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Impact of Microbiota on Alloimmune Responses in Transplantation

Award Number: R01AI115716
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/03/2014
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Impact of Microbiota on Alloimmune Responses in Transplantation - PROJECT SUMMARY The strength of an immune response against a transplanted organ, termed the alloresponse, depends on the extent of genetic differences between the donor and the recipient and their recognition by the recipient’s immune system. Our studies from the previous funding cycle have shown that the microbiota, the collection of microbes that colonize the body and differ between individuals, is an additional novel factor that can causally modulate the intensity and kinetics of the alloresponse to a transplanted organ. Unlike donor and host genetics, the microbiota can be manipulated therapeutically, thus providing possible new interventions to protect the graft and help reduce the need for immunosuppressive drugs that can cause significant side effects. We initially considered the body’s microbiota as a whole and demonstrated that a reduction in microbial diversity induced by broad-spectrum antibiotic (Abx) pre-treatment, or an absence of microbiota using germ-free (GF) mice, both improved minor mismatched skin graft survival. Fecal microbiome transfer (FMT) from control, but not Abx-pre-treated mice, into GF mice was sufficient to accelerate skin graft rejection. This demonstrated both the causality of the microbiota on affecting graft outcome, and the divergent effects of distinct fecal microbial communities. Abx pre-treatment also delayed rejection of fully mismatched skin grafts, minor mismatched lung grafts, and MHC class II-mismatched heart grafts, indicating that whole-body microbiota affects the outcome of both colonized and sterile organs. We further showed that that some microbial communities could be dominantly protective of rejection. This protection was associated with fecal presence of bacteria of the genus Alistipes. In addition, the half-life of small bowel, lung and skin transplants is much shorter than that of heart and kidney grafts, supporting the hypothesis that the commensals in the graft may also be able to influence alloimmunity. Our recent preliminary experiments demonstrate that colonization of donor skin with the single commensal Staphylococcus epidermidis (S. epi), in the absence of intestinal colonization of the host, can be sufficient to accelerate skin graft rejection. This result clearly demonstrates that microbiota within the allograft also impacts graft outcome. Notably, the mechanism by which skin S. epi accelerates skin graft rejection appears different from how whole-body microbiota in SPF mice or FMT into GF mice accelerates skin graft rejection. We hypothesize a novel paradigm that the recipient gut microbiota affects immune responses in the whole animal by systemically modulating DCs up or down, whereas the microbiota in the donor graft locally affects the effector phase of the alloresponse upon migration of recipient alloreative T cells into the graft. Using a combination of TCR transgenic T cells and p:MHC multimers to track anti-commensal and anti-donor immune responses in parallel, as well as select bacterial colonization of distinct tissues in gnotobiotic mice, we will: 1. Investigate the mechanisms by which gut-only microbes can impact skin graft rejection distally; 2. Define the mechanisms by which skin-only commensals locally accelerate skin graft rejection.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $480,426 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	10	5/16/2024	NON-COMPETING CONTINUATION	$48,042
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	10	11/28/2023	NON-COMPETING CONTINUATION	$432,384
														Subtotal = $480,426

Issue Date FY: 2023 ( Subtotal = $480,426 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	9	11/15/2022	NON-COMPETING CONTINUATION	$480,426
														Subtotal = $480,426

Issue Date FY: 2022 ( Subtotal = $480,426 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	8	11/17/2021	NON-COMPETING CONTINUATION	$480,426
														Subtotal = $480,426

Issue Date FY: 2021 ( Subtotal = $480,426 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	7	11/18/2020	NON-COMPETING CONTINUATION	$480,426
2021	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	6	6/5/2021	COMPETING CONTINUATION	$5
2021	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	5	6/5/2021	NON-COMPETING CONTINUATION	-$5
														Subtotal = $480,426

Issue Date FY: 2020 ( Subtotal = $480,426 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	6	4/4/2020	COMPETING CONTINUATION	$45,318
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	6	12/23/2019	COMPETING CONTINUATION	$480,426
2020	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	5	4/4/2020	NON-COMPETING CONTINUATION	-$45,318
														Subtotal = $480,426

Issue Date FY: 2019 ( Subtotal = $389,432 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	5	11/2/2018	NON-COMPETING CONTINUATION	$389,432
														Subtotal = $389,432

Issue Date FY: 2018 ( Subtotal = $389,432 )
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	4	10/23/2017	NON-COMPETING CONTINUATION	$389,432
														Subtotal = $389,432

Issue Date FY: 2017 ( Subtotal = $389,432 )
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	3	10/28/2016	NON-COMPETING CONTINUATION	$389,432
														Subtotal = $389,432

Issue Date FY: 2016 ( Subtotal = $389,432 )
2016	2016	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	2	10/23/2015	NON-COMPETING CONTINUATION	$389,432
														Subtotal = $389,432

Issue Date FY: 2015 ( Subtotal = $389,432 )
2015	2015	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	11/3/2014	NEW	$389,432
														Subtotal = $389,432

Grand Total All Awards = $4,349,290

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Impact of Microbiota on Alloimmune Responses in Transplantation

Award Number: R01AI115716

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 11/03/2014

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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