title: The rise, fall, and resurgence of immunotherapy in type 1 diabetes.
abstract: Despite considerable effort to halt or delay destruction of β-cells in autoimmune type 1 diabetes (T1D), success remains elusive. Over the last decade, we have seen a proliferation of knowledge on the pathogenesis of T1D that emerged from studies performed in non-obese diabetic (NOD) mice. However, while results of these preclinical studies appeared to hold great promise and boosted patients' hopes, none of these approaches, once tested in clinical settings, induced remission of autoimmune diabetes in individuals with T1D. The primary obstacles to translation reside in the differences between the human and murine autoimmune responses and in the contribution of many environmental factors associated with the onset of disease. Moreover, inaccurate dosing as well as inappropriate timing and uncertain length of drug exposure have played a central role in the negative outcomes of such therapeutic interventions. In this review, we summarize the most important approaches tested thus far in T1D, beginning with the most successful preclinical studies in NOD mice and ending with the latest disappointing clinical trials in humans. Finally, we highlight recent stem cell-based trials, for which expectations in the scientific community and among individuals with T1D are high.
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; IRCCS, Ospedale San Raffaele, Milan, Italy.
authors.forename: Moufida
authors.initials: M
authors.lastname: Ben Nasr
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; IRCCS, Ospedale San Raffaele, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Addio
authors.affiliation: IRCCS, Ospedale San Raffaele, Milan, Italy.
authors.forename: Vera
authors.initials: V
authors.lastname: Usuelli
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; IRCCS, Ospedale San Raffaele, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Tezza
authors.affiliation: Transplantation Research Center, Nephrology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; IRCCS, Ospedale San Raffaele, Milan, Italy. Electronic address: paolo.fiorina@childrens.harvard.edu.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007167:Immunotherapy / Q000379:methods*
keywords: B cells; Hematopoietic stem cells; Immunosuppression; Immunotherapy; NOD mice; T cells; Type 1 diabetes