antigen-specific therapy with PPI-fused with the immunoglobulin (Ig)G Fc fragment (PPI-Fc) in pregnant diabetogenic T-cell receptor-transgenic mice efficiently accumulated in fetuses through the placental FcRn and protected them from subsequent diabetes development [90]. Taken together, these observations show that the islet-specific autoimmune process becomes activated during infancy and environmental events can deviate, prolong, inhibit, trigger or accelerate its progression.…”

Alternative Approach to Immunomodulation for Type 1 Diabetes: Antigen-Specific Immunotherapy In Utero

“…Rather than going in harder with stronger combinatorial immunotherapy, an approach taken by Culina et al (10) in this issue of the Diabetes was to go in early-very early. They used a murine model of T1D to demonstrate that antigen-specific immunotherapy delivered to the fetus is a very effective approach to preventing T1D.…”

“…Culina et al (10) chose proinsulin as the vaccinating b-cell protein because proinsulin is an early target of the T-cell response against the b-cell. They chose to treat at embryonic day 16 because T-cell education starts in the thymus just after this age.…”

“…At a time when we are faced with the side effects associated with combinatorial immunotherapy administered after the onset of autoimmunity, this surely is worth exploring further. (10). A pregnant G9C8 mouse expressing a transgenic T-cell receptor for the B15-23 peptide of proinsulin was immunized with preproinsulin fused with PPI-Fc.…”