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Maintenance and targeting of bone marrow derived allo-reactive human plasma cells

骨髓来源的同种异体反应性人浆细胞的维持和靶向

基本信息

批准号：
9307716
负责人：
Kay Lynn Medina
金额：
$ 19.88万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307716
关键词：
Acute Aftercare Alpha Cell Antibodies Antibody Formation Antigens Apoptosis Apoptotic Biological Assay Biology Bone Marrow Bortezomib Cell Line Cell secretion Chronic Clinical Coculture Techniques Complex Development Drug Targeting Failure Frequencies Graft Survival Hour Human Human Biology Immunoglobulin A Immunoglobulin G Immunosuppressive Agents Immunotoxins In Vitro Interleukin-6 Isoantibodies Kidney Transplantation Leukocytes Longevity Maintenance Memory B-Lymphocyte Mesenchymal Modeling Mus New Agents Organ Transplantation Pathway interactions Patients Phenotype Plasma Cells Plasmablast Protocols documentation Reagent Recombinants Resistance Sampling Serum Signal Transduction Source Stromal Cells System Testing Therapeutic Therapeutic Agents Transplant Recipients Transplantation Waiting Lists desensitization effective therapy efficacy testing enhancing factor experimental study in vitro Model in vivo kidney allograft nanoparticle novel novel therapeutics peripheral blood prevent reagent testing resistance mechanism targeted agent therapy resistant

项目摘要

Abstract Donor-specific alloantibodies (DSA) against HLA Class I and Class II are a major problem in organ transplantation. DSA can cause acute and chronic rejection and can be a major barrier to finding an acceptable donor when present pre-transplant in “sensitized patients”. Unfortunately, no effective therapy exists to either deplete DSAs or block their effect. Our prior studies suggested that bone marrow (BM)-derived long-lived plasma cells (LLPCs) are a major source of persistent serum DSA. LLPCs are rare, poorly characterized and resistant to most current therapy in vivo. The mechanism of resistance to therapy may be due to the fact that LLPCs reside in pro-survival microenvironments/niches in which supporting stromal cells and leukocytes provide factors that enhance LLPCs longevity and prevent erstwhile apoptotic signals. Due to difficulties in procuring, isolating, and culturing human BM LLPCs, much of the biology of human PCs remains unclear and this has hindered the development of effective therapies. To overcome this problem, we developed an in vitro PC/stromal cell co-culture model. We now can maintain human PCs on mouse mesenchymal stromal cell (SC) lines in the presence of recombinant human IL-6. After 6 weeks culture, these PCs retain the typical PC phenotype and robustly secrete IgG and IgA Igs. Using this novel system, we now are poised to study functional BM-derived PCs in vitro and interrogate factors responsible for their longevity and antibody production.

抗HLA I类和II类供者特异性同种抗体（DSA）是目前研究的主要热点，器官移植的问题。DSA可引起急性和慢性排斥反应，在移植前存在于“致敏”的情况下，病人”。不幸的是，没有有效的治疗方法来消除DSA或阻断其作用。我们先前的研究表明，骨髓（BM）来源的长寿命浆细胞（LLPC）是持续性血清DSA的主要来源。LLPC是罕见的，特征不佳，耐药最新的体内治疗。对治疗产生抵抗的机制可能是由于 LLPC位于支持基质细胞的促生存微环境/小生境中，白细胞提供了增强LLPC寿命和防止以前凋亡的因子信号.由于在获得、分离和培养人BM LLPC方面的困难，人类PC的生物学仍然不清楚，这阻碍了有效的治疗为了克服这个问题，我们开发了一种体外PC/基质细胞共培养模型。我们现在可以在小鼠间充质基质细胞（SC）系上维持人PC，存在重组人IL-6。培养6周后，这些PC保持典型PC 表型并强烈分泌IgG和伊加Ig。利用这个新系统，我们现在可以体外研究功能性BM衍生PC并询问负责其寿命的因素和抗体生产。