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.

摘要针对 HLA I 类和 II 类的供体特异性同种抗体 (DSA) 是一种主要的抗体。器官移植中的问题可能会导致急性和慢性排斥反应。当移植前存在“致敏”时，寻找可接受的供体的主要障碍不幸的是，目前还没有有效的疗法可以消除 DSA 或阻止其作用。我们之前的研究表明，骨髓 (BM) 来源的长寿浆细胞 (LLPC) 持久性血清 DSA 的主要来源是罕见的、特征较差且具有抗性。目前大多数体内治疗的耐药机制可能是由于这一事实。 LLPC 存在于有利于生存的微环境/生态位中，其中支持基质细胞白细胞提供了增强 LLPC 寿命并防止昔日细胞凋亡的因子由于获取、分离和培养人类 BM LLPC 存在困难，许多人类 PC 的生物学特性仍不清楚，这阻碍了有效性的发展为了克服这个问题，我们开发了体外 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) 系上维持人类 PC 存在重组人 IL-6 培养 6 周后，这些 PC 保留了典型的 PC。使用这个新颖的系统，我们现在准备好了。体外研究功能性 BM 衍生 PC 并探究影响其寿命的因素和抗体的产生。