Abstract
Autoimmune endocrine disorders, such as type 1 diabetes (T1D) and thyroiditis, at present are treated with only hormone replacement therapy. This emphasizes the need to identify personalized effective immunotherapeutic strategies targeting T and B lymphocytes. Among the genetic variants associated with several autoimmune disorders, the C1858T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, encoding for Lyp variant R620W, affects the innate and adaptive immunity. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes) that selectively inhibit variant allele expression. In this manuscript, we improved lipoplexes carrying siRNA for variant C1858T by functionalizing them with Fab of Rituximab antibody (RituxFab-Lipoplex) to specifically target B lymphocytes in autoimmune conditions, such as T1D. RituxFab-Lipoplexes specifically bind to B lymphocytes of the human Raji cell line and of human PBMC of healthy donors. RituxFab-Lipoplexes have impact on the function of B lymphocytes of T1D patients upon CpG stimulation showing a higher inhibitory effect on total cell proliferation and IgM+ plasma cell differentiation than the not functionalized ones. These results might open new pathways of applicability of RituxFab-Lipoplexes, such as personalized immunotherapy, to other autoimmune disorders, where B lymphocytes are the prevalent pathogenic immunocytes.
Highlights
Autoimmune diseases encompass a broad category of tissue-targeted conditions including organ-specific ones, often affecting endocrine glands like insulin-dependent diabetes mellitus and thyroiditis, and non-organ specific ones like systemic lupus erythematosus (SLE), vasculitides, rheumatoid arthritis (RA) and systemic sclerosis (SS) [1]
We provided evidence of the feasibility of exposing Fab of a monoclonal antibodies (MoAbs), that is, Rituximab on lipoplexes delivering siRNA against the C1858T protein tyrosine phosphatase non-receptor type 22 (PTPN22) variant
Functionalized lipoplexes bound themselves with high specificity to B lymphocytes of the human Raji cell line and within the peripheral blood mononuclear cells (PBMC) pool
Summary
Autoimmune diseases encompass a broad category of tissue-targeted conditions including organ-specific ones, often affecting endocrine glands like insulin-dependent diabetes mellitus (type 1 diabetes, T1D) and thyroiditis, and non-organ specific ones like systemic lupus erythematosus (SLE), vasculitides, rheumatoid arthritis (RA) and systemic sclerosis (SS) [1]. The C1858T polymorphism of PTPN22, which replaces the amino acid Arg (R) 620 with Trp (W) (R620W), encodes for a more active phosphatase, namely Lyp variant R620W This is a potent inhibitor of T cell activation involved in several autoimmune diseases [17,18]. This is a potent in of 18 hibitor of T cell activation involved in several autoimmune diseases [17,18]. We demonstrated the possibility relevant target for immunomodulation in the treatment of C1858T patients affected by an of achieving target down-modulation of variant C1858T PTPN22 gene by delivering autoimmune disease, that is, T1D [6,27]. (Rituximab) [30] in order to target B lymphocytes in autoimmune diseases
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