Targeting the B Cell Response to Treat Antibody-Mediated Rejection

靶向 B 细胞反应来治疗抗体介导的排斥反应

• 批准号: 10636822
• 负责人: Stuart Johnston Knechtle
• 金额: $ 258.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636822
• 关键词: Affect; Allogenic; Allografting; American; Antibodies; Antibody Therapy; Antibody-Producing Cells; Arteritis; B cell therapy; B-Cell Activation; B-Lymphocytes; Binding; Biological Assay; Biopsy; Cell Communication; Cell Compartmentation; Cell physiology; Cells; Chronic; Clinical; Cluster Analysis; Conduct Clinical Trials; Controlled Study; Cytomegalovirus; Data; Diagnosis; Dialysis procedure; End stage renal failure; Ensure; Ethics; Failure; Graft Survival; Half-Life; Healthcare; Heart Transplantation; Hemodialysis; Histologic; Human; Image Analysis; Immune; Immune Targeting; Immune system; Immunity; Immunologics; Infection; Inflammation; Injury; Intervention; Intervention Studies; Intravenous Immunoglobulins; Investigational Therapies; Isoantibodies; Kidney; Kidney Transplantation; Level of Evidence; Life; Longevity; Lung Transplantation; Lymphocyte Activation; Malignant Neoplasms; Measures; Mediating; Memory; Memory B-Lymphocyte; Methods; Modeling; Monitor; Organ Donor; Organ Transplantation; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Plasma Cells; Plasmablast; Plasmapheresis; Population; Predisposition; Prevention; Process; Prognosis; Proteasome Inhibition; Proteasome Inhibitor; Proteinuria; Public Health; Randomized; Reaction; Regimen; Renal function; Resistance; Risk; Risk Assessment; Safety; Solid; Standardization; Structure of germinal center of lymph node; Surrogate Markers; System; T-Lymphocyte; Testing; Therapeutic Uses; Time; Transplant Recipients; Transplantation; Treatment Efficacy; Tubular formation; United States; Visual; antibody-mediated rejection; care costs; comparison control; deep learning; desensitization; digital; digital imaging; donor-specific antibody; effective therapy; experience; health goals; human data; improved; improved outcome; infection risk; interstitial; kidney biopsy; machine learning algorithm; mortality; nonhuman primate; novel; pathogen; post-transplant; predict clinical outcome; predicting response; prevent; prospective; public health relevance; response; restoration; retransplantation; rituximab; targeted treatment; tool; treatment comparison; treatment response; whole slide imaging

ABSTRACT Antibody-mediated rejection (AMR) of solid organ transplants is the leading cause of immunologic graft injury, shortening the half-life of transplants and consequently of transplant recipients. This immunologically mediated process depends on B lymphocyte activation with differentiation to plasma cells (PC) that produce antibodies to the donor organ. Once established, antibodies have proven difficult to eradicate. Establishing an effective and safe way to treat patients with established AMR would potentially increase the half-life of transplanted organs, extend the lives of patients, and reduce the need for re-transplantation, ultimately increasing the number of patients who could receive life-saving organ transplants. Our lab has described an effective therapy in a non- human primate (NHP) sensitized model of kidney transplantation for lowering donor-specific antibody (DSA) and preventing injury from AMR. The treatment depends on PC depletion in combination with germinal center disorganization which together lower alloantibody levels. Dual targeting of the immune system by complementary drugs is based on NHP and human data using a proteasome inhibitor and belatacept. B cell activation and differentiation is inhibited at the same time that PC are depleted. Consequently, DSA declines, inflammation in the kidney resolves, and renal function stabilizes. The impact of this intervention on infection risk is not well defined but is anticipated to increase. We propose to measure the impact of therapy on both HLA-specific and pathogen-specific B memory cells and PC. We hypothesize that there is a hierarchy of susceptibility to therapy, with protective immunity being more resistant than allogeneic B cell memory. We will evaluate the impact of the regimen on T-cell function focusing on cytomegalovirus (CMV). Current therapy of late AMR using therapeutic plasma exchange (TPE) and intravenous immune globulin (IVIG) with or without rituximab has shown variable results and frequent rebound of DSA. A low level of evidence supports the efficacy of these treatments, implying a tremendous need for well-conducted clinical trials to guide treatment of AMR. We propose a Phase I/II randomized, controlled, prospective interventional study of AMR in human kidney transplant patients using combined carfilzomib/belatacept (C/B) therapy with TPE and IVIG compared to TPE/IVIG alone. Outcomes will include the clinical impact of therapy on AMR using the recently validated iBox score for AMR assessment and the number and type of infections using standardized definitions of infection. We will measure the impact of therapy on HLA and pathogen-associated B memory and PC as well as CMV-specific polyfunctional T-cells. We will assess computational digital imaging analysis of AMR non-visual biopsy features to assess whether machine learning algorithms can improve on Banff criteria of AMR to better guide treatment and predict clinical outcome. Since late active and chronic active AMR have such a poor prognosis for kidney transplant patients, we believe that this trial is ethically justified and would potentially yield important safety and preliminary efficacy data that may lead to improved immune management of transplant patients.

摘要