Customized cell-based treatment options to combat autoimmunity and restore beta-cell function in type 1 diabetes mellitus: current protocols and future perspectives.
Type 1 diabetes mellitus (T1D) is considered a classical autoimmune disease which commonly starts during childhood but may appear later in adulthood in a proportion of 30-40% of affected individuals. Its development is based on a combination of a genetic predisposition and autoimmune processes that result in gradual destruction of the beta-cells of the pancreas and cause absolute insulin deficiency. Evidence for an autoimmune origin of T1D results from measurable islet beta-cell autoantibody directed against various autoantigens such as proinsulin or insulin itself, glutamic acid decarboxylase 65, the islet tyrosine phosphatase IA-2, and the islet-specific glucose-6-phosphatase catalytic subunit-related protein. In addition, T-cell lines with specificity for insulin or glutamic acid decarboxylase have been identified within peripheral blood lymphocytes. Importantly, in most instances the pathogenesis of T1D comprises a slowly progressive destruction of beta-cell tissue in the pancreas preceded by several years of a prediabetic phase where autoimmunity has already developed but with no clinically apparent insulin dependency. Unless immunological tolerance to pancreatic autoantigens is re-established, diabetes treated by islet cell transplantation or stimulation/regeneration of endogenous beta-cells would remain a chronic disease secondary to immune suppression related morbidity. Hence, if islet cell tolerance could be re-induced, a major clinical hurdle to curing diabetes by islet cell neogenesis may be overcome. Targeted immunotherapies are currently explored in a variety of clinical studies and hold great promise for causative treatment to readjust the underlying immunologic imbalance with the goal to cure the disease. This chapter will outline possible treatment options to stop or reverse the beta-cell-specific autoimmune and inflammatory process within pancreatic islets. Special emphasis is given to stem cells of embryonic, mesenchymal, and haematopoietic origin, which, besides their use for regenerative purposes, possess potent immunomodulatory functions and thus have the potential to suppress the autoimmune response. At the end of this chapter we will introduce a novel type of in vitro modified monocytes with immunosuppressive and anti-inflammatory properties. These tolerogenic monocytes provide a feasible option to be used as autologous cellular transplants to halt autoimmunity and to protect still viable beta-cells within Langerhans islets.
Fändrich
Fred
F
Clinic for Applied Cellular Therapy (CACT), University of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. fred.faendrich@uksh-kiel.de
Ungefroren
Hendrik
H
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology; D000941:Antigens / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008214:Lymphocytes / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D012307:Risk Factors; D013997:Time Factors
D000941:Antigens; D001324:Autoantigens