Malt1 Protease Deficiency in Mice Disrupts Immune Homeostasis at Environmental Barriers and Drives Systemic T Cell–Mediated Autoimmunity

Abstract

This information is current as Mediated Autoimmunity − Barriers and Drives Systemic T Cell Immune Homeostasis at Environmental

Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology

“…Collectively, the systemic inflammatory pathology induced by long-term MLT-943 treatment in rats resulted in activation and/or recruitment of both innate and adaptive immune cells in the GI tract. These data are in line with the elevated serum IgE and the systemic T cell activation observed previously in the MALT1 PD mouse model as a result of the reduced regulatory T cell compartment (13)(14)(15)(16)25).…”

“…The suggested combination of MALT1 inhibitors with checkpoint inhibitors like anti-PD-1 antibodies (28,29) might accelerate the appearance of side effects by impacting additional immunoregulatory networks. T cells and IFN-γ are major drivers of the progressive pathology observed in MALT1 PD mice (14,25). Combination with T cell depleting agents (25) or other immunomodulatory drugs dampening the dominant pathogenic cell subsets and pathways (e.g., IFNγ receptor signaling) might delay or prevent the development of the severe immune alterations observed upon long-term MALT1 protease inhibition but might also introduce the risk of excessive immunosuppression.…”

“…T cells and IFN-γ are major drivers of the progressive pathology observed in MALT1 PD mice (14,25). Combination with T cell depleting agents (25) or other immunomodulatory drugs dampening the dominant pathogenic cell subsets and pathways (e.g., IFNγ receptor signaling) might delay or prevent the development of the severe immune alterations observed upon long-term MALT1 protease inhibition but might also introduce the risk of excessive immunosuppression. Potential treatment of lymphomas with a MALT1 inhibitor has been contemplated based on numerous studies showing that MALT1 protease function is a key driver for proliferation of e.g., ABC-DLBCL lymphomas (10,11) and MALT1 protease inhibitors are now entering clinical trials for these indications (43).…”

“…The exact cause of death associated with these findings has remained unclear but contribution of interferon γ-producing cells in mediating the neuropathology (14), and antibodies driving autoimmune gastritis (15) was proposed. We recently determined that the systemic and lethal disease component is mediated by T lymphocytes, while dysregulated humoral responses at environmental barriers lead to the production of microbiota-and food-reactive IgG1 and IgE antibodies in MALT1 PD mice (25). By contrast, the lack of lymphocyte effector functions in immunodeficient MALT1 KO mice results in only mild clinical symptoms despite a more severe reduction in Treg cells (13)(14)(15)(16).…”

Long-Term MALT1 Inhibition in Adult Mice Without Severe Systemic Autoimmunity

“…Noteworthy, a first-in-human phase I clinical study in participants with relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia has recently been initiated ( https://clinicaltrials.gov/ct2/show/NCT03900598 ). A major concern was, however, raised by several independent studies showing that knock-in mice constitutively expressing a catalytically inactive MALT1 “protease-dead” mutant ( Malt1 -PD mice) rapidly develop lethal autoimmune inflammation in multiple organs ( Gewies et al., 2014 ; Jaworski et al., 2014 ; Yu et al., 2015 ; Bornancin et al., 2015 ; Demeyer et al., 2019 ; Martin et al., 2019 ). This was somewhat surprising because a previous study had shown that pharmacological inhibition of MALT1 in mice for up to 3 weeks does not cause any side effects ( Mc Guire et al., 2014 ).…”