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Examining the Mechanisms of RBC Alloimmunization Hyperresponders

检查红细胞同种免疫高反应者的机制

基本信息

批准号：
10685385
负责人：
Connie M Arthur
金额：
$ 43.23万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685385
关键词：
Adoptive Transfer Alloantigen Alloimmunization Antibody Formation Antigen Targeting Antigens B-Cell Activation B-Cell Antigen Receptor B-Lymphocytes CD4 Positive T Lymphocytes Cellular Structures Chronic Clinical Data Dendritic Cells Development Erythrocyte Transfusion Erythrocytes Event Future Genetic Polymorphism Goals Immune Immune system Immunologic Factors Immunologics Immunology Individual Inflammation Interferon Type I Isoantibodies Mediating Medicine Morbidity - disease rate Ovum Pathway interactions Patients Peptide Initiation Factors Poly I-C Population Pre-Clinical Model Process Reaction Receptor Signaling Risk Role Series T-Cell Activation T-Lymphocyte Testing Therapeutic Intervention Toll-like receptors Transfusion Viral Work enhancing factor immune function imprint innate immune pathways insight interferon-alpha B memory CD4 T lymphocyte mortality prevent response stem trafficking

项目摘要

Summary: Red blood cell (RBC) alloimmunization can make it difficult to procure compatible RBCs for future transfusion, which can directly increase morbidity and mortality in transfusion-dependent individuals. While patients who develop multiple alloantibodies against distinct alloantigens are particularly challenging to manage, the immune events during initial alloimmunization that may increase the likelihood of generating additional alloantibodies following subsequent transfusion remain unknown. Our long-term goal is to identify immune factors that enhance subsequent alloimmunization events in previously alloimmunized individuals in order to prevent the accumulation of multiple alloantibodies in transfusion dependent individuals. Our central hypothesis is that initial alloimmunization events directly enhance subsequent RBC alloimmunization by inducing CD4 T cells that possess the ability to directly activate B cells against a completely unrelated RBC alloantigen following subsequent transfusion. Our hypothesis is formulated on the basis of our recent discovery that B cells specific for one antigen (the HOD (HEL, OVA and Duffy) antigen) not only internalize HOD following RBC engagement, but likewise remove and internalize additional RBC components, suggesting that B cells may possess the ability to remove multiple antigens following engagement of the target antigen. Consistent with this, adoptive transfer of CD4 T cells primed by KEL RBC transfusion in the presence of poly I:C, which induces viral-like inflammation, directly enhances alloantibody formation against the completely distinct HOD antigen following subsequent transfusion of RBCs expressing HOD and KEL. Depletion of marginal zone (MZ) B cells, a unique B cell population previously shown to be critical in the initiation of alloantibodies, inhibits KEL RBC priming and the HOD RBC boost following HOD x KEL RBC transfusion, suggesting that MZ B cells work in concert with previously recognized bridging channel 33D1+ dendritic cells (33D1+ DCs) shown to be critical in the initial activation of CD4 T cells following HOD RBC transfusion. In contrast, while KEL RBC-induced alloimmunization requires type I interferons (IFNab) and HOD RBC-induced alloimmunization requires toll-like receptor (TLR) signaling, KEL-induced alloimmunization in the presence of PIC requires both IFNab and TLRs, suggesting that while innate immune pathways may differ for KEL and HOD RBC-induced alloimmunization, PIC allows KEL RBCs to engage TLRs and prime a subsequent HOD boost. We will use a series of pre-clinical models to define the key priming and subsequent boosting pathways by testing the following specific aims: Aim 1: Define the role of MZ B cells, 33D1+ DCs, IFNab and TLRs in PIC/KEL RBC-induced priming. Aim 2: Define the role of MZ B cells, 33D1+ DCs, and TLRs in subsequent KEL-mediated HOD RBC boost. We think that successful completion of these aims will define key immunological priming and boosting events that facilitate alloimmunization and therefore will provide an important framework to develop rational approaches to prevent the development of RBC alloantibodies against multiple alloantigens in chronically transfused individuals.

摘要：红细胞（RBC）同种异体免疫使将来难以获得相容的红细胞

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Detection of Phosphatidylserine Exposure on Leukocytes Following Treatment with Human Galectins.

用人半乳糖凝集素处理后白细胞上磷脂酰丝氨酸暴露的检测。

DOI：
10.1007/978-1-0716-2055-7_28
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Stowell,SeanR;Dias-Baruffi,Marcelo;Cummings,RichardD;Arthur,ConnieM
通讯作者：
Arthur,ConnieM

The Development and Consequences of Red Blood Cell Alloimmunization.

DOI：
10.1146/annurev-pathol-042320-110411
发表时间：
2023-01-24
期刊：
Annual review of pathology
影响因子：
0
作者：
通讯作者：

Storage differentially impacts alloimmunization to distinct red cell antigens following transfusion in mice.

DOI：
10.1111/trf.17251
发表时间：
2023-03
期刊：
TRANSFUSION
影响因子：
2.9
作者：
Maier, Cheryl L. L.;Jajosky, Ryan P. P.;Patel, Seema R. R.;Verkerke, Hans P. P.;Fuller, Megan D. D.;Allen, Jerry William;Zerra, Patricia E. E.;Fasano, Ross M. M.;Chonat, Satheesh;Josephson, Cassandra D. D.;Gibb, David R. R.;Eisenbarth, Stephanie C. C.;Luckey, C. John;Hudson, Krystalyn E. E.;Hendrickson, Jeanne E. E.;Arthur, Connie E. M.;Stowell, Sean R. R.
通讯作者：
Stowell, Sean R. R.

Purification of Recombinant Galectins from Different Species Using Distinct Affinity Chromatography Methods.

使用不同的亲和色谱方法纯化不同物种的重组半乳糖素。

DOI：
10.1007/978-1-0716-2055-7_3
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Paul,Anu;Wu,Shang-Chuen;Patel,KashyapR;Ho,AlexD;Allen,JerryWilliamLynn;Verkerke,Hans;Arthur,ConnieM;Stowell,SeanR
通讯作者：
Stowell,SeanR

Examining Galectin Binding Specificity Using Glycan Microarrays.

使用聚糖微阵列检查半乳糖凝集素结合特异性。

DOI：
10.1007/978-1-0716-2055-7_9
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Stowell,SeanR;Rodrigues,LilianC;Dias-Baruffi,Marcelo;Cummings,RichardD;Arthur,ConnieM
通讯作者：
Arthur,ConnieM