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; 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（由申请人提供）：血小板的输血是一种潜在的挽救生命的疗法，可维持严重血小板减少症患者的止血。正在进行的血小板输血的主要障碍之一是对血小板同型抗原的体液免疫，主要是HLA抗原（MHC I类）。一旦形成同抗体，接受者就可以迅速清除HLA不兼容的血小板，从而导致n个血小板计数很小或没有增加，因此基本上没有治疗益处。如果患者针对多个HLA表位产生同种抗体，那么寻找兼容的血小板可能会变得困难，并且在许多情况下是不可能的。通过同种免疫到多种HLA类型，血小板可以停止成为血小板减少症的可行疗法。对于只需要血小板输血的瞬时支持的患者，同种免疫通常不是一个严重的问题。但是，在需要持续治疗的患者中，抗HLA抗体可以消除挽救生命的疗法，通常没有可行的替代品。除了使血小板输血无效外，抗HLA抗体的诱导还可能使随后的移植复杂化。由于在等待器官移植的同时向某些患者种群进行血小板输血作为支持，因此抗HLA抗体的诱导对该人群产生了额外的负面影响，这是从使移植复杂化的角度以及可能使患者降落的供体器官的候补名单的角度。过滤器白细胞的实施降低了同种异体对血小板输血的速率，但剩余率仍为约20％，每5个输血接受者中有1个被同应释放。因此，需要采取其他干预措施以降低同种免疫率。联合刺激性封锁是一种防止同种免疫化的策略，该策略现已在FDA批准CTLA4-Ig批准下实现。该赠款应用程序是临床前的努力，开始将CTLA4-IG转换用于防止同种免疫化到输血的血小板。这种方法不会用于一般人群中，而是专注于特别容易受到HLA同种异体免疫性（需要持续输血和/或等待移植的患者）的精选患者人群。我们已经开发了一种同种免疫化的鼠模型，以输血的滤清器白细胞血小板。在该系统中，CTLA4-IG废除了同种免疫化，并防止受体变得难治性到血小板输血。该模型系统已设计为具有足够的工具，可以详细阐明CTLA4-IG功能。拟议的研究是一种假设驱动的努力，旨在既可以对血小板同种免疫的免疫学和CTLA4-IG作用机制进行基本理解，但是独特的侧重于随后对CTLA4-IG治疗的人类试验所必需的临床前问题，以防止对转染的血小板进行全异化。