Prevention of Platelet Alloimmunization by Costimulatory Blockade

描述(申请人提供)：输注血小板是一种潜在的挽救生命的疗法，可以维持严重血小板减少症患者的止血。进行中的血小板输注的主要障碍之一是对血小板同种异体抗原的体液免疫，主要是对人类白细胞抗原(MHC I类)的免疫。一旦形成同种异体抗体，受体可以迅速清除人类白细胞抗原血型不合的血小板，导致血小板数量很少或没有增加，因此基本上没有治疗上的好处。如果患者产生针对多个人类白细胞抗原表位的同种异体抗体，那么找到相容的血小板可能会变得困难，在许多情况下是不可能的。随着对多种HLA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疗法。对于那些只需要通过输注血小板获得短暂支持的患者，异基因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，抗人类白细胞抗原抗体可以消除一种通常没有可行替代品的挽救生命的疗法。除了使血小板输注无效外，抗人类白细胞抗原抗体的诱导也会使随后的移植复杂化。由于一些患者在等待器官移植期间接受了血小板输注作为支持，诱导抗人类白细胞抗原抗体对这一群体产生了额外的负面影响，从使移植复杂化的角度来看，还可能使患者在等待器官捐赠的名单上排名靠后。滤过性白细胞减少率的实施降低了输注血小板的异体免疫率，但残留率保持在20%左右，每5个输血受者中就有1人获得同种免疫。因此，需要采取更多干预措施来降低同种免疫率。共刺激阻断是一种防止同种免疫的战略，随着FDA批准CTLA4-Ig，这一战略现在已经取得成果。这项赠款申请是一项临床前工作，目的是开始翻译CTLA4-Ig，用于防止对输注的血小板进行同种异体免疫。这种方法不会用于普通人群，而是侧重于特别容易受到人类白细胞抗原异基因免疫的特定患者群体(需要持续进行血小板输注和/或等待移植的患者)。我们建立了一种小鼠异基因免疫输注滤过性去白细胞血小板的模型。在这个系统中，CTLA4-Ig取消了同种异体免疫，防止了受体对血小板输注的抵抗力。模型系统已经设计成有足够的工具来详细地从机制上阐明CTLA4-Ig的功能。拟议的研究是一项假说驱动的努力，旨在促进对血小板同种异体免疫的免疫学和CTLA4-Ig作用机制的基本了解，但特别关注CTLA4-Ig疗法的后续人体试验所必需的临床前问题，以防止对输注的血小板进行同种异体免疫。

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.