Diabetes and other autoimmune endocrine diseases

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Improving Efficacy of Tolerogenic Dna Vaccines for Type 1 Diabetes

Thursday, June 15
5:45 PM - 7:00 PM

Type 1 diabetes (T1D) is a beta cell-targeted autoimmune disease mediated by CD4 and CD8 T cells.
Antigen-specific therapies (ASTs) aim to restore T cell tolerance by blocking or reprograming the response
of diabetogenic T cells. However, various attempts at applying ASTs to treat T1D in humans have failed ,
likely due to lim ited antigen representation and inability to target neoantigen-specific T cells. DNA vaccines
offer flexibility in expressing epitopes from multiple antigens as well as neoantigen-emulating mimotopes,
but DNA-based endogenous antigen delivery primarily target CD8 T cells. Targeting of both CD4 and CD8
T cells across a broader range of antigen specificities will likely be required to reestablish tolerance fully
and durably. Thus, we developed DNA constructs encoding major epitopes and mimotopes for several beta
cell antigens, whereby groups of epitopes are differentially targeted within transfected cells for efficient and
simultaneous engagement of CD4 and CD8 T cells, or alternatively secreted for acquisition and
presentation by other antigen-presenting cells. Shortly after a single administration of these DNA vaccines
in vivo, responses by multiple antigen-specific CD4 and CD8 T cells (adoptively transferred and/or identified
by MHC tetramers) were evident in the draining lymph nodes (especially with the secreted antigens) and
distinct from the response to endogenous antigens in pancreatic lymph nodes. This response included the
induction of antigen-specific Foxp3+ CD4 T cells, suggestive of a tolerogenic outcome. Our studies suggest
that pDNA tolerizing vaccination can efficiently target diabetogenic CD4 and CD8 T cells and enhance
protection against T1D

Jorge Postigo

Columbia Center for Translational Immunology, Columbia University


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    Remi J. Creusot

    columbia university


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