Preproinsulin Designer Antigens Excluded from Endoplasmic Reticulum Suppressed Diabetes Development in NOD Mice by DNA Vaccination

Katja Stifter; Cornelia Schuster; Jana Krieger; Andreas Spyrantis; Bernhard Otto Boehm; Reinhold Schirmbeck

doi:10.1016/j.omtm.2018.12.002

Preproinsulin Designer Antigens Excluded from Endoplasmic Reticulum Suppressed Diabetes Development in NOD Mice by DNA Vaccination

Mol Ther Methods Clin Dev. 2018 Dec 13:12:123-133. doi: 10.1016/j.omtm.2018.12.002. eCollection 2019 Mar 15.

Authors

Katja Stifter¹, Cornelia Schuster^{1

2}, Jana Krieger¹, Andreas Spyrantis¹, Bernhard Otto Boehm^{3

4}, Reinhold Schirmbeck¹

Affiliations

¹ Department of Internal Medicine I, Ulm University Hospital, Albert Einstein Allee 23, 89081 Ulm, Germany.
² Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
³ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
⁴ Imperial College London, London, UK.

Abstract

DNA vaccines against autoimmune type 1 diabetes (T1D) contain a nonpredictable risk to induce autoreactive T cell responses rather than a protective immunity. Little is known if (and how) antigen expression and processing requirements favor the induction of autoreactive or protective immune responses by DNA immunization. Here, we analyzed whether structural properties of preproinsulin (ppins) variants and/or subcellular targeting of ppins designer antigens influence the priming of effector CD8⁺ T cell responses by DNA immunization. Primarily, we used H-2^b RIP-B7.1 tg mice, expressing the co-stimulator molecule B7.1 in beta cells, to identify antigens that induce or fail to induce autoreactive ppins-specific (K^b/A_12-21 and/or K^b/B_22-29) CD8⁺ T cell responses. Female NOD mice, expressing the diabetes-susceptible H-2^g7 haplotype, were used to test ppins variants for their potential to suppress spontaneous diabetes development. We showed that ppins antigens excluded from expression in the endoplasmic reticulum (ER) did not induce CD8⁺ T cells or autoimmune diabetes in RIP-B7.1 tg mice, but efficiently suppressed spontaneous diabetes development in NOD mice as well as ppins-induced CD8⁺ T cell-mediated autoimmune diabetes in PD-L1 ^-/- mice. The induction of a ppins-specific therapeutic immunity in mice has practical implications for the design of immune therapies against T1D in individuals expressing different major histocompatibility complex (MHC) I and II molecules.

Keywords: DNA vaccines; endoplasmic reticulum; mouse models; preproinsulin/proinsulin antigens; type 1 diabetes.