L. lactis secreting proinsulin autoantigen and IL-10 triggers Treg production to suppress autoimmune responses.
Scientists have managed to reverse type 1 diabetes (T1D) in experimental mice by giving the animals an oral course of harmless gut bacteria that had been engineered to secrete the whole proinsulin autoantigen (PINS) and the immunomodulatory human cytokine IL-10 (hIL10). An international team led by scientists at the KU Leuven in Belgium, combined the engineered Lactococcus lactis therapy with a short, low-dose systemic course of the nonspecific immune modulating monoclonal antibody (mAb) anti-CD3.
Treated non-obese diabetic (NOD) mice demonstrated stable levels of glycemia for over three months of follow-up, and suppression of diabetes-related autoantigen immune responses specifically, without any effect on their immune responses to nondisease antigens. The stable reversal of established diabetes in animals given the combination treatment was accompanied by increased numbers of local antigen-specific Foxp3+ regulatory T cells (Tregs) that accumulated in pancreatic islets.
Chantal Mathieu, M.D., and colleagues claim their findings suggest the same approach could be harnessed as an effective treatment for T1D in humans. The researchers describe their technique and report on their in vivo experiments in the Journal of Clinical Investigation in a paper titled “Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice.”
Interestingly, the team reports, there was no evidence that the L. lactis-anti-CD3 therapy actually triggered beta-cell proliferation. Rather, it seemed to enable regranulation or reactivation of beta cells that had been deactivated by diabetes-related immune inflammation. This suggests that the treatment may only work when there are enough potentially functional beta cells present to start with. “These observations further strengthen the argument that early diagnosis of T1D and the rapid initiation of immunomodulatory therapies will be necessary for efficacy,” they state.
“Our intervention effectively reverted diabetes in newly diagnosed diabetic NOD mice, with a success rate seldom approached in NOD mice,” the authors conclude. “The therapy allowed us to exploit lower doses of anti-CD3 (ideally to circumvent side effects and undesired reactions) in combination with other interventions to enhance therapeutic efficacy. In particular, our combination therapy using L. lactis expressing PINS and hIL10 and low-dose anti-CD3 preserved functional β cell mass, resolved severe insulitis, and increased the frequencies of functional CD4+CD25+Foxp3+CTLA4+ Tregs.”