Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man Phase I safety study

Thrower, S. L., James, L., Hall, W., Green, K. M., Arif, S., Allen, J. S., Van-Krinks, C., Lozanoska-Ochser, B., Marquesini, L., Brown, S., Wong, Florence Susan ORCID: https://orcid.org/0000-0002-2812-8845, Dayan, Colin Mark ORCID: https://orcid.org/0000-0002-6557-3462 and Peakman, M. 2009. Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man Phase I safety study. Clinical and Experimental Immunology 155 (2) , pp. 156-165. 10.1111/j.1365-2249.2008.03814.x

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Abstract

Immunotherapeutic strategies under consideration for type 1 diabetes include modification of the autoimmune response through antigen-specific routes. Administration of short peptides representing T cell epitopes targeted by patients with the disease represents one approach. This study evaluated safety and mechanistic outcomes during first-in-man intradermal administration of a human leucocyte antigen-DR4 (HLA-DR4)-restricted peptide epitope of proinsulin (C19-A3). This randomized, open-label study assessed two major theoretical risks of peptide immunotherapy, namely induction of allergic hypersensitivity and exacerbation of the proinflammatory autoimmune response, using clinical assessment and mechanistic assays in vitro. Patients with long-standing type 1 diabetes and HLA-DRB1*0401 genotype received 30 mg (n = 18) or 300 mg (n = 18) of peptide in three equal doses at 0, 1 and 2 months or no intervention (n = 12). Proinsulin peptide immunotherapy in the dosing regimen used is well tolerated and free from risk of systemic hypersensitivity and induction/reactivation of proinsulin-specific, proinflammatory T cells. Peptide-specific T cells secreting the immune suppressive cytokine interleukin (IL)-10 were observed at month 3 in four of 18 patients in the low-dose group (versus one of 12 in the control group; P = not significant).Mean IL-10 response to peptide in the low-dose group increased between 0 and 3 months (P = 0·05 after stimulation with 5 mM peptide in vitro) and then declined to baseline levels between 3 and 6months (P = 0·01 at 10 mM peptide in vitro). These studies pave the way for future investigations in new-onset patients designed to examine whether proinsulin peptide immunotherapy has beneficial effects on markers of T cell autoimmunity and preservation of b cell mass.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR180 Immunology R Medicine > R Medicine (General)
Uncontrolled Keywords:	immunotherapy, peptide, proinsulin, regulatory T cells, type 1 diabetes
Publisher:	Wiley-Blackwell
ISSN:	0009-9104
Last Modified:	20 Oct 2022 07:45
URI:	https://orca.cardiff.ac.uk/id/eprint/26286

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