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Mechanisms underlying inflammation-induced alloimmunization to RBC antigens in lupus

Mechanisms underlying inflammation-induced alloimmunization to RBC antigens in lupus
狼疮中炎症诱导的红细胞抗原同种免疫的机制
批准号:
10458054
负责人:
David R Gibb
金额:
$8.35万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-08-01 至 2023-07-31

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英文摘要
Abstract Approximately 50% of patients with systemic lupus erythematosus (SLE) suffer from anemia, for which red blood cell (RBC) transfusion is a common therapy. While RBC transfusion can be life-saving, production of alloantibodies against non-self RBC antigens causes clinically significant hemolytic events during RBC transfusion, pregnancy, and renal transplant. Prior human and animal studies have demonstrated that inflammation in a transfusion recipient, including autoimmune-associated inflammation, can induce or enhance RBC alloantibody responses. For example, while 3-5% of hospitalized patients in the United States produce RBC alloantibodies, more than 20% of patients with SLE produce RBC alloantibodies, representing the second highest prevalence compared to all other studied disease populations. However, mechanisms underlying autoimmune- induced RBC alloimmunization are poorly understood. Using murine transfusion models, we previously reported that acute viral-like stimuli and influenza infection induce pro-inflammatory type 1 interferons (IFNα/β), which critically regulate alloimmunization to human RBC antigens expressed on mouse RBCs. Approximately two- thirds of adults and nearly all children with SLE express an IFNα/β gene signature, defined as the production of numerous interferon stimulated genes by innate immune cells. Thus, we hypothesized and recently reported that IFNα/β also promotes RBC alloimmunization during acute inflammation in a lupus mouse model, prior to development of autoimmunity. It is unclear, however, whether chronic inflammation, in the presence of autoantibodies and lupus-like pathology, promotes RBC alloimmunization. In addition, it is unclear whether the lupus phenotype or IFNα/β directly promotes alloimmunization in the chronic setting. In this application, we propose to utilize lupus models with chronic inflammation to generate preliminary data for a future R01. We will test the hypothesis that chronic inflammation in lupus promotes RBC alloantibody production by an IFNα/β-dependent mechanism by determining the role of the lupus phenotype and IFNα/β in regulating RBC alloantibody production (Aim1) and identifying innate immune signaling pathways that promote inflammation- induced alloimmunization in models of chronic lupus (Aim 2). While the K08 focused on basic mechanisms of IFNα/β production and IFNα/β-mediated alloimmunization in the absence of inflammation or disease, this application diverges by examining mechanisms of chronic inflammation-induced alloimmunization in lupus models. Findings will provide a potential mechanistic basis for past observations of autoimmunity-associated alloimmunization. In addition, results may uncover novel pathways underlying inflammation-induced alloimmunization and provide preclinical data to strengthen an R01 proposal that will include investigation of mechanisms underlying RBC alloimmunization in patients with SLE. With mentorship from experts in RBC alloimmunization, lupus, IFNα/β, and other innate immune responses, we are well-equipped to complete the proposed aims.
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Autoantibody-induced type 1 interferons and RBC alloimmunization in sickle cell disease
  • 批准号:
    10642866
  • 项目类别:
  • 资助金额:
    $41.75万
  • 财政年份:
    2022
  • 负责人:
    David R Gibb
  • 依托单位:
Autoantibody-induced type 1 interferons and RBC alloimmunization in sickle cell disease
  • 批准号:
    10504262
  • 项目类别:
  • 资助金额:
    $41.75万
  • 财政年份:
    2022
  • 负责人:
    David R Gibb
  • 依托单位:
Mechanisms underlying inflammation-induced alloimmunization to RBC antigens in lupus
  • 批准号:
    10281785
  • 项目类别:
  • 资助金额:
    $8.35万
  • 财政年份:
    2021
  • 负责人:
    David R Gibb
  • 依托单位:
The role of type 1 interferon in regulating alloimmune responses to transfused red blood cells
  • 批准号:
    10194579
  • 项目类别:
  • 资助金额:
    $16.41万
  • 财政年份:
    2018
  • 负责人:
    David R Gibb
  • 依托单位:
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