Solid organ transplantation is a life-saving procedure to treat end-stage organ failure. However, transplantation of organs between genetically distinct individuals results in acute graft rejection by the immune system unless patients take immunosuppressive drugs for the rest of their lives. The strength of the anti-transplant immune response, also called the alloresponse, is determined by both genetic and environmental factors. In mouse models of skin and heart transplantation, we have previously found that bacterial infections at the time of transplantation can enhance the alloresponse and promote transplant rejection. This supports the role of microbial infections as environmental factors that can modulate alloresponses, although these are not frequent environmental factors. In contrast, the communities of commensal bacteria that inhabit our body, collectively called the microbiota, share many microbial patterns with infectious bacteria, and are constantly present at barrier surfaces such as the skin and the intestine. Recent evidence indicates that the composition of the microbiota is determined by the immune system and that the microbiota, in turn, drives several effector functions of the immune system. Therefore, we have proposed the hypothesis that the microbiota is an important and omnipresent environmental factor that can enhance alloresponses and promote graft rejection. To address this question, we have used both sterile mice devoid of microbiota and conventional mice treated with broad spectrum antibiotics to reduce microbiota diversity. Our preliminary results show that both sets of mice display prolonged skin graft survival compared with control animals, demonstrating that the microbiota indeed enhances the strength of the alloresponse and accelerates graft rejection. In this application, we propose to investigate the mechanisms by which the microbiota promotes graft rejection, as well as the consequences on the composition of the microbiota of immunosuppression and ongoing alloresponses. Finally, we will attempt to manipulate the microbiota for therapeutic purposes to limit the strength of the alloresponse and prolong graft survival. This research will guide follow up studies in humans to identify the impact of microbiota on alloimmunity and graft outcome. As the composition of the microbiota can be manipulated via anti-microbials, as well as prebiotics (diet), probiotics (beneficial bacteria) and postbiotics (products of bacterial metabolism), this line of research has important possible clinical benefits.

Public Health Relevance

Our preliminary results indicate that the complex communities of commensal microbes that inhabit the body, collectively called the microbiota, contribute to activate the immune system following solid organ transplantation and promote transplant rejection. In this application, we propose to investigate the mechanisms by which the microbiota enhances the anti-transplant immune response and explore approaches to manipulate the microbiota to promote graft survival. Because the microbiota is very amenable to therapeutic manipulation by antibiotics or probiotics, results from this research can be translated to the clinc to improve the health of transplanted patients and the outcome of transplanted organs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI115716-04
Application #
9378789
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2014-11-03
Project End
2019-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Riella, Leonardo V; Bagley, Jessamyn; Iacomini, John et al. (2017) Impact of environmental factors on alloimmunity and transplant fate. J Clin Invest 127:2482-2491
Lei, Yuk Man; Chen, Luqiu; Wang, Ying et al. (2016) The composition of the microbiota modulates allograft rejection. J Clin Invest 126:2736-44
Alegre, Maria-Luisa; Lakkis, Fadi G; Morelli, Adrian E (2016) Antigen Presentation in Transplantation. Trends Immunol 37:831-843
Molinero, Luciana L; Yin, Dengping; Lei, Yuk Man et al. (2016) High-Fat Diet-Induced Obesity Enhances Allograft Rejection. Transplantation 100:1015-21
Sivan, Ayelet; Corrales, Leticia; Hubert, Nathaniel et al. (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084-9
Theriault, Betty; Wang, Ying; Chen, Luqiu et al. (2015) Long-term Maintenance of Sterility Following Skin Transplantation in Germ-free Mice. Transplant Direct 1:
Lei, Yuk Man Kevin; Nair, Lekha; Alegre, Maria-Luisa (2015) The interplay between the intestinal microbiota and the immune system. Clin Res Hepatol Gastroenterol 39:9-19
Bartman, Caroline; Chong, Anita S; Alegre, Maria-Luisa (2015) The influence of the microbiota on the immune response to transplantation. Curr Opin Organ Transplant 20:1-7
Alegre, M-L; Mannon, R B; Mannon, P J (2014) The microbiota, the immune system and the allograft. Am J Transplant 14:1236-48