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Immunoregulation by indoleamine 2,3-dioxygenases in tuberculosis

Award Number: R01AI137344
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: 05/01/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Immunoregulation by indoleamine 2,3-dioxygenases in tuberculosis - Abstract Indoleamine, 2,3-dioxygenase (IDO) is the enzyme that catalyzes the first step of the tryptophan catabolic kynurenine pathway. The T cell immunosuppressive properties of IDO, mediated through various metabolites from this pathway (collectively known as kynurenines (Kyn)), are well established. Abundant evidence shows that IDO-mediated immunosuppressive mechanisms are operative in certain infections and may compromise optimal immune responses to pathogens. There are two isoforms of IDO in mice and humans, designated IDO1 and IDO2, which possess overlapping and distinct immunoregulatory functions. This suggests that the mechanisms by which IDO modulates immune responses are more complex than has been previously appreciated. This complexity is further compounded by the fact that IDO isoforms are expressed by a wide variety of cells, and the cellular source of the enzyme can be important in determining its impact on immune responses. Our observations from analyses of anti-tuberculosis (TB) immunity in isoform-specific ido1-/- and ido2-/- knockout mice suggest the two enzymes exert shared as well as distinct functions in regulating the activities of several important CD4+ T cell subsets in the lungs of Mycobacterium tuberculosis (Mtb)-infected mice. Overall, in the absence of either isoform, the Th1, Th17 and neutrophilic responses are up-regulated, while the Treg response is attenuated, reflecting the immunosuppressive property of IDO1 and IDO2. Interestingly, relative to the ido2-/- strain, Mtb-infected ido1-/- mice consistently display a stronger Th1 and Th17 phenotypes, suggesting that the two isoforms may mediate overlapping and distinct immunomodulating functions in TB. Of note, BCG immunization of ido1-/- and ido1-/-ido2-/- mice elicits a Th1 response that is superior to that observed in vaccinated wild-type animals. Importantly, administration of IDO inhibitors concomitant with BCG immunization augments vaccine-elicited Th1 response. We have also observed that iNKT cell function can be regulated by various immunosuppressive Kyn species. Finally, study of the ido1-/- mouse involving a high inoculum infection with Mtb revealed an anti-inflammatory role of this isoform. This notion is further supported by the observation that IDO expression by non-hematopoietic cells in the lungs is essential for restricting pulmonic inflammation in TB. This latter result also suggests that specific function of IDO may be cell source-dependent. Based on the above, we will generate and use a panel of cell- and isoform-specific IDO-deficient mouse strains for the studies proposed. We will focus on studying myeloid lineage cells, since these express both IDO1 and IDO2 and possess potent immunoregulatory properties. A range of genetic, pharmacologic and murine chimera approaches will be used to stringently test the hypothesis that Mtb activates the immunosuppressive IDO pathway in order to secure an immunosuppressed local environment in infected tissues, thereby promoting persistence. We will also determine if the IDO pathway plays a role in restricting the development of excessive lung inflammation in a tuberculous host, and assess ways of manipulating the IDO pathway and iNKT cell functions to augment vaccine immunogenicity. This proposal brings together the expertise of three laboratories with a long history of close collaboration to rigorously study the roles of IDO1 and IDO2 in shaping host immunity to Mtb. Understanding the mechanisms of IDO-mediated immunosuppression will provide useful information for the design of strategies for improving vaccination and host-directed therapies for prevention and treatment of TB.


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: 2025 ( Subtotal = -$11,754 )
2025	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	7	11/22/2024	NON-COMPETING CONTINUATION	-$11,754
														Subtotal = -$11,754

Issue Date FY: 2022 ( Subtotal = $783,413 )
2022	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	004	7	5/13/2022	NON-COMPETING CONTINUATION	$445,336
2022	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	005	7	5/13/2022	NON-COMPETING CONTINUATION	-$445,336
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	002	7	4/25/2022	NON-COMPETING CONTINUATION	$783,413
2022	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	003	5	5/13/2022	NON-COMPETING CONTINUATION	-$445,336
2022	2021	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	006	6	5/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$445,336
2022	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	5	12/20/2021	NON-COMPETING CONTINUATION	-$299,905
2022	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	001	6	12/20/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$299,905
														Subtotal = $783,413

Issue Date FY: 2021 ( Subtotal = $806,468 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	5	4/20/2021	NON-COMPETING CONTINUATION	$806,468
														Subtotal = $806,468

Issue Date FY: 2020 ( Subtotal = $806,468 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	4	4/7/2020	NON-COMPETING CONTINUATION	$806,468
														Subtotal = $806,468

Issue Date FY: 2019 ( Subtotal = $806,468 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	3	4/25/2019	NON-COMPETING CONTINUATION	$806,468
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	004	2	5/16/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$4,487
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	2/12/2019	NEW	-$302,490
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	2	2/12/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$302,490
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	003	1	5/16/2019	NEW	-$4,487
														Subtotal = $806,468

Issue Date FY: 2018 ( Subtotal = $806,468 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	5/1/2018	NEW	$806,468
														Subtotal = $806,468

Grand Total All Awards = $3,997,531

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Immunoregulation by indoleamine 2,3-dioxygenases in tuberculosis

Award Number: R01AI137344

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: 05/01/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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