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

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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 (TREG) 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 TREG inducing pathways. In this paper, we use poly (lactic-co-glycolide) (PLGA) to co-encapsulate type 1 diabetes (T1D)-relevant antigen and 3 distinct TREG-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 TREG differentiation, and reduce inflammatory cytokines in pancreatic-reactive T cells.

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Data availability

All data generated or analyzed during this study are included in this published article. All data files, Flowjo workspaces, and JMP files are available upon request.

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Funding

This work was supported in part by the Juvenile Diabetes Research Foundation (2-SRA-2016–319-S-B) and the National Institute of Health (R01 # EB026896 NIBIB).

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Authors and Affiliations

  1. Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA

    Sean T. Carey, Joshua M. Gammon & Christopher M. Jewell

  2. US Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD, 21201, USA

    Christopher M. Jewell

  3. Robert E. Fischell Institute for Biomedical Devices, College Park, MD, 20742, USA

    Christopher M. Jewell

  4. Department of Microbiology and Immunology, University of Maryland Medical School, Baltimore, MD, 21201, USA

    Christopher M. Jewell

  5. Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, 21201, USA

    Christopher M. Jewell

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  1. Sean T. Carey
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All authors contributed to manuscript preparation and experimental design. SC performed experiments and analyzed data.

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Correspondence to Christopher M. Jewell.

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All studies involving animals were approved and carried out under the supervision of the University of Maryland Institutional Animal Care and Use Committee (IACUC) in compliance with local, state, and federal guidelines.

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Conflict of interest

CJ is an employee of the VA Maryland Health Care System. CJ has equity positions with Avidea Technologies and Cellth Systems, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Appendix

Appendix

Table 1 List of P-values between 10 µg treatment groups in Fig. 2c. Significant comparisons (p < 0.05) are in bold
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Table 2 List of P-values between 2 µg treatment groups in Fig. 2d. Significant comparisons (p < 0.05) are in bold
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Carey, S.T., Gammon, J.M. & Jewell, C.M. Biomaterial-enabled induction of pancreatic-specific regulatory T cells through distinct signal transduction pathways. Drug Deliv. and Transl. Res. 11, 2468–2481 (2021). https://doi.org/10.1007/s13346-021-01075-5

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