Symposium
Neuro-Immune Crosstalk: Its role in the pathogenesis and perspectives for novel therapies
シンポジウム
神経変性疾患治療のパラダイムシフト |
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| 7月27日（土）9:18～9:47 第6会場（朱鷺メッセ 2F 201A）
3S06m-2
二次進行型多発性硬化症のバイオマーカーおよび治療標的の免疫学的探索
Shinji Oki（大木 伸司）
国立精神・神経セ神経研免疫
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with a general relapsing/remitting disease course (RRMS). Although RRMS is well-controlled by newly-developed disease modifying therapies to date, some RRMS patients with a long disease duration change to a different form of the disease secondary progressive form (SPMS) with chronic neuroinflammation and progressing symptoms. Interestingly, the exclusive formation of leptomeningeal follicle-like structures in SPMS patients strongly suggests immune cell-mediated pathogenesis. Yet, we have not succeeded in preventing conversion from RRMS to SPMS and curing this intractable form of MS. In addition, diagnosis is generally retrospective and subjective due to the lack of understanding of the pathogenesis of SPMS and of sensitive biomarkers reflecting the progressive or stationary disease status.
Experimental autoimmune encephalomyelitis (EAE) has been used as a model of MS with Th17 cell-mediated acute CNS inflammation. Recently, we have identified that EAE in late/chronic phase is caused by a second wave accumulation of helper T cells expressing the transcription factor Eomes. Inhibition of Eomes significantly suppressed the severity of chronic EAE and similar Eomes+Th cells have been found to increase in the peripheral blood and cerebrospinal fluid from patients with SPMS, but not RRMS (Nat. Commun. 2015). Therefore, Eomes+Th cell-mediated late/chronic EAE acts as a novel mouse model of SPMS. Analysis on frequency of Eomes+Th cells in PBMC indicated Eomes-lo and Eomes-hi phenotype within SPMS patients. Clinical information revealed that Eomes-hi was linked to actively progressing SPMS, whereas Eomes-lo represented stationary status of SPMS, suggesting that frequency of Eomes+Th in PBMC was a reliable biomarker for SPMS patients at risk of progression.
Through detailed EAE analysis, we found that extrapituitary prolactin secreted by B cells and other antigen-presenting cells (APC) plays a crucial role for induction of Eomes+ Th cells in the CNS, suggesting that prolonged neuroinflammation shapes the profiles of infiltrated APCs to facilitate the development of Eomes+Th cells and promote the progression of chronic disease through the ectopic expression of prolactin. Taken together, Eomes+Th cells could act as a biomarker indicating disease status of SPMS patients and may provide new therapeutic targets for treatment of SPMS. | | 7月27日（土）9:47～10:16 第6会場（朱鷺メッセ 2F 201A）
3S06m-3
ミスフォールドTDP43特異認識intrabodyによるALS治療の可能性
Makoto Urushitani（漆谷 真）
滋賀医科大学 内科学講座 脳神経内科
Accumulating evidence indicates that protein misfolding underlies diversity of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). In ALS, the misfolded forms of TAR DNA-binding protein 43kDa (TDP-43) is a promising candidate for molecular targeting in the sporadic ALS. Antibody medicine is an ideal but a challenging approach to associate to tackle only pathogenic structures. Above all, the site of actions of the pathogenic proteins could mediate cell-autonomous or non-cell-autonomous pathologies of diverse diseases; cell-to-cell propagation theory might prompt the passive immunization. In the case of TDP-43, however, there is a limited number of evidence in vivo to strongly support extracellular behaviors. Using a monoclonal antibody 3B12A, which recognizes E245/D246 the exposed residues in the misfolded TDP-43, we generated a variable fragment of single chain (scFv) fused with chaperon-mediated autophagy (CMA) signal, to facilitate the degradation of aggregate-scFv complexes.
Moreover, 3B12A VH contains PEST-like sequence, gifting the dual proteolytic properties of 3B12A scFv. Another requirement is an effective aggregation model of TDP-43, in which the cytosolic mislocalization does not suffice to produce cytosolic inclusions numerous and large enough to validate for high thruput screening. We previously found that intramolecular disulfide bond in RNA-recognition motif (RRM1) crucially regulates the conformation of TDP-43, breakage of which readily produces phoslphorylated and ubiuitinated TDP-43 inclusions mimicking round inclusions in ALS.
Here, we show the efficacy of our autolytic intrabody to eliminate pathogenic forms of TDP-43 in cultured cells and muce embryonic brain. Further investigation for the efficacy and safety is on the way using transgenic mice model for sporadic ALS, and wild-type primates. Autolytic intrabody is an ideal approach to discriminate and scavenge only pathogenic species, while the autolytic signal is expected to promote self-decay in the absence of the aggregates. | | 7月27日（土）10:16～10:45 第6会場（朱鷺メッセ 2F 201A）
3S06m-4
Harnessing the immune system to combat age-related dementia and Alzheimer’s disease
Michal Schwartz（Schwartz Michal）
Neurobiology, Weizmann Institute of Science
The brain is no longer considered a completely autonomous tissue with respect to its immune activity. Rather, immune surveillance is required for supporting brain functional plasticity and repair. Essential immune cells include the microglia, the resident immune cells of the brain, and circulating immune cells. Both the resident microglia and the circulating immune cells are under tight regulatory control to allow risk-free benefit from immunological interventions. We found that access of circulating immune cells to the brain is controlled by the brain’s epithelial barrier, the blood cerebrospinal barrier. Using immunological and immunogenomic tools, we discovered that in brain aging and under neurodegenerative conditions, this barrier does not optimally function to enable brain repair. We further showed in mouse models of Alzheimer’s disease (AD), that activating the immune system by immunotherapy directed against the inhibitory PD-1/PD-L1 immune checkpoint pathway drives an immune-dependent cascade of processes that start in the periphery and culminate with recruitment of monocyte-derived macrophages to the brain. This treatment is effective in modifying the diseased brain milieu, reversing cognitive loss, reducing brain inflammation, and mitigating disease pathology in a mouse model of AD driven by amyloid plaques, and in mouse models of dementia, driven by tauopathy. Overall, our results indicate that targeting the immune system outside the brain, rather than brain-specific disease-escalating factors within the central nervous system, may provide a multi-dimensional disease-modifying therapy for AD and dementia. | | | |
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