Prevention of Platelet Alloimmunization by Costimulatory Blockade

描述（由申请人提供）：输注血小板是一种潜在的挽救生命的治疗方法，用于维持严重血小板减少症患者的止血。血小板输注的主要障碍之一是血小板异体抗原的体液免疫，主要是HLA抗原（MHC I类）。一旦同种异体抗体形成，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效果。如果患者产生针对多个HLA表位的同种异体抗体，那么寻找相容的血小板就会变得困难，在许多情况下是不可能的。随着对多种HLA类型的同种免疫，血小板可能不再是治疗血小板减少症的可行方法。对于只需要短暂的血小板输注支持的患者，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抗体可以消除一种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抗体的诱导也会使后续移植复杂化。由于一些患者在等待器官移植时接受血小板输注作为支持，诱导抗hla抗体对这一人群有额外的负面影响，无论是从使移植复杂化的角度来看，还是从潜在地使患者推迟等待供体器官的名单来看。滤过性白细胞诱导的实施降低了血小板输注的同种免疫率，但剩余率仍保持在约20%，每5个输注受者中就有1人进行同种免疫。因此，需要采取额外的干预措施来降低同种免疫接种率。共刺激阻断是一种防止同种免疫的策略，随着FDA批准CTLA4-Ig，这一策略现已取得成果。这项拨款申请是一项临床前工作，旨在开始翻译CTLA4- Ig用于预防输注血小板的同种异体免疫。这种方法不会用于一般人群，而是专注于对HLA异体免疫特别脆弱的患者群体（需要持续输注血小板和/或等待移植的患者）。我们建立了一种小鼠滤过性白细胞诱导血小板输注的同种免疫模型。在这个系统中，CTLA4-Ig消除同种异体免疫，防止受体对血小板输注变得难治。该模型系统已被设计为具有足够的工具，以允许详细的机制阐明CTLA4-Ig功能。拟议的研究是一项假设驱动的努力，旨在对血小板同种异体免疫的免疫学和CTLA4-Ig的作用机制产生基本的了解，但特别关注CTLA4-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。

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.