Defining the relationship between host-microbiome interactions and rejection after intestinal transplantation

定义宿主-微生物组相互作用与肠移植后排斥反应之间的关系

• 批准号: 10609513
• 负责人: Joshua Weiner
• 金额: $ 19.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-17 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609513
• 关键词: Alloantigen; Allografting; Antigen-Presenting Cells; Area; Attenuated; Bacteria; Blood; Bone Marrow; Cells; Chimerism; Clinical; Clone Cells; Data; Department chair; Discipline; Disease; Engraftment; Equilibrium; Failure; Functional disorder; Funding; Goals; Graft Rejection; Growth; Gut Mucosa; Homeostasis; Host Defense; Human; Immersion; Immune; Immunobiology; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Longitudinal Studies; Malignant Neoplasms; Mentors; Mentorship; Microbe; Microbiology; Mucous Membrane; Paneth Cells; Parenteral Nutrition; Patients; Play; Qualifying; Research; Research Personnel; Resources; Role; Scientist; Surgeon; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Time; Translating; Transplant Recipients; Transplant Surgeon; Transplantation; Transplantation Immunology; Virus; Volatile Fatty Acids; Work; analytical method; antimicrobial peptide; career; career development; commensal microbes; cross reactivity; dysbiosis; experience; fecal transplantation; fungus; gastrointestinal transplantation; graft vs host disease; gut inflammation; gut microbes; gut microbiome; host microbiome; microbial; microbiome; microbiome analysis; microorganism antigen; migration; novel; novel marker; novel therapeutics; pathogenic microbe; preservation; programs; residence; response; side effect

PROJECT SUMMARY Dr. Weiner is a transplant surgeon and immunology researcher. His long-term career goal is to become a leading surgeon-scientist in the practice of intestinal transplantation (ITx) and the understudied discipline of intestinal immunobiology with the unique expertise and immersion in both to translate novel scientific findings into major clinical advances. To that end, his short-term career goals are to 1) gain clinical expertise in intestinal transplantation, 2) build on current understanding of the pathophysiology of rejection after ITx, 3) augment his personal understanding of microbiology, innate immune defenses, and advanced microbial and T cell analytic methods, and 4) develop an independent research career that is funded by R01 support. He has organized a mentoring team with the expertise and experience to facilitate career development in this field, and he has the commitment of resources and protected research time from his department chair and division chief. The significance of his project is that ITx is the only therapeutic option for patients with intestinal failure once parenteral nutrition fails. However, its use is limited by high rates of rejection, which necessitates increased immunosuppression levels, predisposing patients to morbid side effects. This proposal investigates how the relationship between the gut microbiome and host mucosal defenses correlates with rejection after ITx. Prior work demonstrates that rejection is associated with both modulations in the gut microbiome and dysfunction of host defenses that maintain homeostasis with flora. It is also known that rejection is associated with decreased ratios of graft-versus-host (GVH)-reactive donor T cells relative to host-versus-graft (HVG)-reactive recipient T cells within the graft. Based on these concurrent findings, Dr. Weiner hypothesizes that homeostasis between the gut microbiome and mucosal defenses plays an essential role in maintaining the balance of GVH:HVG- reactive T cells in the graft, thus regulating rejection. If true, rejection could be targeted with novel therapies, such as fecal transplantation. Thus far, no longitudinal studies in human ITx patients have investigated microbiome modulations in relationship to clinical course, T cell chimerism, GVH:HVG-reactive T cell ratios in the graft, and rejection. Therefore, this work will characterize how changes in the microbiome in the gut after ITx correlate with decreased chimerism and GVH:HVG ratios in the blood and graft, which are associated with higher rates of rejection.

项目总结

项目成果

Current review on the role of ileostomy following intestinal transplantation.

肠移植后回肠造口术作用的最新综述。

• DOI: 10.1097/mot.0000000000000966
• 发表时间: 2022
• 期刊: Current opinion in organ transplantation
• 影响因子: 2.2
• 作者: Venick,RobertS

An analysis of the outcomes of Clostridioides difficile occurring in intestinal transplant recipients requiring hospitalization.

对需要住院的肠道移植受者中艰难梭菌的结果进行分析。

• DOI: 10.1111/tid.13951
• 发表时间: 2023
• 期刊: Transplant infectious disease : an official journal of the Transplantation Society
• 作者: Amjad,Waseem;Schiano,Thomas;Segovia,MariaC;Malik,Adnan;Weiner,Joshua;Horslen,Simon;Jafri,Syed-Mohammed
• 通讯作者: Jafri,Syed-Mohammed

Update on immunosuppressive strategies in intestinal transplantation.

• DOI: 10.1097/mot.0000000000000958
• 发表时间: 2022-04-01
• 期刊: Current opinion in organ transplantation
• 影响因子: 2.2
• 作者: Merola J;Shamim A;Weiner J
• 通讯作者: Weiner J

The First Collective Examination of Immunosuppressive Practices Among American Intestinal Transplant Centers.

• DOI: 10.1097/txd.0000000000001512
• 发表时间: 2023-09
• 期刊: Transplantation direct
• 影响因子: 2.3