Prevention of Platelet Alloimmunization by Costimulatory Blockade

通过共刺激阻断预防血小板同种免疫

• 批准号: 8783253
• 负责人: JAMES C. ZIMRING
• 金额: $ 46.75万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783253
• 关键词: Acute Myelocytic Leukemia; Affect; Alloantigen; Alloimmunization; Antibodies; Antigens; Applications Grants; Biological Models; Blood Platelets; Bone Marrow Transplantation; CTLA4 gene; CTLA4-Ig; Data; Disease; Drops; Engineering; Epitopes; Event; FDA approved; General Population; Genetic Polymorphism; Goals; Grant; HLA Antigens; Hemorrhage; Hemostatic function; Histocompatibility Antigens Class I; Human; Human Platelet Antigens; Immune response; Immune system; Immunity; Immunization; Immunology; Immunosuppression; Immunosuppressive Agents; Intervention; Isoantibodies; Lead; Life; Medical; Modeling; Mus; Organ; Organ Donor; Organ Transplantation; Pathology; Patients; Platelet Count measurement; Platelet Transfusion; Population; Pre-Clinical Model; Prevention; Process; Prophylactic treatment; Proteins; Reagent; Refractory; Regimen; Residual state; Risk; Series; Solid; System; T memory cell; Technology; Testing; Therapeutic; Thrombocytopenia; Time; Transfusion; Translations; Transplantation; Virus Diseases; Waiting Lists; Work; base; control trial; design; immunosuppressed; leukocyte antigen typing; novel therapeutic intervention; pathogen exposure; patient population; pre-clinical; prevent; public health relevance; tool; ultraviolet irradiation

DESCRIPTION (provided by applicant): Transfusion of platelets is a potentially life-saving therapy to maintain hemostasis in patients with severe thrombocytopenia. One of the main impediments to ongoing platelet transfusions is humoral immunization to platelet alloantigens, predominantly HLA antigens (MHC class I). Once alloantibodies have been formed, HLA incompatible platelets can be rapidly cleared by the recipient, resulting in little or no increase n platelet counts and thus essentially no therapeutic benefit. If a patient generates alloantibodies against multiple HLA epitopes, then finding compatible platelets can become difficult, and in many cases impossible. With alloimmunization to multiple HLA types, platelets can cease to be a viable therapy for thrombocytopenia. For patients who only need transient support with platelet transfusion, alloimmunization is not typically a serious problem; however, in patients who require ongoing therapy, anti-HLA antibodies can eliminate a life-saving therapy for which there is typically no viable substitute. In addition to rendering platelet transfusions ineffective the induction of anti-HLA antibodies can also complicate subsequent transplantation. As platelet transfusions are given to some patient populations as support while they are awaiting organ transplantation, induction of anti-HLA antibodies has an additional negative impact on this population, both from the standpoint of complicating the transplant and also potentially moving the patient down the waiting list for donor organs. The implementation of filter leukoreduction has decreased rates of alloimmunization to platelet transfusion, but residual rates remain at approximately 20%, with 1 in every 5 transfusion recipients becoming alloimmunized. Thus, additional interventions are required to reduce alloimmunization rates. Co-stimulatory blockade is a strategy to prevent alloimmunization, which has now come to fruition with the FDA approval of CTLA4-Ig. This grant application is a pre-clinical effort to begin translation of CTLA4- Ig for use in preventing alloimmunization to transfused platelets. This approach would not be used in the general population, but focused on select patient populations who are particularly vulnerable to HLA alloimmunization (patients requiring ongoing platelet transfusion and/or awaiting transplantation). We have developed a murine model of alloimmunization to transfusion of filter leukoreduced platelets. In this system, CTLA4-Ig abrogates alloimmunization and prevents recipients from becoming refractory to platelet transfusion. The model system has been engineered to have sufficient tools to allow detailed mechanistic elucidation of CTLA4-Ig function. The proposed studies are a hypothesis driven effort designed to both generate basic understanding of the immunology of platelet alloimmunization and CTLA4-Ig mechanisms of action, but with a distinct focus on pre-clinical issues necessary for subsequent human trials of CTLA4-Ig therapy to prevent alloimmunization to transfused platelets.

描述（由申请方提供）：血小板输注是一种潜在的挽救生命的治疗方法，可维持重度血小板减少症患者的止血。持续血小板输注的主要障碍之一是血小板同种异体抗原的体液免疫，主要是HLA抗原（MHC I类）。一旦形成同种抗体，HLA不相容的血小板可以被受体迅速清除，导致血小板计数很少或没有增加，因此基本上没有治疗益处。如果患者产生针对多个HLA表位的同种抗体，那么寻找相容的血小板可能变得困难，并且在许多情况下是不可能的。随着对多种HLA类型的同种异体免疫，血小板可能不再是血小板减少症的可行疗法。对于仅需要血小板输注短暂支持的患者，同种异体免疫通常不是一个严重的问题;然而，在需要持续治疗的患者中，抗HLA抗体可以消除通常没有可行替代品的挽救生命的治疗。除了使血小板输注无效外，抗HLA抗体的诱导也可使随后的移植复杂化。由于在等待器官移植的同时向一些患者群体给予血小板输注作为支持，因此从使移植复杂化以及还可能使患者在供体器官的等待名单上向下移动的观点来看，抗HLA抗体的诱导对该群体具有额外的负面影响。过滤器去白细胞的实施降低了血小板输注的同种免疫率，但残留率仍保持在20%左右，每5名输血者中就有1人获得同种免疫。因此，需要采取额外的干预措施来降低同种免疫率。共刺激阻断是一种预防同种免疫的策略，随着FDA对CTLA 4-IG的批准，该策略现已实现。该授权申请是临床前努力，以开始翻译CTLA 4- IG，用于防止输注血小板的同种异体免疫。这种方法不会用于一般人群，而是专注于选择特别容易受到HLA同种异体免疫的患者人群（需要持续血小板输注和/或等待移植的患者）。我们建立了一种输注过滤去白细胞血小板的同种异体免疫小鼠模型。在该系统中，CTLA 4-IG消除同种异体免疫并防止受体变得对血小板输注难治。该模型系统已被设计为具有足够的工具，以允许详细的CTLA 4-IG功能的机制阐明。所提出的研究是一种假设驱动的努力，旨在产生对血小板同种异体免疫的免疫学和CTLA 4-IG作用机制的基本理解，但明显侧重于CTLA 4-IG治疗的后续人体试验所需的临床前问题，以防止输注血小板的同种异体免疫。