Biomaterial-enabled induction of pancreatic-specific regulatory T cells through distinct signal transduction pathways

Abstract

Autoimmune diseases-where the immune system mistakenly targets self-tissue-remain hindered by non-specific therapies. For example, even molecularly specific monoclonal antibodies fail to distinguish between healthy cells and self-reactive cells. An experimental therapeutic approach involves delivery of self-molecules targeted by autoimmunity, along with immune modulatory signals to produce regulatory T cells (T REG ) that selectively stop attack of host tissue. Much has been done to increase the efficiency of signal delivery using biomaterials, including encapsulation in polymer microparticles (MPs) to allow for co-delivery and cargo protection. However, less research has compared particles encapsulating drugs that target different T REG inducing pathways. In this paper, we use poly (lactic-co-glycolide) (PLGA) to co-encapsulate type 1 diabetes (T1D)-relevant antigen and 3 distinct T REG -inducing molecules -rapamycin (Rapa), all-trans retinoic acid (atRA), and butyrate (Buty) -that target the mechanistic target of Rapa (mTOR), the retinoid pathway, and histone deacetylase (HDAC) inhibition, respectively. We show all formulations are effectively taken up by antigen presenting cells (APCs) and that antigen-containing formulations are able to induce proliferation in antigen-specific T cells. Further, atRA and Rapa MP formulations co-loaded with antigen decrease APC activation levels, induce T REG differentiation, and reduce inflammatory cytokines in pancreatic-reactive T cells.

Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps

“…Additional groups have coencapsulated other self-antigens and rapamycin to promote protection in the context of the autoimmune diseases rheumatoid arthritis, type 1 Diabetes (T1D), and vitiligo. [41][42][43][44] Taken as a whole, biomaterial encapsulation of drugs alone or with selfantigen enables tolerance induction via a traditionally suppressive drug class-mTOR inhibitors-highlighting the utility of materials in this application.…”

“…autoimmunity-both in vitro and in vivo contexts. [42,47] The goal of these studies is to use delivered antigen to expand antigenspecific cells, while retinoic acid promotes differentiation of those expanded cells into regulatory cells.…”

“…Leveraging this ability, multiple groups have used coencapsulation of antigen and retinoic acid in liposomes and polymer particles to expand regulatory T cells—a population important for specific suppression of autoimmunity—both in vitro and in vivo contexts. [ 42,47 ] The goal of these studies is to use delivered antigen to expand antigen‐specific cells, while retinoic acid promotes differentiation of those expanded cells into regulatory cells.…”

Epitope-based precision immunotherapy of Type 1 diabetes

“… 105 For example, hepatocyte-restricted delivery can be achieved using N-acetylgalactosamine-modified antigens 95 (approach used by Anokion, Table 3 ) or using liver-specific promoter coupled with micro-RNA targets restricting expression in non-hematopoietic cells in the case of transgene-encoded antigens. 104 When the type of APCs cannot be restricted, codelivery of immunomodulatory drugs (e.g., rapamycin 76 , 106 or cytokines (e.g., IL-10) 79 , 107 with antigens helps maintain the tolerogenic function of APCs. Importantly, a single DNA vaccine encoding antigen and multiple cytokines (IL-2, IL-10 and TGF-β) has been validated 49 and is being tested clinically, providing a 4-in-1 drug option that is easy and economical to manufacture.…”

Harnessing Biomaterials to Study and Direct Antigen-Specific Immunotherapy

“…As alluded to, metabolic changes also underpin the differentiation of T REG cell populations from naïve populations. To take advantage of this, our lab has coloaded T1D autoantigen with various metabolic modulators demonstrated to promote T REG . We demonstrated in vitro that these compounds could promote an increase in T REG while decreasing DC activation levels among disease-relevant cell populations.…”