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Tertiary Lymphoid Organs in Transplantation

移植中的第三淋巴器官

基本信息

批准号：
10610893
负责人：
Martin H Oberbarnscheidt
金额：
$ 38.56万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-17 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10610893
关键词：
Acceleration Acute Address Allografting Antibodies Antibody Formation Applications Grants Atherosclerosis Autoimmunity B-Cell Activation B-Lymphocytes Biopsy Cell physiology Chronic Chronic rejection of renal transplant Complement Data Experimental Models Functional disorder Goals Graft Rejection Helper-Inducer T-Lymphocyte High Endothelial Venule Human Image Immune response Immunologic Techniques Immunologics Incidence Interruption Kidney Transplantation Knowledge Laboratory Animals Lymphoid Lymphoid Cell Lymphoid Tissue Malignant Neoplasms Mediating Modeling Molecular Mus Organ Transplantation Outcome Pathogenesis Pathway interactions Patients Peyer&apos s Patches Play Process Prognosis Regulatory T-Lymphocyte Rheumatoid Arthritis Role Severity of illness Solid Synovial Membrane T-Lymphocyte Testing Therapeutic immunosuppression Tissues Transplantation Wild Type Mouse allograft rejection chronic infection cytokine experimental study heart allograft immune activation immune function improved insight isoimmunity kidney allograft lung allograft lymph nodes novel therapeutics prevent secondary lymphoid organ skin allograft tertiary lymphoid organ transplant model two-photon

项目摘要

Abstract In solid organ transplantation, immunosuppressive therapy has significantly improved short-term organ allograft survival by reducing acute rejection rates. However, chronic rejection - mediated by T cells, antibodies (Abs), or both - has not declined in incidence and remains an important obstacle to long-term allograft survival. A likely, important contributor to the pathogenesis of chronic rejection is the formation of tertiary lymphoid organs (TLO) within the graft. Evidence that TLO play a causative role in rejection derives from both mice and humans, as TLO have been documented in a majority of chronically rejected mouse and human allografts, and experimental models have shown that they support naïve T and B cell activation and influence graft outcome. Moreover, analysis of human renal allograft biopsies has demonstrated B cell hypermutation and Ab production within TLO. Together, these studies support the hypothesis that TLO are niduses of local (intragraft) immune activation in chronic allograft rejection. In Aim 1 of this grant application, we will establish the cause-effect relationship between TLO and chronic renal transplant rejection in the mouse. In Aim 2, we will investigate the cellular and cytokine mechanisms responsible for TLO formation in allografts, with particular emphasis on innate lymphoid cell (ILC) subsets. In Aim 3, we will delineate the specific immunologic functions of TLO in chronic rejection, with focus on B cell activation and antibody production. The proposed studies address the unmet challenge of treating and preventing chronic rejection and will also shed light on other conditions in which TLO play a prominent role, such as autoimmunity and cancer.

摘要