4.7 Article

A multi-epitope DNA vaccine enables a broad engagement of diabetogenic T cells for tolerance in Type 1 diabetes

Journal

JOURNAL OF AUTOIMMUNITY
Volume 98, Issue -, Pages 13-23

Publisher

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2018.11.003

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Funding

  1. Diabetes Research Center [P30DK063608]
  2. Columbia University [UL1TR001873]
  3. Berrie Foundation
  4. American Diabetes Association [1-18-PDF-151]
  5. National Institute of Allergy and Infectious Diseases [HHSN272201300006C]
  6. Office of the Director, NIH [S10RR027050, S1 0OD020056]
  7. National Institute of Diabetes and Digestive and Kidney Diseases, NIH [P30DK063608]

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Type 1 diabetes (T1D) is caused by diabetogenic T cells that evaded tolerance mechanisms and react against multiple beta-cell antigens. Antigen-specific therapy to reinstate tolerance (typically using a single beta-cell antigen) has so far proved unsuccessful in T1D patients. Plasmid DNA (pDNA)-mediated expression of proinsulin has demonstrated transient protection in clinical trials, but long-lasting tolerance is yet to be achieved. We aimed to address whether pDNA delivery of multiple epitopes/mimotopes from several beta-cell antigens efficiently presented to CD4(+) and CD8(+) T cells could also induce tolerance. This approach significantly delayed T1D development, while co-delivery of pDNA vectors expressing four full antigens protected more mice. Delivery of multiple epitopes resulted in a broad engagement of specific T cells, eliciting a response distinct from endogenous epitopes draining from islets. T-cell phenotypes also varied with antigen specificity. Unexpectedly, the repertoire of T cells reactive to the same epitope was highly polyclonal. Despite induction of some CD25(+) Foxp3(+) regulatory T cells, protection from disease did not persist after treatment discontinuation. These data demonstrate that epitope-based tolerogenic DNA vaccines constitute effective precision medicine tools to target a broad range of specific CD4(+) and CD8(+) diabetogenic T-cell populations for prevention or treatment of T1D.

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