전신홍반루푸스 모델에서 중간엽 줄기세포에 의한 체액성 자가면역반응 조절

Abstract

전신홍반루푸스(systemic lupus erythematosus)는 대표적인 체액성 자가면역질환으로 자가항체 역가가 높은 특징을 보이고 흔히 신장염을 동반한다. 아직까지 스테로이드, 항말라리아제를 포함한 면역억제제들이 치료의 근간을 이루나 효능이 제한적이고 부작용을 초래하기 때문에 새로운 치료제의 개발이 필요하다. 중간엽 줄기세포는 면역원성(immunogenicity)이 낮고 면역 조절 기능이 있어 여러 난치성 면역질환 치료에 사용 가능성이 제시되었으나 그 작용기전에 대한 연구는 아직 미흡한 실정이다. 본 연구에서는 전신홍반루푸스에서 중간엽 줄기세포의 효능 및 작용기전을 조사하기 위하여 NZB/W F1마우스 모델에 정상인의 골수에서 유래된 중간엽 줄기세포를 전임상적시기와 발병 초기에 반복적으로 정맥주사하였다. 모든 중간엽 줄기세포 주사군은 대조군에 비하여 생존율이 개선되고 질환 발병율과 단백뇨 수치가 유의성 있게 낮았다. 하지만 항-이중나선 DNA항체 역가는 그룹간 차이가 없었다. 콩팥 조직 절편을 과요오드산 쉬프염색으로 관찰한 결과 중간엽 줄기세포 주사군에서 사구체신염지수가 현저히 감소하였다. 중간엽 줄기세포 주사군의 비장과 림프절에서 체액성 자가면역질환에 중요한 역할을 하는 여포보조 T세포, 종자중심 B세포, 형질세포의 비율 및 세포수가 대조군에 비해 감소하였다. 혈액내 순환성 여포보조 T세포 빈도도 감소하였다. 실제로 중간엽 줄기세포가 여포보조 T세포의 발생을 억제하는지 알아보기 위하여 미감작 CD4+T세포를 여포보조 T세포 분화조건에서 배양할 때 중간엽 줄기세포를 첨가하면 여포보조 T세포의 마스터 전사인자인 BCL-6의 발현이 감소하였다. 그러므로, 이 실험결과들은 중간엽 줄기세포가 체내에서 여포보조 T세포 분화를 억제하여 체액성 면역반응을 조절하는 기전을 통해 루푸스의 예방 및 치료 효과에 기여함을 추정케한다.|Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to components of the cell nucleus. Immune complex-mediated inflammatory responses are known to precipitate clinical manifestations in multiple organs including nephritis. Several recent studies provided therapeutic effects of mesenchymal stem cells (MSCs) in experimental SLE, but the mechanism underlying such effects remains unclear. Here we addressed where MSCs impinge on the pathogenesis of SLE using a SLE model, female F1 hybrids crossed NZB mice with NZW mice, referred to as NZBxNZW. These mice with disease in the preclinical and early clinical phases were injected intravenously with MSCs derived from healthy human bone marrow, and disease onset and progression were analyzed. MSC-treated mice exhibited a higher survival rate, a lower incidence of proteinuria, and a lower histologic score of nephritis than vehicle-treated mice. These effects were more prominent in the mice treated during the preclinical phase than in mice treated during the early clinical phase. Spleens and lymph nodes from MSC-treated mice contained significantly fewer follicular helper T cells, germinal center B cells and plasma cells than those from vehicle-treated mice. Fewer plasma cells were found in the kidney of MSC-treated mice. In in vitro settings, MSC treatment suppressed the differentiation of naive CD4+ T cells toward cells expressing BCL6, a master transcription factor for follicular helper T cells. Thus, the effect of MSC to prevent and/or ameliorate SLE seems to be mediated by their potential to suppress the development of follicular helper T cells and subsequent activation of humoral immune components.; Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to components of the cell nucleus. Immune complex-mediated inflammatory responses are known to precipitate clinical manifestations in multiple organs including nephritis. Several recent studies provided therapeutic effects of mesenchymal stem cells (MSCs) in experimental SLE, but the mechanism underlying such effects remains unclear. Here we addressed where MSCs impinge on the pathogenesis of SLE using a SLE model, female F1 hybrids crossed NZB mice with NZW mice, referred to as NZBxNZW. These mice with disease in the preclinical and early clinical phases were injected intravenously with MSCs derived from healthy human bone marrow, and disease onset and progression were analyzed. MSC-treated mice exhibited a higher survival rate, a lower incidence of proteinuria, and a lower histologic score of nephritis than vehicle-treated mice. These effects were more prominent in the mice treated during the preclinical phase than in mice treated during the early clinical phase. Spleens and lymph nodes from MSC-treated mice contained significantly fewer follicular helper T cells, germinal center B cells and plasma cells than those from vehicle-treated mice. Fewer plasma cells were found in the kidney of MSC-treated mice. In in vitro settings, MSC treatment suppressed the differentiation of naive CD4+ T cells toward cells expressing BCL6, a master transcription factor for follicular helper T cells. Thus, the effect of MSC to prevent and/or ameliorate SLE seems to be mediated by their potential to suppress the development of follicular helper T cells and subsequent activation of humoral immune components.