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UVB-WBC INDUCED TOLERANCE IN BONE MARROW TRANSPLANTATION

UVB-WBC 在骨髓移植中诱导耐受

基本信息

批准号：
6183312
负责人：
K J Kao
金额：
$ 21.27万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-07 至 2002-06-30
项目状态：
已结题

项目摘要

The long term objective of this proposal is to establish a safe and effective method of using UVB-irradiated peripheral blood leukocytes to induce specific immune tolerance for transplantation of allografts. Prompted by the recent feasibility of preparing UvB- treated platelet concentrates (PC) for patient use and by animal studies suggesting that transfusions of Uv-treated PC can induce partial immune tolerance, we have conducted a series of experiments to characterize immune tolerance induced by transfusions of UvB- irradiated leukocytes in a murine model. Results of our study show that the use of purified UVB-leukocytes with little contamination of plasma and platelets is the key to achieve 100% induction of complete humoral immune tolerance to non-self MHC antigens. However, it is not known whether cellular immune tolerance can be induced by the same approach and applied to allogeneic bone marrow transplantation (BMT) or transplantation of solid allografts. In order to answer these questions, three specific aims are proposed in this application. Specific Aim l is to demonstrate the induction of cellular immune tolerance of UVB-leukocytes. Three approaches will be used: l) to determine whether graft-versus.-host disease (GVHD) induced by allogeneic BMT can be prevented by using bone marrow from donors tolerant to recipient MHC antigens; 2) to investigate whether cytotoxic T cell activity restricted to H-2 antigen of UVB-leukocytes is attenuated after tolerance induction; and 3) to study whether bone marrow (BM) mixed chimerism can be more easily established after sublethal irradiation in mice tolerant to BM donors. Specific Aim 2 is to characterize cellular mechanism of tolerance induction of UVB-leukocytes. We will determine: i) role of class II MHC positive cells in tolerance induction, 2) in vitro cytokine production profile by T cells of tolerant mice, 3) MHC specificity and durability of the induced cellular immune tolerance, and 4) identity of the induced suppressor cells in tolerant mice. Specific Aim 3 is to investigate potential application of UVB-leukocytes in allogeneic BMT to prevent GVHD while preserving graft-versus.-leukemia (GVL) activity. We will investigate whether better GVL activity will result without GVHD in lethally irradiated mice engrafted with BM from tolerant donors, and whether leukemic growth can be prevented in tolerant mice with established BM mixed chimerism. Allogeneic BMT system is chosen for our study mainly for its technical simplicity, and our interest and expertise in BMT. The study proposed herein should enable us to obtain the necessary information for translating tolerance induction b UVB-leukocytes to clinical practice.

这项建议的长远目标是建立一个安全和一种有效利用UVB照射外周血的方法白细胞诱导移植特异性免疫耐受同种异体移植由于最近制备UVB的可行性，患者使用和动物使用的经处理血小板浓缩物（PC）研究表明，输注紫外线处理的PC可以诱导部分免疫耐受，我们进行了一系列实验，为了表征由UvB输注诱导的免疫耐受，小鼠模型中的辐射白细胞。我们的研究结果表明，使用几乎没有污染的纯化的UVB白细胞血浆和血小板是实现100%诱导的关键。对非自身MHC抗原的完全体液免疫耐受。然而，尚不清楚细胞免疫耐受是否可以被通过相同的方法诱导并应用于同种异体骨髓移植（BMT）或实体同种异体移植物的移植。在为了回答这些问题，提出了三个具体目标在这个应用中。具体目的是证明诱导 UVB-白细胞的细胞免疫耐受性。三种方法将用于：l）确定移植物是否与. -宿主病同种异体骨髓移植诱导的移植物抗宿主病（GVHD）可以通过骨移植来预防来自对受体MHC抗原耐受的供体的骨髓; 2）研究细胞毒性T细胞活性是否局限于H-2 耐受诱导后UVB-白细胞抗原减弱; 3）研究骨髓（BM）混合嵌合体是否可被小鼠亚致死照射后更容易建立对骨髓捐赠者的耐受性。具体目标2是表征细胞 UVB-白细胞耐受诱导的机制。我们将确定：i）II类MHC阳性细胞在耐受性中的作用诱导，2）通过T细胞的体外细胞因子产生概况，耐受小鼠，3）诱导的MHC特异性和持久性细胞免疫耐受，以及4）诱导的耐受小鼠中的抑制细胞。具体目标3是调查 UVB-白细胞在异基因骨髓移植中的潜在应用，防止GVHD，同时保留移植物抗宿主。白血病（GVL）活动我们将研究更好的GVL活动是否会移植BM的致死性照射小鼠中无GVHD的结果以及是否可以预防白血病的生长在具有已建立的BM混合嵌合体的耐受小鼠中。同种异体选择BMT系统进行研究，主要是因为其技术简单性，以及我们对BMT的兴趣和专业知识。研究在此提出的建议应使我们能够获得必要的将耐受诱导B UVB-白细胞转化为临床实践