Modeling Immune Desensitization in Renal Transplantation

描述（由申请人提供）：供体特异性抗体（DSA）仍然是肾移植的实质性障碍。DSA是针对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。超过18000名肾移植等待名单上的患者有显著的同种抗体水平，25%的活体肾供者因ABO血型不合而被排除在外。抗abo抗体通过结合供体血管内皮引起肾移植排斥反应，导致大血管血栓形成和器官丧失。为了避免敏感或ABO不相容受体的排斥反应，移植前免疫脱敏（IMDS）是必要的。IMDS原cols结合了几种治疗方法：(i)通过治疗性血浆交换（PLEX）去除循环DSA； （ii）静脉注射免疫球蛋白（IVIG）治疗改变DSA的部分分解代谢；（iii）药理学浆细胞消耗抑制DSA合成；（iv） B细胞消耗治疗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安全阈值或出现副作用（特别是出血和感染）时，许多患者无法进行IMDS。目前还没有被广泛接受的工具来指导IMDS药物的时间、剂量和选择。[这个项目的总体目标是开发一个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)构建和验证抗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)验证PLEX和IVIG治疗改变抗abo IgG B细胞稳态的假设，并扩展模型，以便在需要时考虑这一特征；(3)验证目标1和目标2中建立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IgG合成和分解代谢动力学的室室模型，以适应实际的临床方案。在接受PLEX、IVIG和血浆细胞消耗治疗的患者中，将测量抗abo抗体水平和B细胞表型。这些数据将用于开发和改进模型，并估计模型参数。最后，我们将评估该模型在接受ABO不相容肾移植标准免疫脱敏患者的独立样本中预测免疫脱敏成功或失败的程度，该标准免疫脱敏结合了PLEX， IVIG和血浆细胞消耗疗法。]

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. ]