Immunobiology of Alloimmunization by Platelet Transfusion

血小板输注同种免疫的免疫生物学

• 批准号: 10418747
• 负责人: JAMES C. ZIMRING
• 金额: $ 55.06万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418747
• 关键词: Affect; Alloantigen; Allogenic; Alloimmunization; Animals; Antibodies; Antibody Response; Antigens; Area; Biological Models; Blood Cells; Blood Platelets; CD4 Positive T Lymphocytes; Cell Therapy; Cellular biology; Cessation of life; Data; Disease; Dissection; Engineering; Excision; Exposure to; Female; Functional disorder; Generations; Goals; HLA Antigens; Hemorrhage; Hemostatic function; Human; Immune response; Immune system; Immunity; Immunization; Immunize; Immunobiology; Immunologics; Inherited; Investigation; Isoantibodies; Kinetics; Lead; Leukocytes; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Mediating; Medical; Modeling; Modification; Morbidity - disease rate; Multigravidities; Mus; Organ Transplantation; Patients; Persons; Platelet Transfusion; Population; Population Study; Pregnancy; Randomized Controlled Trials; Refractory; Research Proposals; Residual state; Resources; Rest; Risk Factors; Series; Severities; T cell response; Testing; Thrombocytopenia; Transfusion; Transplantation; Variant; base; cellular engineering; cost; fetal; immunogenicity; immunoregulation; improved; in utero; innovation; life-sustaining therapy; mortality; mouse model; novel; novel therapeutics; patient population; personalized medicine; precision medicine; prevent; response; tool; translational approach

Project Summary Transfusion of platelets is a vital life-sustaining therapy for numerous diseases that result in thrombocytopenia. However, platelet transfusion can also result in humoral alloimmunization, predominantly to human leukocyte antigens (HLA). With immunization to multiple alloantigens, patients can become refractory to platelet transfusion, resulting in difficulty supporting platelet transfusion needs, and in extreme cases can eliminate platelets as a viable therapy, leading to morbidity and/or mortality from hemorrhage. Anti-HLA alloantibodies can also be substantial barriers to transplantation, rendering patients ineligible for transplant in some cases, or if they do get transplanted, leading to an increased kinetics and/or severity of rejection. Multigravid females are particularly prone to alloimmunization – pregnancy appears to prime for subsequent alloimmunization to platelet transfusion. Thus, alloimmunization to HLA is a significant problem in a number of settings. Although leukoreduction of platelets has reduced rates of alloimmunization, residual immunity remains substantial. Importantly, there are provocative data that distinct leukocyte subsets affect immunity differently (some promoting immunity and others suppressing). Thus, the bulk removal of leukocytes may remove suppressing (as well as immunizing) populations. A detailed understanding of the differential effects of distinct leukocyte subsets would allow a more sophisticated engineering of platelet units with regards to selective modification of leukocyte composition, if immunizing subsets can be removed and suppressing subsets retained. Such information may also be of great utility in cellular therapies outside the context of platelet transfusion. This proposal utilizes an innovative, novel, and tractable murine model, that allows a detailed dissection of the relative contribution of different leukocyte subsets to alloimmunization. We have already used this platform to make the observation that there is cooperativity between MHC alloantigens in inducing an immune response; alloimmunization to the same alloantigen differs based upon the context of the mismatch, opening the door to sophisticated matching/mismatching strategies for transfusion and transplantation in an era of personalized medicine. We have also discovered that in mice, as in humans, pregnancy primes for a subsequent increased alloimmune response rate to transfusion. We propose two specific aims, focusing on the cellular mechanisms of alloimmune responses to different leukocyte subsets in naïve recipients and in pregnancy primed recipients, respectively. We have built into this approach a further analysis of how context of mismatch alters immunogenicity of a given alloantigen, to expand on our initial findings. The models generated for this proposal use naturally occurring MHC alloantigens in mice, but focus on specific alloantigens for which cutting edge tools are available to perform a detailed analysis of both alloreactive CD4+ T cell biology and alloantibody generation. In aggregate, the proposed studies combine novel tools with innovative hypotheses to ask mechanistic questions relevant to alloimmunization in the context of PLT transfusion and cellular therapies.

项目总结

项目成果

In utero exposure to alloantigens primes alloimmunization to platelet transfusion in mice.

• DOI: 10.1111/trf.16224
• 发表时间: 2021-03
• 期刊: Transfusion
• 影响因子: 2.9
• 作者: Poston JN;Jash A;Hannan LM;Hay AM;Usaneerungrueng C;Howie HL;Kapp LM;Zimring JC
• 通讯作者: Zimring JC