Modeling Immune Desensitization in Renal Transplantation

肾移植中的免疫脱敏建模

• 批准号: 8234272
• 负责人: Martin S Zand
• 金额: $ 38.34万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234272
• 关键词: ABO blood group system; Accounting; Adverse effects; Antibodies; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; Carbohydrates; Caring; Catabolism; Cells; Clinical; Clinical Protocols; Clinical Treatment; Combined Modality Therapy; Data; Dose; Enzyme-Linked Immunosorbent Assay; Equation; Excision; Failure; Flow Cytometry; Generations; Goals; Hemorrhage; Homeostasis; Human; Immune; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Therapy; Immunoglobulins; Immunotherapy; Individual; Infection; Intravenous Immunoglobulins; Isoantibodies; Kidney; Kidney Transplantation; Kinetics; Left; Life; Living Donors; MHC antigen; Measurable; Measures; Mediating; Memory B-Lymphocyte; Metabolic Clearance Rate; Metabolism; Methods; Modeling; Organ; Patients; Peripheral; Phenotype; Plasma Cells; Plasma Exchange; Plasmablast; Plasmapheresis; Population; Population Analysis; Production; Protocols documentation; Sampling; Structure; Structure of germinal center of lymph node; Testing; Thrombosis; Time; Tissues; Transplantation; Vaccines; Validation; Vascular Endothelium; Waiting Lists; desensitization; design; human subject; improved; inhibitor/antagonist; mathematical model; men; multicatalytic endopeptidase complex; novel; pathogen; peripheral blood; response; rituximab; success; therapy design; tocol; tool

DESCRIPTION (provided by applicant): Donor-specific antibodies (DSA) continue to be a substantial barrier to renal transplantation. DSA are directed at MHC antigens (alloantibody), tissue antigens, or ABO blood group carbohydrates. These antibodies are thought to arise from germinal center (GC) and marginal zone (MZ) B cells, respectively. Over 18,000 pa- tients on the kidney transplant waiting list have significant alloantibody levels, and 25% of living kidney donors is excluded due to ABO incompatibility. Anti-ABO antibodies cause rejection of kidney transplants by binding to donor vascular endothelium, leading to macrovascular thrombosis and organ loss. To avoid rejection in sen- sitized or ABO incompatible recipients, pre-transplant immune desensitization (IMDS) is needed. IMDS proto- cols combine several therapies: (i) removal of circulating DSA by therapeutic plasma exchange (PLEX) (ii) pooled intravenous immunoglobulin (IVIG) therapy to alter the fractional catabolism of DSA, (iii) pharmacologic plasma cell depletion to suppress DSA synthesis, and (iv) B-cell depleting therapies to decrease donor-specific memory B cells. However, many patients fail IMDS when DSA levels cannot be reduced to a threshold safe for a kidney transplant or when side effects occur, especially bleeding and infection. No widely-accepted tools currently exist to guide the timing, dosing, and selection of IMDS agents. [The overall objective of this project is to develop a mathematical model of immune desensitization as a clinical tool to guide personalized therapy. The specific goals are: (1) to construct and validate a differential equation model of anti-ABO IgG kinetics and clinical therapies for immune desensitization, including exploration of alternative models; (2) to test the hypothesis that PLEX and IVIG therapies alter anti-ABO IgG B cell homeostasis, and to extend the model so it accounts for this feature, if needed; (3) to validate the ability of the model developed in Aims 1 and 2 to predict the response of individual patients to IMDS therapy and potential complications. We will further develop a compartmental model of IgG synthesis and catabolism kinetics which accommodates actual clinical protocols. Anti-ABO antibody levels and B cell phenotypes will be measured in patients undergoing PLEX, IVIG and plasma cell depleting therapies. This data will be used to develop and refine the model, and to estimate model parameters. Finally, we will evaluate how well the model predicts the success or failure of immune desensitization in an independent sample of patients undergoing standard immune desensitization for ABO incompatible kidney transplantation, which combines PLEX, IVIG, and plasma- cell depleting therapies. ] PUBLIC HEALTH RELEVANCE: This project proposes to develop a highly clinically applicable model to design treatment for a type of kidney transplantation. If successful, it would greatly advance the field of kidney transplantation, and improve the chances of success for a living donor, ABO incompatible kidney transplant.

描述（由申请方提供）：供体特异性抗体（DSA）仍然是肾移植的实质性障碍。DSA针对MHC抗原（同种抗体）、组织抗原或ABO血型碳水化合物。这些抗体被认为分别来自生发中心（GC）和边缘区（MZ）B细胞。肾移植等候名单上超过18，000名患者具有显著的同种抗体水平，并且25%的活体肾供体由于ABO不相容而被排除在外。抗ABO抗体通过与供体血管内皮结合而引起肾移植排斥，导致大血管血栓形成和器官丧失。为了避免敏感或ABO血型不合的受者发生排斥反应，需要进行移植前免疫脱敏（IMDS）。IMDS原型结合了联合收割机几种疗法：（i）通过治疗性血浆置换（PLEX）去除循环DSA，（ii）合并静脉内免疫球蛋白（IVIG）疗法以改变DSA的部分催化剂，（iii）药理学浆细胞耗竭以抑制DSA合成，和（iv）B细胞耗竭疗法以减少供体特异性记忆B细胞。然而，当DSA水平不能降低到肾移植的安全阈值或发生副作用时，许多患者的IMDS失败，特别是出血和感染。目前还没有广泛接受的工具来指导IMDS药物的时机、剂量和选择。 [The本项目的总体目标是开发免疫脱敏的数学模型，作为指导个性化治疗的临床工具。具体目标是：（1）构建并验证抗ABO IgG动力学和免疫脱敏临床治疗的微分方程模型，包括探索替代模型;（2）检验PLEX和IVIG治疗改变抗ABO IgG B细胞稳态的假设，并扩展该模型，以便在需要时解释该特征;（3）验证目标1和2中开发的模型预测个体患者对IMDS治疗的反应和潜在并发症的能力。我们将进一步开发一个房室模型的IgG合成和catalysts动力学，以适应实际的临床协议。将在接受PLEX、IVIG和浆细胞耗竭治疗的患者中测量抗ABO抗体水平和B细胞表型。这些数据将用于开发和完善模型，并估计模型参数。最后，我们将评估该模型在接受标准免疫脱敏治疗的ABO血型不合肾移植患者的独立样本中预测免疫脱敏成功或失败的程度，该标准免疫脱敏治疗结合了PLEX、IVIG和浆细胞耗竭疗法。] 公共卫生相关性：本项目旨在开发一种高度临床适用的模型，以设计一种类型的肾移植治疗。如果成功的话，它将大大推进肾移植领域，并提高活体供者ABO血型不合肾移植的成功率。