신장이식을 위한 면역관용유도항체 기반의 면역조절 방안 개발 Development of immune regulatory protocol for kidney transplantation based on tolerance-inducing therapeutic antibody원문보기
본 연구팀이 자체적으로 개발한 T 면역관용 유도항체인 MD-3를 동종신장이식에 적용하기 위한 면역조절 프로토콜을 확립하기 위하여 본 연구를 수행하였음. ● MD-3 항체(이식전 3회 투여)와 기존 면역조절약물과의 병합 투여 프로토콜 5가지의 효능을 비교 평가하였으며, mycophenolate mofetil(MMF) 병합 투여가 공여자 특이 항체(donor-specific antibody, DSA) 생성억제에 매우 효과적임을 확인하였음. ● MD-3와 항-CD154 항체 병합 투여 프로토콜 2가지를 비교 평가하였으며, 항-
본 연구팀이 자체적으로 개발한 T 면역관용 유도항체인 MD-3를 동종신장이식에 적용하기 위한 면역조절 프로토콜을 확립하기 위하여 본 연구를 수행하였음. ● MD-3 항체(이식전 3회 투여)와 기존 면역조절약물과의 병합 투여 프로토콜 5가지의 효능을 비교 평가하였으며, mycophenolate mofetil(MMF) 병합 투여가 공여자 특이 항체(donor-specific antibody, DSA) 생성억제에 매우 효과적임을 확인하였음. ● MD-3와 항-CD154 항체 병합 투여 프로토콜 2가지를 비교 평가하였으며, 항-CD154 항체와 MMF를 지속 투여하여 현재 1년 이상 거부반응이 발생하지 않고 있으며, DSA도 생성되지 않았음. ● MD-3를 3개월간 반복 투여하는 프로토콜은 현재 2개월 가까이 거부반응이 발생하지 않았고 있음. ● 한편, MD-3에 의한 초기 신호전달 기전을 규명하였으며, 특허 출원하였음. ● 또한, MD-3가 수지상세포뿐만 아니라 myeloid derived suppressor cell(MDSC)의 발달과 기능을 조절함으로써 면역관용에 관여함을 규명하였음.
(출처 : 보고서 요약서 4p)
Abstract▼
Although currently used immunosuppressive drugs had prolonged allo-graft survival, they cause diverse side effects such as infection, organ damage, and increased cancer incidence. An ideal strategy to overcome this situation is the induction of transplantation tolerance.
In the present study,
Although currently used immunosuppressive drugs had prolonged allo-graft survival, they cause diverse side effects such as infection, organ damage, and increased cancer incidence. An ideal strategy to overcome this situation is the induction of transplantation tolerance.
In the present study, we tried to develop safe and effective immune regulation protocol for a long term survival of renal allograft, based on the T cell tolerance-inducing MD-3 antibody. For this, we established kidney allograft model in Rhesus monkeys, and evaluate the effect of MD-3 antibody in the prevention of graft rejection. We first tested 5 protocols in which MD-3 was combined with currently used immunosuppressants. We then tested 2 protocols using MD-3 and anti-CD154 antibody. We are now investigating whether MD-3 treatment for extended period allows longer survival of renal allograft with fewer side effects, compared with tested protocols. We also dissected intracellular signaling pathway transduced by ICAM-1 molecules via MD-3 treatment and immune regulating mechanisms by MD-3 antibody.
To set up a renal allo-transplantation model in non-human primates, surgical techniques, pre-transplantation screening methods, and post-operative monitoring methods were established Then, when MD-3 was applied in combination with anti-thymocyte globulin (ATG), tacrolimus, mycophenolate mofetil (MMF), steroid, or rapamycin, MMF was effective in prolongation of graft survival an prevention of donor-specific antibody (DSA) development. When MD-3 and anti-CD154 antibodies were administrated with MMF, graft is both alive and are currently well maintained more than 1 year without rejection episode or DSA development. In Rhesus that received renal graft 2 months ago with extended MD-3 administration protocol, graft is also well functioning until now. Regarding intracellular signaling pathway, we found two signaling molecules activated by ICAM-1 ligation via MD-3, and Affymetrix microarray revealed that several genes involved in tolerance induction or anti-viral immunity are upregulated in MD-3-treated monocytes compared with another anti-ICAM-1 antibody, R6.5.D6-treated cells. We identified conformation epitope of ICAM-1 recognized by MD-3, and critical motif for signal transduction, which is essential for MD-3 function. We also found that MD-3 is able to suppress T cell immune response via modulating monocyte and myeloid-derived suppressor cells in addition to dendritic cells. For functional study, we developed transgenic mice expressing human ICAM-1 and found MD-3 block dendritic cells generation process form precursor cells in bone marrow.
In next step, we are willing to select the best protocol and perform preclinical studies for application of MD-3-based protocol in patients who receive renal allo-transplantation as well as other solid organ transplantation. The selected protocol will be applicable to the other immune-related disorders such as autoimmune disease and graft-versus-host disease.
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